Lepsio Special Precautions

Hepatotoxicity: Hepatic failure in fatalities has occurred in patients receiving valproic acid. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by nonspecific such as malaise, 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. 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 in 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 valproic acid 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 this 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 hypertoxicity, especially those with aforementioned conditions. When valproic acid is used is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of 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.
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).
Valproic acid is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase y (POLG; e.g., Alpers-Huttenlocher syndrome) and children under two years of age who are suspected of having a POLG-related (see Contraindications). Valproate induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in gene for mitochondrial DNA polymerase y (POLG) (e.g., Alpers-Huttenlocher syndrome) at a higher rate than those without these syndromes.
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, opthalmoplegia, 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.
Pancreatitis: Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. 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 should be warned that abdominal pain, nausea, vomiting, and/or anorexia 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.
Urea cycle disorder (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 the 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 a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history or 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 Hyperammoniemia and encephalopathy associated with concomitant topiramate under Precautions).
Suicidal behavior and ideation: An increase in the risk of suicidal thoughts or behavior in patients taking 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 for epilepsy than for psychiatric or other conditions, but the absolute risk differences were depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Anyone considering prescribing valproic acid or any other AEDs must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illness 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 patients 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 unusable 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: Carbapenem antibiotics (ertapenem, imipenem, meropenem) may reduce serum valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorated (see Carbapenem antibiotics under Interactions).
Somnolence in the elderly: In elderly with dementia, there was a significantly higher proportion of valproate patients had a somnolence. In some patients with somnolence, 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 a higher BUN. 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).
Thrombocytopenia: The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may be dose-related. The probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥110 mcg/mL (females) or ≥135 mcg/L (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects.
This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine).
Women of childbearing potential should use effective contraception while using valproate.
Hepatic dysfunction: See Contraindications and Hepatotoxicity under Precautions.
Hyperammonemia: Hyperammonemia has been reported 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. Hyperammonia should also be considered in patients who present with hypothermia (see Hypothermia under Precautions). 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 urea cycle disorders (see Contraindications and Urea cycle disorders and Hyperammonemia and encephalopathy associated with concomitant topiramate use under Precautions)
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.
Hyperammonemia and encephalopathy associated with concomitant topiramate use: Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with ow 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 manifesto of hyperammonemia (see Precautions). 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 under Precautions).
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 valproate after starting topiramate with valproate after starting topiramate treatment of after increasing the daily dose of topiramate (see Topiramate under Interactions and Hyperammonemia and encephalopathy associated with concomitantly topiramate use and Hyperammonemia.)
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 systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.
Brain atrophy: There have been reports of reversible and irreversible cerebral and cerebellar atrophy temporally associated with the use of valproate products. In some cases, patients recovered with permanent sequalae (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 products (see Use in Pregnancy & Lactation).
General: Because of reports of thrombocytopenia (see Thrombocytopenia under Precautions), inhibition of the secondary phase if platelet aggregation, and abnormal coagulation parameters (e.g.. low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy planned surgery. There was an evidence of hemorrhage, bruising or a disorder of hemostatics/coagulation for reduction of dosage or withdrawal of therapy. Since valproate may interact with concurrently administered drugs which are capable of enzyme reduction, periodic plasma concentration of valproate and concomitant drugs are recommended during the early course of therapy (see Interactions).
Valproate is partially eliminated in the urine as a keto-metabolite, which 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.
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 HOC infected patients receiving valproate or when following infected patients clinically.
Multiorgan hypersensitivity reactions: Multiorgan hypersensitivity reactions have been rarely reported in close temporal association after the imitation of valproate in adult and pediatric patients. Although there have been a limited number of reports, many of these cases in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients lymphaedenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritis, 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 with multiorgan 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 under Precautions) and be told to inform the prescriber if any of these symptoms occur.
Since valproic acid may produce CNS depression, especially when combined with another CNS depressants (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 form the drug.
Since valproic acid has been associated with certain types of birth defects, female patients of childbearing age considering the use of valproic acid should be advised of the risks associated with the use of valproic acid during pregnancy (see Use in Pregnancy as follows.)
