Index of drugs

Generalized epileptic seizures in the form of seizures of unconsciousness, myoclonic and tonic-clonic seizures. Partial and secondary generalized seizures. Combination treatment of other types of seizures, e.g. partial and simple partial seizures, secondary generalized seizures refractory to treatment with standard antiepileptic drugs. Treatment of manic episodes in bipolar disorder, where lithium is contraindicated or poorly tolerated; continued valproate treatment may be considered in patients who have responded clinically to valproate therapy in the acute phase of mania.
Note: the previously used valproic acid pharmaceutical form (other than the non-retarded release) can be changed to Orfiril long in a 1: 1 ratio over a period of 1-2 days. Care should be taken to ensure that serum levels of valproic acid are adequate. In infants, preparations containing valproic acid are the first-line agents in exceptional cases; Orfiril long can only be used with caution and after careful consideration of the benefit-risk balance, if possible as monotherapy.

One long-duration capsules contain 150 mg or 300 mg of sodium valproate. 1 sachet with extended-release mini tablets (long) contains 500 mg or 1000 mg sodium valproate.

Anticonvulsant. One of the possible mechanisms of action is the intensification of the inhibition occurring in the presence of GABA through presynaptic influence on GABA metabolism and / or direct post-synaptic effects on the ion channels of neuronal membranes. The main mechanism of action in bipolar disorders is still unexplained. Therapeutic benefits associated with the use of the drug in bipolar disorders may result from the action on a number of peripheral neurotransmitters (including Dopamine and serotonin). Following oral administration, valproic acid and its sodium salt are rapidly and almost completely absorbed from the gastrointestinal tract. C_max occurs after 8.2 ± 2.5 h. The concentration of valproic acid in the cerebrospinal fluid is 10% of the plasma concentration. Valproic acid binds to 90-95% plasma proteins; after administration of higher doses, the degree of protein binding decreases. In older people and patients with impaired renal or hepatic function, the degree of plasma protein binding is lower. Biotransformation occurs through conjugation with glucuronic acid and through beta-, omega- and omega-1-oxidation. About 20% of the administered dose is excreted in the urine as glucuronides, less than 5% in the unchanged form. In monotherapy, medium T_0,5 is 12-16 h and does not change in long-term treatment. When used with other anti-epileptic medicines (eg with primidone, phenytoin, phenobarbital, carbamazepine) T_0,5 it is shortened to 4-9 h. In newborns and children under 18 months of age. T_0,5 is in the range of 10-67 h. The prolonged half-life occurs in patients with liver disease.

Hypersensitivity to sodium valproate or other ingredients. Liver disease in a history of the patient or a family history and severe liver or pancreatic disorders. Death of siblings caused by hepatic failure during treatment with valproic acid. Porphyria. Coagulation disorders.

Special care should be taken: in infants and children requiring the simultaneous use of several antiepileptic drugs, in children with multiple disorders and in adolescents with severe forms of epilepsy. In infants, medicines containing valproic acid are the first-line medicines only in exceptional cases. In infants and children <3 yrs, especially those with severe forms of epilepsy associated with brain organic changes, mental retardation or congenital metabolic diseases, there is an increased risk of severe, life-threatening liver and / or pancreatic damage, especially when valproate is used with other antiepileptic drugs - valproate should be used as monotherapy in these patient groups, with particular caution.Most cases of liver damage were observed within the first 6 months of treatment, especially between 2 and 12 weeks. The incidence of liver damage is significantly reduced in older age groups (especially after 10 years of age). Patients should be monitored for clinical signs of liver or pancreatic dysfunction, which usually occur before any changes in the results of laboratory tests are observed. Particular care should be taken in patients with bone marrow damage, metabolic disorders (especially in inherited diseases due to enzyme deficiency), renal insufficiency and hypoproteinaemia, with visceral Lupus erythematosus. The drug should be discontinued in the case of unexplained deterioration of the general condition, suspected severe liver or pancreatic function (3-fold increase in AST or AIAT, improperly long prothrombin time, increased alkaline phosphatase and bilirubin, changes in plasma protein concentration). There have been reports of suicidal ideation and suicidal behavior in patients taking anti-epileptic drugs - patients undergoing treatment should be under permanent medical supervision. Kaps. long 300 contain quinoline yellow, which can cause allergic reactions.

