Index of drugs

Different forms of epilepsy, in particular: epilepsy with primary generalized seizures (petit mal, grand mal); myoclonic epilepsy; photosensitive epilepsy; other forms of epilepsy - as a second choice drug, also with other antiepileptic drugs (except phenobarbital). Treatment of manic episodes in bipolar disorder, when lithium is contraindicated or poorly tolerated. Continuation of valproate treatment may be considered in patients who have responded clinically to acute mania valproate therapy.

1 tabl powl. contains 200 mg of Magnesium valproate.

Anticonvulsant. The mechanism of action is not fully understood, but it is believed to consist in increasing the concentration of gamma aminobutyric acid (GABA) in the brain. It inhibits the spread of pathological discharges within the brain, but does not directly affect the function of an epileptic focus. Valproate is rapidly and completely absorbed from the gastrointestinal tract, with the presence of food slightly reducing the speed of this process. The rate of absorption of magnesium valproate is slightly lower than that of sodium valproate. Maximum concentration in blood reaches 1-4 h after oral administration. Plasma protein binding is 80-90% and depends on the concentration of valproate in the blood. Valproate is metabolized in the liver and excreted mainly in the form of metabolites in the urine, and in small amounts also with faeces and expiratory air. It passes through the blood-brain barrier, the placental barrier and in small amounts it gets into the milk of breast-feeding mothers. T_0,5 it is 8-22 h, which is shorter in patients receiving concurrent medications inducing microsomal enzymes, including some antiepileptic drugs (eg carbamazepine, phenytoin, phenobarbital).

Hypersensitivity to magnesium valproate or to any of the excipients. Porphyria. Liver disease (also in the past and in the family history) and / or severe liver or pancreatic dysfunction. Death of siblings due to liver failure in the course of treatment with magnesium valproate.

Take special care with the preparation: in infants and children requiring the simultaneous use of several antiepileptic drugs; in children with many disabilities and young people with severe forms of epilepsy; in patients with bone marrow damage; in patients with coagulation disorders or thrombocytopenia; in patients with inherited enzyme deficiencies; in patients with renal insufficiency and hypoproteinaemia. In children and adolescents taking magnesium valproate, there is a risk of severe, life-threatening damage to the liver or pancreas (especially when combined with other antiepileptic medicines). The most vulnerable are infants and children under 3 years with epileptic seizures, in particular patients who have also suffered brain damage, developmental delay and / or hereditary metabolic diseases. In these patient groups, the preparation should be used very carefully, as monotherapy. The incidence of liver damage is significantly reduced in patients from older age groups (especially after 10 years of age). Most cases of liver damage were observed within the first 6 months of treatment (especially between 2 and 12 weeks) and were most commonly associated with the use of additional antiepileptic drugs. In the case of non-specific clinical symptoms (eg loss of appetite, vomiting, epigastric pain, malaise, increased epileptic seizures, nosebleeds, localized or generalized edema, lethargy) the patient should be closely monitored. If severe liver or pancreatic disorders are suspected, treatment should be discontinued immediately. The 3-fold increase in AST or ALT, abnormally long prothrombin time, increased alkaline phosphatase and bilirubin, changes in plasma protein concentration may be considered as criteria for discontinuation of therapy.In neonates, magnesium valproate can be used as a first line treatment only in exceptional cases, with extreme caution and after careful consideration of the risk-benefit ratio. Whenever possible, it should be used alone. It is recommended that the following laboratory tests be performed in children using the drug: before the start of treatment: complete blood count (including platelet count), coagulation system parameters (thromboplastin time, fibrinogen concentration), serum amylase activity, AST, ALT, alkaline phosphatase, total bilirubin, protein, Glucose in the blood; monthly for the first 6 months of treatment, every 3 months for the Next six months and every 4-6 months for 12 months of treatment: when there are no clinical disorders - complete blood count (including platelet count) and activity assay liver transaminases, and every second test also coagulation system tests. With the same frequency as laboratory tests, clinical trials should also be carried out. It is also recommended that in the period between laboratory tests, parents / carers should be in regular telephone contact with the attending physician, which enables early diagnosis of toxic effects of the drug or other clinical symptoms. Adolescents and adults should undergo a careful clinical and laboratory examination (such as in children) prior to initiation of therapy, and later, especially during the first 6 months, regular check-ups are recommended. These should include complete blood counts (including platelet counts), liver function tests and pancreatic function tests. Do not rely completely on the results of biochemical tests, because not always side effects are related to their deviations - the medical history and physical examination of the patient are very important. It should be remembered that some patients without hepatic impairment may experience a temporary increase in liver enzymes, especially at the beginning of treatment. The use of the drug may cause hyperammonaemia - if apathy, drowsiness, vomiting, low blood pressure and an increase in seizure frequency occur, ammonia and valproic acid levels in plasma should be determined and the dose reduced as necessary. The concentration of ammonia should be investigated before treatment is started in patients suspected of having urea cycle enzyme disorders. In patients with symptoms of lupus erythematosus, the drug can only be used after careful consideration of the risks and benefits. If the patient taking the medicine develops unexpected bleeding from mucous membranes or an increased tendency to form hematomas, coagulation tests should be performed. Patients with a significant prolongation of thromboplastin time and other laboratory changes, such as a decrease in fibrinogen or concentrations of coagulation factors (mainly factor VIII) or an increase in bilirubin or liver enzymes should be particularly carefully observed. It is recommended that the number of platelets, thromboplastin time, bleeding time and fibrinogen should be measured before surgery or dental procedures. Patients with a history of bone marrow failure should be closely monitored. In patients with renal insufficiency, plasma levels of free valproic acid may increase, therefore an appropriate dose reduction may be necessary. Both withdrawal of the preparation and conversion to another antiepileptic drug should be carried out carefully and gradually; sudden changes can cause a rapid increase in the frequency of epilepsy attacks. The results of some testsin vitro indicate that valproate may promote HIV replication (it is not known if this is clinically relevant). Co-administration with carbapenem drugs is not recommended. Patients should be carefully monitored for signs of suicidal ideation and behaviors and, if necessary, considered appropriate treatment. The safety and efficacy of the drug in the treatment of manic episodes in bipolar disorder in patients under 18 years have not been established.

