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Hepatotoxicity: Hepatic failure resulting in fatalities has occurs 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 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. Liver function tests should be performed prior to therapy, and at frequent intervals thereafter, especially during the first six months. However, physicians should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.
Caution should be observed when administering valproic acid 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. Experience has indicated that children under the age of two years are at considerably increased risk of developing fatal hepatotoxicity, especially those with aforementioned conditions. When valproic acid 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 of group, experience 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. In some cases, hepatic dysfunction has progressed in spite of discontinuation of the drug.
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 used 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 Disorders (UCD): Hyperammonemic encephalopathy, sometimes fatal has been reported following initiation of valproate therapy in patients with Urea Cycle Disorders (UCD), 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 Contraindications and Precautions).
Suicidal Behavior and Ideation: An increase in the risk of suicidal thoughts or behavior in patients taking Anti-Epileptic Drugs (AEDs) for any indication has been reported. The increased risk of suicidal thoughts or behavior with AEDs was observed as early 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. Patients treated with an 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 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 AEOs 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, 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 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 deteriorates (see Interactions).
Somnolence in the Elderly: 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 in 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 (see Precautions) may be dose-related. The therapeutic benefit that may accompany the higher doses should, therefore, be weighed against the possibility of greater incidence of adverse effects.
Use in Pregnancy: According to published and not published reports, valproic acid may produce teratogenic effects, such as neural tube defects (e.g. spina bifida) in 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 when compared with some other antiepileptic drugs. Therefore, 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 the treatment. There are multiple reports that indicate that the use of antiepilepsy drugs during 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 data described as follows were gained almost exclusively from women who received valproate to treat epilepsy. 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 be approximately 1 to 2%.
Other congenital anomalies (e.g. craniofacial defects, cardiovascular malformations and anomalies involving various body system), compatible and incompatible with life, have been reported. Sufficient data to determine the incidence of these congenital anomalies are not available.
The higher incidence of congenital anomalies in antiepileptic drug-treated women with seizure disorders cannot be regarded as a cause and effect relationship. There are intrinsic methodological problems in obtaining adequate data on drug teratogenicity in humans; genetic factors or the epileptic condition itself, may be more important than drug therapy in contributing to congenital anomalies.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproic acid during pregnancy.
Patients taking valproate may develop clotting abnormalities. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
Hepatic failure, resulting in the death of newborn and of an infant, has been reported following the use of 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 seizure do not pose some hazard to the developing embryo of fetus.
Use in Lactation: Valproate is excreted in breast milk. It is not known what the effect this would have on a nursing infant. Consideration should be given to discontinuing nursing when valproic acid administered to a nursing woman.
