Valproic acid - instructions for use, dose, side effects, contraindications

	300 mg	500 mg
Active substances:
Valproic acid, in terms of sodium valproate	100.2000 mg	167.0000 mg
Valproate sodium	199.8000 mg	333.0000 mg
Excipients:
Magnesium aluminometasilicate	100.0000 mg	166.7000 mg
Giprolase	130.0000 mg	125.0000 mg
Silica colloidal dioxide	8.6000 mg	14.3300 mg
Magnesium stearate	4,600 mg	7.8300 mg
Uncoated tablet weight:	530.0000 mg	791.8600 mg
Shell composition:
Hypromellose E6	15.1620 mg	19.8000 mg
Titanium dioxide	5,0540 mg	6.6000 mg
Macrogol 6000	3,7905 mg	4.9500 mg
Talc	1.2635 mg	1.6500 mg
Weight of coated tablets	555.2700 mg	824.8600 mg

Description:

Oblong, biconvex tablets covered with a film coat of white or almost white color with a risk. On the cross section, the nucleus is white or almost white in color.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.G.01 Valproic acid

Pharmacodynamics:

Antiepileptic drug, which has central muscle relaxant and sedative effect.

It shows antiepileptic activity in various types of epilepsy.

The main mechanism of action, apparently,is associated with an increase in the content of gamma-aminobutyric acid (GABA) in the central nervous system (CNS) and the activation of GABA-ergic transmission.

Pharmacokinetics:

Absorption

The bioavailability of sodium valproate and valproic acid when administered is close to 100%.

When taking valproic acid at a dose of 1000 mg / day, the minimum plasma concentration (C_min) is 44.7 ± 9.8 μg / ml, and the maximum plasma concentration (C_mOh) is 81.6 ± 15.8 μg / ml. Time to reach the maximum plasma concentration (T_mOh) is 6.58 ± 2.23 hours. The equilibrium concentration (C_ss) is achieved within 3-4 days of regular intake of the drug.

The average therapeutic range of serum concentrations of valproic acid is 50-100 mg / l. If the need to achieve higher plasma concentrations is warranted, the ratio of expected benefits and the risk of side effects, especially dose-dependent, should be weighed carefully. at concentrations above 100 μg / ml, an increase in side effects is expected up to the development of poisoning. At a plasma concentration of more than 159 μg / ml, a dose reduction is required.

Distribution

The volume of distribution of valproic acid depends on age and is usually 0.13-0.23 l / kg body weight or, in young patients, 0.13-0.19 l / kg body weight. The connection with blood plasma proteins (mainly with albumin) is high, reaching 90-95%) and is dose-dependent and saturated. In elderly patients, patients with renal and hepatic insufficiency, the association with plasma proteins decreases. In severe form of renal failure, the concentration of the therapeutically active (free) valproic acid fraction may increase to 8.5-20%.

With hypoproteinemia, the total concentration of valproic acid (free and associated with plasma proteins of the fraction) may both not change or decrease because of an increase in the metabolism of the free valproic acid fraction.

Valproic acid penetrates into the cerebrospinal fluid and into the brain tissue. The concentration of valproic acid in cerebrospinal fluid is 10% of that in serum.

Valproic acid penetrates into breast milk. When C is reached_ss the concentration of valproic acid in breast milk is 1 to 10% of its serum concentration.

Metabolism

The metabolism of valproic acid is carried out in the liver by glucuronation, as well as beta, omega and omega₁-oxidation. More than 20 metabolites were detected. Metabolites formed after omega-oxidation have a hepatotoxic effect. Valproic acid does not induce enzymes that are part of the metabolic system of cytochrome P450: unlike most other antiepileptic drugs, valproic acid does not affect the intensity of both its own metabolism and the degree of metabolism of substances such as estrogens, progestogens and indirect anticoagulants.

Excretion

After conjugation with glucuronic acid and beta-oxidation valproic acid is excreted mainly by the kidneys. Less than 5% Valproic acid is excreted by the kidneys unchanged.

