Epilepsan

Valproic acid.

Each 5 mL contains: Sodium Valproate 288 mg equivalent to Valproic Acid 250 mg.

Pharmacology: Valproic acid undergoes dissociation into valproate ion in the gastrointestinal tract. The mechanism of action of Valproic acid as an antiepileptic agent is not yet known for sure, thought to be related with an increase in gamma-aminobutyric acid (GABA) in the brain.

EPILEPSAN is used as a monotherapy or adjunctive therapy in the treatment of partial epilepsy (simple and complex epilepsy) and absence seizures (petit mal).

Valproic Acid is given orally. The recommended starting dose is 15 mg/kg body weight/day, increased at 1 week intervals of 5-10 mg/kg body weight/day until seizures can be controlled or side effects do not become more severe. The maximum recommended dose is 60 mg/kg body weight/day. If the total daily dose exceeds 250 mg, Valproic Acid must be given in several divided doses.
The following table is a guide for starting Valproic Acid daily (15 mg/kg/day) (see table).


Click on icon to see table/diagram/image


The frequency of side effects could depend on the dose (especially the increase in liver enzymes). Improved seizure control with the use of higher doses must be considered the possibility of greater side effects.
There is no correlation data available between daily dose, serum concentration, and therapeutic effect. However, the serum concentration of therapy in most patients ranges from 50-100 mcg/ml. Sometimes patients can be controlled with serum concentrations lower or higher than that range. If blood levels of Valproic Acid increase, the concentration of Phenobarbital and/or Phenytoin in the blood can be affected. Patients who experience gastrointestinal irritation can be given Valproic acid along with food or by titration of the dose starting from the lowest dose.

Overdosage with Valproic Acid can cause drowsiness, heart block, and coma. Because Valproic Acid is absorbed quickly, the success of gastric emptying depends greatly on the time since administration. General supportive therapy can be done with special attention given to maintaining adequate bladder emptying.
Naloxone has been reported to reverse the effects of central nervous system depression due to an overdose of Valproic Acid. This drug must be used cautiously because Naloxone theoretically could reverse the antiepileptic effects of Valproic Acid.

Should not be given to patients with significant liver disease or liver dysfunction.
Not recommended for patients who are hypersensitive to this drug.
Contraindicated in patients with urea cycle disorders.

Hepatotoxicity: Liver failure that causes death has been reported in patients using Valproic Acid. The use of Valproic Acid especially in children under 2 years can lead to the risk of fatal hepatotoxicity. Use of Valproic Acid in patients using 2 or more anticonvulsant drugs, patients with congenital metabolic disorders accompanied by mental retardation, and patients with organic mental disease, Valproic Acid must be used with extreme caution and as a monotherapy. The benefits of therapy must be considered against the risk, the risk of fatal hepatotoxicity decreases in groups of patients over the age of 2 years. This event usually occurs during the first 6 months of therapy with Valproic Acid. Serious or fatal hepatotoxicity can be preceded by non specific symptoms, such as loss of control over seizures, malaise, weakness, lethargy, facial edema, anorexia and vomiting. Patients must be closely monitored for these symptoms. Liver function tests should be done before therapy and at fairly frequent intervals thereafter, especially during the first 6 months of therapy.
Teratogenicity: Valproate can produce teratogenic effects such as damage of neural tubes (e.g. spina bifida). Therefore, the use of Valproate in woman who are potentially pregnant requires consideration of the benefits and risks to the fetus. This is very important for therapy in conditions that the cure is spontan and is not related to permanent damage or risk of death (e.g. migraine) are considered for administration.
Pancreatitis: Cases of life-threatening pancreatitis have been reported in children and adult patients using Valproate. Some cases are hemorrhages with rapid progression from the onset of symptoms to death. Cases that have been reported occur shortly at the beginning of use and also after several years of use. Patients and families should be warned if abdominal pain, nausea, vomiting, and/or anorexia are symptoms of pancreatitis that requires medical treatment. If the patient is diagnosed with pancreatitis, the use of Valproate must be stopped. Alternative therapies for other medical conditions must be given according to clinical indications (see Precautions).