Risk associated with valproic acid: In humans: Valproic acid may produce teratogenic effects, such as neural tube defects (e.g. spina bifida) on the offspring of human females receiving the drug during pregnancy. There are data that suggest an increased incidence of congenital malformations associated with the use of valproic acid during pregnancy and weighed against the potential benefits of treatment.
There are multiple reports in the clinical literature that indicate the use of antiepileptic drugs during the pregnancy results in an increased incidence of birth defects in the offspring. Therefore, antiepileptic drugs should be administered to women of childbearing potential only if they are clearly shown to be essential in the management of their disease.
The incidence of neural tube defects in the fetus may be increased in mothers receiving valproate during the first trimester of pregnancy. The United States Centers for Disease Control (CDC) has estimated the risk of valproic acid exposed women having children with spina bifida to approximately 1-2%
Other congenital anomalies (e.g., craniofacial defects, cardiovascular malformations, hypospadias and anomalies involving various body systems), compatible and incompatible with life, have been reported.
There was an increased incidence of congenital malformations in children born to epileptic women exposed to valproate monotherapy during pregnancy.
Available data indicate dose-dependency of this effect.
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores that children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproic acid during pregnancy.
Exposure in utero to valproate products has been associated with cerebral atrophy with varying degrees/manifestation of neurological compromise, including developmental delays and psychomotor impairment (see Adverse Reactions and Precautions).
In animals: Animal studies have demonstrated valproate-induced teratogenicity. Increased frequencies of malformations, as well as intrauterine growth retardation and death, have been observed in mice, rats, rabbits, and monkeys following prenatal exposure to valproate. Malformations of the skeletal system are the most common structural abnormalities produced in experimental animals, but neural tube defects have been seen in mice exposed to maternal plasma valproate concentrations exceeding 230 mcg/mL (2.3 times the upper limit of the human therapeutic range) during susceptible periods of embryonic development.
Risk in neonates: Pregnant women taking valproate may develop clotting abnormalities, including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the including death (see Thrombocytopenia and General previously).
If valproate is used in pregnancy, the clotting parameters should be monitors carefully.
Hepatic failure, resulting in the death of a newborn and of an infant, has been reported following the use of valproate during pregnancy.
Cases of hypoglycemia gave been received for neonates whose mothers have taken valproate during pregnancy.
Tests to detect neural tube and other defects using current accepted procedures should be considered a part of routine prenatal care in childbearing women receiving valproate.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases, where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazards to the developing embryo or fetus.
Effects on ability to drive and use machines: Since valproic acid products 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.
Women of childbearing potential: Because of the risk to the fetus of major congenital malformations (including neural tube defects) valproic acid should be considered for women of childbearing potential only after the risks have been thoroughly discussed with the patient and weighed against the potential benefits of treatment (see Use in Pregnancy & Lactation).
Use in Pregnancy: Since valproic acid has been associated with certain types of birth defects, female patients of childbearing age considering the use of valproic acid should be advised of the risks associated with the use of valproic acid during pregnancy (see Use in Pregnancy & Lactation).
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy. However, if cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.
Use in Lactation: Valproate is excreted in breast milk. Concentrations in breast milk have been reported to be 1-10% of serum concentrations. It is not known what effect this would have on a nursing infant. Consideration should be given to discontinuing nursing when valproic acid is administered to a nursing woman (see Use in Pregnancy previously).
Use in Children: Experience has indicated that patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially whose with the aforementioned conditions (see Hepatotoxicity previously). When valproic acid 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-including 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.
Use in Elderly: A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. 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.
Valproate therapy in elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence (see Somnolence in the elderly previously). The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence (see Dosage and Administration).
This medicinal product contains glucose. This should be taken into account in patients with diabetes mellitus. Patients with rare hereditary problems of fructose intolerance, glucose and galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.
May be harmful to the teeth.
This medicinal product contains methylhydroxybenzoate. Those may cause allergic reactions (possibly delayed).
This medicinal product contains sorbitol.
Patients with rare hereditary problems of fructose intolerance should not take this medicine.