Plasma clearance of valproic acid in patients with epilepsy is 12.7 ml / min.

The half-life (T_1/2) is 15-17 hours. With simultaneous administration of valproic acid with antiepileptic drugs that induce microsomal enzymes of the liver, the plasma clearance of valproic acid increases, and T_1/2decreases, the severity of these changes depends on the degree of induction of microsomal liver enzymes by other antiepileptic drugs.

In case of an overdose, an increase in T_1/2up to 30 hours.

Hemodialysis is affected only by the free fraction of valproic acid in the blood (10%).

Other patient groups

The values of T_1/2the children over 2 months of age are close to those of adults.

In patients with manifestations of hepatic insufficiency T_1/2 valproic acid is increased.

With an increase in the volume of distribution of valproic acid in the third trimester of pregnancy, its renal and hepatic clearance increases. In this case, against the background of taking the drug at a constant dose, it is possible to reduce the serum concentrations of valproic acid. In pregnancy, the relationship of valproic acid with plasma proteins can change, which can lead to an increase in serum levels of the therapeutically active (free) valproic acid fraction.

Tablets of valproic acid in the form of prolonged action in comparison with the form, covered with an enteric coating, in equivalent doses are characterized by the following:

- absence of delayed intake after receiving;

- prolonged absorption;

- identical bioavailability;

- a smaller value of C_mOh (decrease in C_mOh by about 25%), but with a more stable plateau phase from 4 to 14 hours after administration;

- a more linear correlation between the dose and concentration of the drug in the blood plasma.

Indications:

Have adults:

- For the treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoclonic, atonic; Lennox-Gastaut syndrome (in monotherapy or in combination with other antiepileptic drugs);

- For the treatment of partial epileptic seizures: partial seizures with or without secondary generalization (in monotherapy or in combination with other antiepileptic drugs);

- For the treatment and prevention of bipolar affective disorders.

Have children

- For the treatment of partial epileptic seizures: partial seizures with or without secondary generalization (in monotherapy or in combination with other antiepileptic drugs).

Contraindications:

- Hypersensitivity to valproate sodium, valproic acid, semlariate valproate, valpromide or to any of the components of the drug;

- aboutsevere hepatitis;

- xRheumatic hepatitis;

- tsevere liver disease (especially drug-induced hepatitis) in the patient's and / or close blood relatives' anamnesis;

- tsevere liver damage with a fatal outcome when using valproic acid in close blood relatives of the patient;

- tsevere violations of the liver or pancreas;

- Phepatic porphyria;

- theestablished mitochondrial diseases caused by mutations of a nuclear gene encoding a mitochondrial enzyme γ-polymerase (POLG), for example, Alpers-Huttenlohera syndrome, and suspected disease-related diseases γ-polymerase, in children younger than 2 years of age (refers to the use of valproic acid dosage forms, which are intended for use by children) (see.section "Special instructions");

- Ppatients with established disorders of the carbamide cycle (urea cycle) (see section "Special instructions");

- aboutsimultaneous reception with mefloquine, with preparations of St. John's wort perfumed;

- dUp to 6 years of age (risk of falling into the airway during swallowing).

Carefully:

- Diseases of the liver and pancreas in history;

- pregnancy;

- congenital fermentopathy;

- oppression of bone marrow hemopoiesis (leukopenia, thrombocytopenia, anemia);

- renal failure (dose adjustment required);

- hypoproteinemia (see sections "Pharmacokinetics", "Method of administration and dose");

- simultaneous administration of several anticonvulsants (due to an increased risk of liver damage);

- simultaneous use of drugs that provoke convulsive seizures or reduce the threshold of convulsive readiness, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazine derivatives, butrofenone derivatives, chloroquine, bupropion, tramadol (risk of convulsive seizures);

- simultaneous administration of neuroleptics, monoamine oxidase (MAO) inhibitors, antidepressants, benzodiazepines (the possibility of enhancing their effects);