Liver Disorders (Hepatotoxicity): Fatal liver disorders can occur in patients receiving Valproic Acid. These events usually occur during the first six months of treatment with Valproic Acid. Serious or fatal hepatotoxicity can be preceded by non-specific symptoms, such as loss of control of seizures, malaise, weakness, lethargy, facial edema, anorexia and vomiting. Patients must be closely monitored for these symptoms.
Liver function tests should be done before therapy and at sufficient intervals after, especially during the first 6months of therapy. However, doctors should not rely entirely on the results of serum biochemical tests because these tests may not show abnormal results in some cases, but must also consider the results of medical records and physical examinations carefully.
Be careful if Valproic Acid is given to patients who have history of liver disease. Patients who use two or more anticonvulsants, pediatrics, patients who have congenital metabolic disorders, patients with severe seizure disorders with mental retardation, and patients with organic mental disorders (organic brain diseases) are at high risk of hepatotoxicity. The use of Valproic Acid in children under 2 years old can increase the risk of fatal hepatotoxicity, especially in pediatric patients with conditions above. When Valproic Acid is used in this group of patients, it must be used with extreme caution and as a single compound. The benefits of therapy must be considered against the risks. The risk of fatal hepatotoxicity decreases in groups of patients older than 2years old.
This medication should be stopped immediately if there is a suspected or impaired liver function. In some cases, liver dysfunction develops although drug use has been stopped.
Due to reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation and the presence of abnormal coagulation parameters, it is recommended to test platelet counts and coagulation before starting therapy and at periodic intervals. Patients who receive Valproic Acid are recommended to be monitored for platelet counts and coagulation parameters before surgery begins. The presence of bruising or haemostasis/coagulation disorders is an indication for a reduction in the dose of Valproic Acid or a replacement of therapy.
Hyperammonemia with or without lethargy or coma has been reported to occur and appear without any abnormal liver function tests. If there is a clinically significant improvement, Valproic Acid must be stopped.
Because Valproic Acid can interact with antiepileptic drugs that are given together, it is recommended to measure levels of antiepileptic drugs in serum periodically during the beginning of therapy.
Valproic Acid is partially eliminated in urine as a ketone metabolite that can cause misinterpretation of ketone and urine tests.
There have been several reports of changes in the results of thyroid gland function tests related to Valproic Acid. The clinical effect of this is unknown.
Valproic Acid can cause CNS depression, especially if combined with other CNS depressants (for example: alcohol), patients should be advised not to engage in dangerous activities, such as driving a car or operating a dangerous machine, until it is certain that the patient is not sleepy due to drug use.
Fertility: The effect of Valproic Acid on testicular development and sperm production and fertility in humans is unknown.
Use in Pregnancy: The use of Valproic Acid in pregnancy has not been proven safe. Valproic Acid is used in pregnant woman with seizures or woman with seizure who will get pregnant, only if this drug is needed in seizure management. Antiepileptic drugs should not be stopped in patients where the administration of these drugs with the aim of preventing the occurrence of more severe seizures because of the possibility of accelerating the occurrence of status epilepticus in the presence of hypoxia and can be life threatening. In individual cases where the severity and frequency of seizures are such that drug withdrawal does not pose a serious threat to the patient, drug withdrawal can be considered before and during pregnancy, although it is not certain that mild seizures are not harmful to the embryo or fetus.
Doctors are expected to consider this or provide counseling to women who suffer from epilepsy and have the potential to become pregnant.
Use in Lactation: Valproic acid is excreted in breast milk. Concentrations in breast milk are reported to be 1-10% of the concentration in serum. There is no known effect of the drug on breastfeeding babies. Be careful if Valproic Acid is given to nursing mothers.
Use in Children: The occurrence of hepatotoxicity appears more common in children, especially those aged less than 2 years and children who use 2 or more anti-epileptic drugs. This drug must be used with extreme caution and be used as a single drug in children under the age of 2 years, and the benefits of using Valproic Acid in children must considered against the risk.

Use in Pregnancy: The use of Valproic Acid in pregnancy has not been proven safe. Valproic Acid is used in pregnant woman with seizures or woman with seizure who will get pregnant, only if this drug is needed in seizure management. Antiepileptic drugs should not be stopped in patients where the administration of these drugs with the aim of preventing the occurrence of more severe seizures because of the possibility of accelerating the occurrence of status epilepticus in the presence of hypoxia and can be life threatening. In individual cases where the severity and frequency of seizures are such that drug withdrawal does not pose a serious threat to the patient, drug withdrawal can be considered before and during pregnancy, although it is not certain that mild seizures are not harmful to the embryo or fetus.
Doctors are expected to consider this or provide counseling to women who suffer from epilepsy and have the potential to become pregnant.
Use in Lactation: Valproic acid is excreted in breast milk. Concentrations in breast milk are reported to be 1-10% of the concentration in serum. There is no known effect of the drug on breastfeeding babies. Be careful if Valproic Acid is given to nursing mothers.