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). Valproate passes into human milk - it reaches 10-100 times lower than in blood - it seems unlikely that it would adversely affect a breastfed child and as a general rule there is no need to avoid or stop breastfeeding.

Very common: abdominal pain, nausea, vomiting. Common: thrombocytopenia, leukopenia, hyperammonaemia, increased or decreased appetite, drowsiness, tremors, paresthesias, temporary hair loss, decreased pigmentation and folding, lack of menstruation, weight gain or loss, changes in liver function tests. Uncommon: transient coma (in some cases with an increased incidence of seizures), haemorrhage. Rare: allergic reactions, hyperandrogenism, hyperinsulinaemia, edema, irritability, delusions, confusion, headache, hyperactivity, spasticity, ataxia, stupor, vasculitis, diarrhea, pancreatitis, salivation, severe liver damage, rash, erythema multiforme, lupus erythematosus, polycystic ovary syndrome, hypothermia, low levels of type-I insulin-like growth factor-binding protein. Very rare: bone marrow disorders, lymphopenia, neutropenia, pancytopenia, anemia, encephalopathy, brain-related dementia, (reversible) Parkinson syndrome, hearing impairment , tinnitus, Stevens-Johnson syndrome, Lyell's syndrome, Fanconi syndrome, children's wetting, decreased fibrinogen and / or factor VIII levels, impaired platelet aggregation, prolonged bleeding time, abnormal thyroid function tests (it is not known if they have importance Clinical). Not known: sedation, extrapyramidal disorder, decreased bone density, osteopenia, osteoporosis and fractures in patients treated for a long time. In isolated cases, especially in patients taking valproic acid in high doses or in combination with other antiepileptic drugs, chronic encephalopathy was found (this was associated with neurological symptoms and disorders of higher cerebral cortex function, until now the exact etiology of such disorders has not been fully elucidated). In very rare cases, pancreatic damage with similar clinical signs to symptoms of liver damage has been observed. Abrupt discontinuation of the drug may lead to an increase in the symptoms of epilepsy.

Orally.Epilepsy20-30 mg / kg daily, in 2-4 doses, with a meal. In elderly patients, the doses that allow to achieve the optimal clinical effect are usually lower than in younger patients, but their dosage is also based on the assessment of the efficacy and tolerance of treatment. In patients with mild and moderate renal impairment, lower doses should be used, while in patients with severe renal impairment, dosing should be based on the free blood valproic acid concentration. The therapeutic serum valproate concentration ranges from 40 to 100 μg / ml (280 to 700 μmol / l). The preparation should not be used interchangeably with other preparations containing magnesium valproate.Manic episodes in bipolar disorder. The daily dose should be determined and checked by the attending physician. Adults: the recommended initial daily dose is 750 mg. In addition, a satisfactory safety profile was obtained in clinical trials at an initial dose 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. To determine the lowest effective dose for a particular patient, the daily dose should be adjusted to the clinical response. The average daily dose is usually 1000 to 2000 mg of valproate. Patients receiving daily doses exceeding 45 mg / kg they should remain under close observation. The continuation of the treatment of manic episodes in bipolar disorder should be adjusted individually so that the patient takes the lowest effective dose.