- simultaneous administration of phenobarbital, primidon, phenytoin, lamotrigine, zidovudine, felbamate, acetylsalicylic acid, indirect anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine, rubinamide (especially in children), protease inhibitors (lopinavir, ritonavir), colestyramine (in connection with a potential possibility of pharmacokinetic interaction at the level of metabolism or at the level of communication with plasma proteins may change the plasma concentrations of these drugs and / or valproic acid (see " Interaction with other drugs ");

- simultaneous administration of carbamazepine (increased risk of development of toxic effects of carbamazepine and a decrease in plasma concentrations of valproic acid);

- simultaneous administration of topiramate or acetazalomide (risk of encephalopathy);

- existing insufficiency carnitine palmitoyltransferase (CBT) type II (higher risk of rhabdomyolysis with valproic acid).

Pregnancy and lactation:

Fertility

In connection with the possibility of developing unwanted effects on the part of the endocrine system and genital organs in women(such as dysmenorrhea, amenorrhea, polycystic ovary, hyperandrogenism), fertility in women may be reduced (see section "Side effect").

In men valproic acid can reduce sperm motility and cause male infertility (see section "Side effect"). Fertility disorders are reversible after discontinuation of treatment.

Pregnancy

The risk associated with the development of epileptic seizures during pregnancy

During pregnancy, the development of generalized tonic-clonic epileptic seizures, epileptic status with the development of hypoxia may pose a risk to both the mother and the fetus in connection with the possibility of a lethal outcome.

The risk associated with the use of valproic acid during pregnancy

Experimental studies on the study of reproductive toxicity, conducted on laboratory mice, rats and rabbits, demonstrated the presence of teratogenic action in valproic acid.

Congenital malformations

The available clinical data confirm that in children born to mothers taking valproic acid during pregnancy,neuromuscular defects, craniofacial deformations, malformations of the limbs, cardiovascular system, hypospadias, as well as the development of multiple intrauterine malformations affecting various organ systems were observed.

Meta-analysis data showed that the incidence of congenital malformations in children born to mothers with epilepsy who received valproic acid monotherapy during pregnancy was 10.73% and is dose-dependent. The risk of these defects was: approximately 1.5 times higher, compared with monotherapy with phenytoin; approximately 2.3 times higher, as compared with monotherapy with carbamazepine or phenobarbital; approximately 3.7 times higher than lamotrigine monotherapy.

The available data suggest the existence of a relationship between intrauterine exposure to valproic acid and the risk of delayed development (in particular, a decline in the verbal IQ) in children born to mothers with epilepsy who took valproic acid during pregnancy. The delay in development is often combined with malformations and the phenomena of disability.However, in cases of developmental delay in these children, it is difficult to pinpoint the cause and effect relationship with valproic acid because of the possibility of simultaneous exposure to other factors such as a low level of intelligence of the mother or both parents; genetic, social factors, environmental factors; Inadequate treatment effectiveness aimed at preventing epileptic seizures in the mother during pregnancy.

Also reported on the development of various autistic disorders in children exposed to intrauterine effects of valproic acid.

Both valproic acid monotherapy and valproic acid combination therapy are associated with an unfavorable outcome of pregnancy, but according to available data, combined antiepileptic therapy including valproic acid is associated with a higher risk of adverse pregnancy outcome compared to valproic acid monotherapy (t the risk of fetal abnormalities is less when using valproic acid in monotherapy). The risk factors for the development of fetal malformations are: a dose of more than 1000mg / day (but a smaller dose does not exclude this risk) and the combination of valproic acid with other anticonvulsants.

In connection with the foregoing, the drug Valproic acid should not be used during pregnancy and in women with childbearing potential without extreme necessity. Its use is possible, for example, in situations where other antiepileptic drugs are not effective or the patient does not tolerate them.

The need to use the drug or the possibility of refusing its use should be decided before the drug is started or reviewed if the woman who is taking valproic acid is planning a pregnancy. Women with childbearing potential should use effective methods of contraception during treatment with valproic acid.