Side effects can be caused by Valproic Acid monotherapy or in combination.
Gastrointestinal: The most common side effects of Valproic Acid after initial therapy with this drug are nausea, vomiting, and indigestion. These side effects are usually temporary and rarely until the cessation of therapy. Diarrhea, stomach cramps and constipation have been reported. Anorexia with weight loss and increased appetite accompanied by weight gain was also reported.
Central nervous system: The effect of sedation has been reported to occur with a single use of Valproic Acid but has been reported to occur more frequently in patients receiving the combination. Sedation is usually reduced if antiepileptic drugs are reduced. Tremors have been reported inpatients receiving valproate and may be dose dependent. Ataxia, headaches, nystagmus, diplopia, asterixis, "spot before eyes" dysarthria, dizziness and incoordination have been reported to be rare. Coma has been reported in patients receiving Valproic Acid as monotherapy or in combination with Phenobarbital.
Dermatology: An increase in temporary hair loss has been reported. Photosensitivity skin rash, generalized pruritus, erythema multiforme and Stevens-Johnson syndrome are rarely reported.
Psychiatry: Emotional disorders, depression, psychosis, aggression, hyperactivity, and destructive behavior have been reported.
Musculoskeletal: Weaknesses have been reported.
Hematology: Thrombocytopenia has been reported. Valproic Acid inhibits the platelet aggregation phase. This can cause changes in bleeding time. Petechiae, bruising, hematoma formation and hemorrhage have been reported (see Warnings and Precautions).
Lymphocytosis and hypofibrinogemia have been recorded. Leukopenia, esonophilia, anemia, and bone marrow suppression have been reported.
Hepatic: Slight increases in serum concentrations of transaminases (such as SGPT and SGOT) and LDH (lactate dehydrogenase) are often reported to occur and are likely to be dose dependent. Occasionally, laboratory test results include an increase in serum bilirubin and abnormal changes in other liver function tests. These results can illustrate the possibility of serious hepatotoxicity (see Warnings and Precautions).
Endocrine: Irregular menstruation and secondary amenorrhea have been reported. Rarely, breast enlargement and galactorrhea are reported in patients receiving Valproic acid. Abnormal thyroid function tests have been reported.
Pancreatic: Acute pancreatitis, including rare fatal cases, has been reported in patients using Valproic Acid.
Metabolic: Hyperammonemia (see Warnings and Precautions), hyperglycinemiahas been reported and is associated with fatal events in patients with preexistent non ketonic hyperglycinemial.
Others: Edema in extremities has been reported.

Alcohol: Valproic Acid can increase CNS depressant activity from alcohol.
Aspirin, Carbamazepine, and Dicumarol: Valproic Acid use with drugs that have strong protein bonds (such as Aspirin, Carbamazepine, and Dicumarol) can cause changes in the concentration of the drug in serum.
Phenobarbital: There is evidence to suggest that Valproic Acid can cause an increase in Phenobarbital serum through non-renal clearance. This condition can cause severe CNS depression, a combination of Valproic Acid and Phenobarbital has also been reported to cause CNS depression without a significant increase in serum barbiturate or valproate concentrations. All patients receiving barbiturate therapy must be monitored closely for neurological toxicity. If possible, serum barbiturate concentrations should be known and if necessary, barbiturate doses can be reduced.
Pirimidone: Pirimidone is metabolized into barbiturates. Therefore, Pirimidone can also be involved in the same or similar interactions.
Phenytoin: Seizures have been reported to occur when Valproic Acid is combined with Phenytoin. In most reports, there has been a decrease in the total concentration of Phenytoin in plasma. However, an increase in the total concentration of phenytoin in serum has also been reported.
A decrease in total Phenytoin concentrations at the beginning of therapy followed by an increase in Phenytoin concentrations has also been reported. In addition, decreased total serum Phenytoin concentrations accompanied by increased levels of free (non-protein bound) Phenytoin have been reported. The dose of Phenytoin must be adjusted according to the clinical situation.
Clonazepam, Ethosuximide: Use of Valproic Acid and Clonazepam can negate the effects of drugs with each other. There is evidence of the effect of Valproate on serum Ethosuximide concentrations. Patients receiving valproate and Ethosuximide, especially along with other anticonvulsants, should be monitored for changes in serum concentrations of both drugs.
Aspirin and Warfarin: Be careful if Valproic Acid is given along with drugs that affect blood coagulation such as Aspirin and Warfarin.

Store below 30°C.
Use within 3 months after opening.

Anticonvulsants

N03AG01 - valproic acid ; Belongs to the class of fatty acid derivatives antiepileptic.

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