COMPOSITION :
Berval® Syrup 250 mg/5 ml, each 5 ml (a measurement spoonful) contains : Sodium valproate equivalent to Valproic acid 250 mg.
DESCRIPTIONS :
Berval® contains Sodium valproate (equivalent to Valproic acid) as active ingredient is available in syrup 250 mg/5 ml.
INDICATIONS :
Berval® may be used as sole or adjunctive therapy in the treatment of partial seizures (both elementary and complex) and absence seizures (petit mal seizures).
DOSAGE AND ADMINISTRATIONS :
Berval® is administered orally. The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 – 10 mg/kg/day, until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in a divided regimen.
The following table is a guide for the initial daily dose of Berval® (15 mg/kg/day) :
| Weight | Total daily dose (mg) | Number of measurement spoonful of syrup | |||
| (kg) | (lb) | Dose 1 | Dose 2 | Dose 3 | |
| 10 – 24.9 | 22 – 54.9 | 250 | 0 | 0 | 1 |
| 25 – 39.9 | 55 – 87.9 | 500 | 1 | 0 | 1 |
| 40 – 59.9 | 88 – 131.9 | 750 | 1 | 1 | 1 |
| 60 – 74.9 | 132 – 164.9 | 1000 | 1 | 1 | 2 |
| 75 – 89.9 | 165 – 197.9 | 1250 | 2 | 1 | 2 |
The frequency of adverse effects (particulary elevated liver enzymes) may be dose-related. The benefit of improved seizure control which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse reaction.
A good correlation has not been established between daily dose, serum level and therapeutic effect. However, therapeutic serum levels for most patients will range from 50 – 100 mcg/ml. Occasional patients may be controlled with serum levels lower or higher than this range.
As the Berval® dosage is titrated upward, blood levels of Phenobarbital and/or Phenytoin may affected.
Gastrointestinal tract irritation : Patients who experience gastrointestinal irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.
OVERDOSAGES :
- Overdosage with Valproate may result in somnolence, heart block and deep coma. Fatalities have been reported; however, patients have recovered from Valproate levels as high as 2120 mcg/ml.
- In overdose situations, the fraction of drug not bound to protein is high and hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output.
- Naloxone has been reported to reverse the CNS depressant effects of Valproate overdosage. Because Naloxone could theoretically also reverse the antiepileptic effects of Valproate, it should be used with caution in patients with epilepsy.
CONTRAINDICATIONS :
- Should not be administered to patients with hepatic disease or significant dysfunction.
- Patient with known hypersensitivity to the drug.
- Patient with known urea cycle disorders (see WARNINGS AND PRECAUTIONS).
WARNINGS AND PRECAUTIONS :
Warnings
- Hepatotoxicity :
Hepatic failure resulting 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 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. 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 Sodium valproate 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 those 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 hepatotoxicity, especially those with the aforementioned conditions. When Sodium valproate products 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. In some cases, hepatic dysfunction has progressed in spite of discontinuation of 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 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 can 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 (see WARNING).
- Urea Cycle Disorders (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 protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of 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 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 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 AEDs are prescribed are themselves associated with morbidity and an increase risk of suicidal thoughts and behavior. If 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.
- 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 DRUG INTERACTIONS).
- Somnolence in the elderly :
A significantly higher proportion of Valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. 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 AND ADMINISTRATIONS).
- 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 a greater incidence of adverse effects.
- Nursing mothers :
Valproate is excreted in breast milk. Concentrations in breast milk have been reported 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.
- Usage in pregnancy :
According to published and unpublished 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 in the clinical literature that indicate 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 below 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 systems), 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 effects 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 development 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 a newborn and of an infant, has been reported following the use of Valproate during pregnancy.
Test 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 hazard to the developing embryo or fetus.
Precautions
- Hepatic dysfunction (see CONTRAINDICATIONS and WARNINGS)
- Pancreatitis (see WARNINGS)
- 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. Hyperammonemia should also be considered in patients who present with hypothermia (see PRECAUTIONS – 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 urea cycle disorders (see CONTRAINDICATIONS and WARNINGS – Urea Cycle Disorders (UCD) and PRECAUTIONS – Hyperammonemia and encephalopathy associated with concomitant Topiramate use).
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 or 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 manifestation of hyperammonemia (see PRECAUTIONS – Hypothermia). 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 WARNINGS – Urea Cycle Disorders and PRECAUTIONS – Hyperammonemia).
- 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 treatment or after increasing the daily dose of Topiramate (see DRUG INTERACTIONS – 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.
- General :
Because of reports of thrombocytopenia (see WARNINGS), 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 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.
Since Valproate 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 DRUG INTERACTIONS).
Valproate 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. 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.
- Multi-organ hypersensitivity reaction :
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), 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 associated with multi-organ hypersensitivity would indicate this to be a possibility.
- Information for patients :
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- Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can 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 PRECAUTIONS – Hyperammonemia) and be told to inform the prescriber if any of these symptoms occur.
- Since Sodium valproate 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.
- Since Sodium valproate has been associated with certain types of birth defects, female patients of child-bearing age considering the use of Sodium valproate should be advised of the risk associated with the use of Valproic acid during pregnancy (see WARNINGS).
- Pediatric use :
Experience 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 WARNINGS). When Sodium valproate 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.
- Geriatric use :
A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence (see WARNINGS – Somnolence in the elderly). 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 ADMINISTRATIONS).
PRESENTATION :
Berval® Syrup 250 mg/5 ml Box, 1 bottle @ 120 ml Reg. No. DKL1702356337A1
STORAGE :
STORE BELOW 30ºC, PROTECT FROM LIGHT
ON MEDICAL PRESCRIPTION ONLY
Manufactured by :
PT. BERNOFARM
Sidoarjo – Indonesia
