Index of drugs

Generalized seizures in the form of seizures of the unconscious, myoclonic and tonic-clonic, focal and secondary generalized seizures and in combination treatment of other forms of seizures, eg focal seizures with simple and complex symptoms and secondary generalized focal seizures, if these seizures do not respond to the usual anti-epileptic treatment.
In small children, up to 3 years of age, antiepileptic drugs containing valproic acid are used only in exceptional cases as first-line treatments.

1 tabl about release contains 199.80 mg sodium valporate and 87 mg valproic acid, corresponding to a total of 300 mg valproic acid or 333 mg sodium valproate and 145 mg valproic acid, which corresponds to a total of 500 mg valproic acid.

Anticonvulsant. The mechanism of action is probably the inhibition of processes dependent on GABAergic transmission by presynaptic action on GABA metabolism and / or direct postsynaptic action on ion channels in the neural membrane. It is absorbed quickly and almost completely after oral administration. The maximum concentration after a dose of 300 mg is achieved after 5-12 h, and after a dose of 500 mg - 4-24 h. Steady state serum concentrations are usually achieved within 3-5 days. In 90-95% it is bound to plasma proteins. Protein binding is reduced at higher doses, in elderly patients with renal or hepatic impairment. Biotransformation occurs through glucuronidation and oxidation. Approx. 20% of the administered dose is excreted in the urine as a glucuronide ester, less than 5% is excreted unchanged. In monotherapy T_0,5 is 12-16 h and is stable in long-term treatment. In combination with other medicines (primidone, phenytoin, phenobarbital and carbamazepine) T_0,5 is reduced by 4-9 hours. For newborns, infants and children learning to walk up to 18 months of age_0,5 is 10-67 h. In patients with liver disease_0,5 it is elongated.

Hypersensitivity to the components of the preparation. Liver disease or severe active liver or pancreatic dysfunction in a family history or interview. Hepatic dysfunction with fatal outcome in siblings during treatment with valproic acid. Porphyria. Blood coagulation disorders.

Severe liver damage or pancreatic damage most frequently occurred in young children (up to 3 years of age) who are susceptible to severe epileptic seizures, especially when valproic acid is given concomitantly with other anticonvulsants or when there is brain injury, mental retardation or hereditary metabolic disease . In this group of patients, valproic acid should be administered with particular caution and monotherapy. Most cases of liver damage are observed within the first 6 months of treatment, especially between 2 and 12 weeks. The incidence of liver disease is reduced in patients over 3 years of age (in particular in patients over 10 years of age). Discontinuation of treatment should be considered in the case of unexplained decline in overall well-being, clinical manifestations of liver and / or pancreatic injury, coagulation disorders, over two or three increases in ALT or AST, also in the absence of clinical symptoms (hepatic enzyme induction should be considered by co-administered medicines), moderate (1-1.5-fold) increases in ALT or AST, accompanied by acute febrile infection, severe deterioration of coagulation parameters or occurrence of dose-related adverse reactions. Patients with a history of bone marrow fracture should be carefully monitored. In patients with systemic lupus erythematosus, the preparation should only be used after careful consideration of the risks and benefits of treatment. In patients with renal insufficiency or hypoproteinaemia, increased plasma concentrations of valproic acid not related to plasma proteins should be considered and the dose reduced as necessary. Patients should be informed about possible weight gain.

Exposition to valproic acid during the first and the beginning of the second trimester of pregnancy is associated with the development of malformations in the fetus. If the use of valproic acid during pregnancy is necessary, the drug should be administered at the lowest effective dose that allows control of seizures, especially during the first trimester. The daily dose should be administered at the lowest effective dose that allows control of seizures, especially during the first trimester. The daily dose should be divided into several smaller ones in women who may become pregnant and necessarily between the 20th and 40th day after conception. In addition, the plasma concentration of the drug should be monitored regularly because during pregnancy even at a constant dose, significant fluctuations may occur. Association with other antiepileptic drugs increases the risk of malformations. Whenever possible, valproic acid should be administered as monotherapy. Early folic acid supplementation should be used during pregnancy and would be beneficial also at the stage of pregnancy planning. There were withdrawal symptoms in the new-born children of mothers treated with valproic acid. Treatment with valproic acid during pregnancy should not be interrupted suddenly. Valproic acid is excreted into breast milk. Due to the small amounts in breast milk, it usually does not pose any risk to the child and discontinuation of breastfeeding is not usually necessary.