Because of the potential for birth defects and developmental defects in infants who have been exposed to valproate in the womb, for the treatment of epilepsy and bipolar disorder in patients who may become pregnant, valproate-containing medicines should only be prescribed when other forms of treatments are not effective or are not well tolerated. Patients should use effective contraception, and treatment should be under the supervision of a doctor who has experience in the treatment of these diseases. For patients who become pregnant or plan to become pregnant while on valproate therapy, alternative treatment options should be considered. The need for testing and a new benefit-risk benefit analysis for women and girls who take valproate should be regularly reviewed. Patients should be informed of the risk of valproate during pregnancy (information on pregnancy in accordance with EMA recommendations of 21/11/2014). The concentration of valproate in human milk is small, 1-10% of maternal serum concentration; no adverse reactions were observed in fed children; as a general rule, it is not necessary to avoid or stop breastfeeding.

Very common: pain, nausea, vomiting. Common: thrombocytopenia, leukopenia, hyperammonaemia, increase or decrease in body weight, increased or decreased appetite, drowsiness, tremors, paresthesia, changes in liver function tests, temporary hair loss, decreased pigmentation and hair curling, amenorrhea. Uncommon: haemorrhage, transient coma (in some cases with an increased incidence of seizures). Rare: lupus erythematosus, vasculitis, hyperandrogenism, hyperinsulinemia, low levels of insulin-like growth factor-binding protein type I, edema, hypothermia, irritability, delusions, confusion, headache, hyperactivity, spasticity, ataxia, stupor, salivary glands, diarrhea, pancreatitis, severe liver damage, rash, erythema multiforme, polycystic ovary syndrome. Very rare: bone marrow disorders, decreased fibrinogen and / or factor VIII levels, impaired platelet aggregation, prolonged bleeding time, lymphopenia, neutropenia, pancytopenia, anemia, abnormal thyroid function tests, encephalopathy (in individual cases, chronic, with neurological symptoms and disorders of higher cortical function), brain-related dementia, extrapyramidal disorders (e.g., reversible Parkinson's syndrome), hearing impairment, tinnitus, Stevens-Johnson syndrome, toxic epidermal necrolysis, Fanconi syndrome, children's wetting. Frequency unknown: sedation. Allergic reactions have been reported.

Orally.Epilepsy. Treatment should be monitored by determining the concentration of valproate in the blood plasma. The lowest dose should be used to ensure optimal prevention of seizures. The therapeutic effect is usually obtained at concentrations of 340 to 700 μmol / l (50 to 100 mg / l).If the preparation is given in combination with other antiepileptic drugs or it substitutes the previously used medicine, the doses of previously used antiepileptic drugs, especially phenobarbital, should be reduced. If it is necessary to stop the current treatment, the drugs should be discontinued gradually. The starting dose of sodium valproate in adults and children is 5-10 mg / kg / day, which should be increased by approximately 5 mg / kg. every 4-7 days to achieve therapeutic or side effects. In some patients, the therapeutic effect of the drug appears after 4-6 weeks and therefore the daily dose should not be increased too early above the average values. The average daily dose in maintenance treatment in adults and elderly is 20 mg / kg, in adolescents - 25 mg / kg, in children - 30 mg / kg. The maximum recommended dose in adults is 2400 mg / day. There are insufficient experience with the use of prolonged-release pharmaceutical forms in children up to 1 year of age, and therefore in this age group, available traditional pharmaceutical forms should be used. In newborns <2 months T_0,5 valproic acid may be up to 60 h, which should be considered when increasing the dose in maintenance therapy.Manic episodes in bipolar disorder. Adults: The starting dose is 750 mg / day. In clinical trials, a satisfactory safety profile was obtained after starting doses of 20 mg / kg. The dose should be increased as soon as possible to achieve the lowest therapeutic concentration that ensures the desired clinical effect. The average daily dose is usually 1000-2000 mg. Patients receiving daily doses exceeding 45 mg / kg they should remain under close observation. Continued treatment of manic episodes in bipolar disorder should be adjusted individually so that the patient takes the lowest effective dose. The safety and efficacy of valproate in the treatment of manic episodes in bipolar disorder have not been established in patients <18 years.Patients with renal insufficiency: the concentration of free valproic acid in the blood plasma should be taken into account and the dose should be reduced accordingly.
The total daily dose of the drug can be divided into 2-4 single doses, and in the case of long preparations - 1-2 doses. The capsules should be swallowed whole with a lot of liquid (eg a glass of water). Capsules can also be taken by opening them and pouring their contents (mini-tabls for prolonged release) into a drink or dessert. However, never shed mini-tablets with prolonged release, because this eliminates the effect of prolonged release of the drug. Sustained-release mini-tablets should be taken in the same way as the contents of open hard gelatin capsules.