Very common: hyperammonaemia without changes in liver function parameters or with accompanying neurological symptoms. Common: transient thrombocytopenia or leukopenia, dose-related weight gain or loss, increased appetite or loss of appetite, dose-related drowsiness, tremor or paresthesia, dose-related transient loss of hair. Uncommon: peripheral edema, bleeding, irritability, excessive mobility, confusion, especially at the beginning of treatment, hallucinations, headache, spasticity, ataxia, especially at the beginning of treatment, transient encephalopathy, stupor, sometimes ending coma, partly associated with an increased frequency of seizures epileptic, hypersalivation, diarrhea, gastrointestinal disorders (nausea, abdominal pain), dose-related, severe (sometimes fatal) liver dysfunction. Rare: lupus erythematosus, chronic encephalopathy with neurological symptoms and disorders of high cortical function, especially at high doses or in combination with other antiepileptic drugs, vasculitis, pancreatic injury, sometimes fatal, erythema multiforme, Fanconi syndrome (transient after discontinuation of the preparation) ), involuntary urination in children, amenorrhea, dysmenorrhea, increased testosterone, polycystic ovary syndrome. Very rare: bone marrow dysfunction leading to lymphopenia, neutropenia, pancytopenia or anemia, prolonged bleeding time due to decreased fibrinogen concentration, impaired platelet aggregation and / or thrombocytopathy caused by factor VIII deficiency (von Villebrand factor), dementia associated with brain atrophy, transient after discontinuation of the drug, transient parkinsonism, muscle weakness, motor disorders (chorea dyskinesia), severe generalized changes in the EEG, severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), hypothermia, transient after discontinuation of the preparation. In addition: tinnitus.

Orally.monotherapy. The starting dose5-10 mg / kg per day. The dose should be increased gradually by approx. 5 mg / kg. every 4-7 days, until the desired therapeutic effect is achieved.Maintenance dose: adults and elderly patients: 20 mg / kg; adolescents: 25 mg / kg; children: 30 mg / kg In children under 6 years of age, data on the use of prolonged release forms are insufficient. Therefore, in this group of patients it is recommended to use conventional dosage forms with a lower content of active substance (eg solution or 150 mg tablet).Combination therapy. If the preparation is used in combination with previously used medicinal products or is replaced by a previously used medicinal product, the dose of the previously used preparation, in particular phenobarbital, should be reduced. If the use of the existing preparation is to be discontinued, the withdrawal must be gradual. Because the induction of enzymes by other antiepileptic drugs is reversible, serum valproic acid should be monitored for approximately 4-6 weeks.after the last dose and if necessary reduce the daily dose of valproic acid. In patients with renal insufficiency or hypoproteinaemia, an increase in the free form of valproic acid in the serum should be considered and the dose reduced if necessary.Method of administration: the daily dose is given in 1 dose or in 2 divided doses, preferably 1 hour before a meal. In the case of gastrointestinal disorders due to treatment, tabl. should be taken during or after a meal. They should be swallowed whole or divided into half, do not chew, drink with a lot of liquid. In general, no dose reduction or withdrawal should be attempted until the patient has been experiencing seizures for at least 2 or 3 years. Withdrawal of the drug should consist of a gradual reduction of the dose over a period of 1-2 years. Instead of adjusting the dose to the age, let the children grow up from the dose counted per kg body weight, with EEG records not going to get worse.