Women with childbearing potential should be informed of the risks and benefits of using valproic acid during pregnancy.

If a woman is planning a pregnancy or has a pregnancy diagnosed, the need to treat with valproic acid should be reassessed depending on the indications:

- when bipolar disorder is indicated, consideration should be given to discontinuing treatment with valproic acid;

- the indication is epilepsy, the issue of continued treatment with valproic acid or its abolition decided, after reassessment, the ratio of benefits and risks. If, after reassessment, the ratio of profit and risk of treatment with the drug should still continue during pregnancy, it is recommended to apply it in the lowest effective daily dose divided into several stages. It should be noted that in pregnancy it is preferable to use dosage forms of the sustained release preparation.

To reduce the risk of developing neural tube defects before pregnancy, folic acid (at a dose of 5 mg / day) should be started.

A special prenatal diagnosis should be carried out (including in the third trimester of pregnancy) to identify possible defects in the formation of the neural tube or other fetal malformations, including detailed ultrasound.

Risk for newborns

In newborns, whose mothers were taking valproic acid during pregnancy, development of single cases was noted:

- hemorrhagic syndrome associated with thrombocytopenia, hypofibrinogenemia and / or a decrease in the content of other coagulation factors. There have also been cases of fetal affinity with lethal outcome. This hemorrhagic syndrome should be distinguished from the vitamin K deficiency caused by phenobarbital and other inducers of microsomal liver enzymes. Therefore, in newborns born to mothers who received treatment with valproic acid during pregnancy, coagulation tests (determining the number of platelets in the peripheral blood, plasma fibrinogen concentration, clotting factors and coagulogram) should be performed;

- hypoglycemia in newborns whose mothers were taking valproic acid during the third trimester of pregnancy;

- hypothyroidism;

- withdrawal syndrome (the appearance of agitation, irritability, hyperreflexia, trembling, hyperkinesia, muscle tone disorders, tremors, seizures and difficulties with feeding).

Breastfeeding period

Excretion of valproic acid in breast milk is low, its concentration in milk is 1-10% of its serum concentration.

There are limited clinical data on the use of valproic acid during breastfeeding, and therefore its use during this period is not recommended.

Based on literature data and a small clinical experience, mothers may plan breastfeeding with valproic acid monotherapy, but the profile of side effects of the drug, especially the hematologic disorders caused by it, should be taken into account.

Dosing and Administration:

Inside, without crushing or chewing, with plenty of water. The daily dose is selected individually by the attending physician.

The drug "Valproic Acid" is intended only for adults and children over 6 years old with a body weight of more than 17 kg. This dosage form is not recommended for children under 6 years of age due to the risk of ingestion of the tablet in the respiratory tract during swallowing. To facilitate swallowing and taking an individually selected dose, the pill can be divided into several parts.

A drug Valproic acid is a tablet of prolonged action.

Delayed release avoids sudden increases in valproate concentrationacid in the blood plasma after administration and for a longer time maintains a constant concentration of valproic acid in the blood during the day.

Dosing regimen for epilepsy

It is necessary to select the minimum effective dose to prevent the development of epilepsy attacks, especially during pregnancy. The daily dose should be selected according to age and body weight. A stepwise (gradual) increase in the dose is recommended until the minimum effective dose is reached.

Due to the fact that there is no direct relationship between the daily dose, plasma concentrations and the therapeutic effect of the drug, the optimal dose is determined by the clinical response. Determining the concentration of valproic acid in blood plasma can serve as a supplement to clinical observation if epilepsy is not controlled or there is a suspicion of side effects. The range of therapeutic concentration of valproic acid in blood plasma is 40-100 μg / ml (300-700 μmol / l).

When monotherapy the initial dose is usually 5-10 mg of valproic acid per kg of body weight,which is gradually increased every 4-7 days at a rate of 5 mg valproic acid per kg body weight to the dose necessary to achieve control of epileptic seizures.

Average daily doses (with prolonged use):

- for children 6-14 years old (body weight 20-30 kg) - 30 mg of valproic acid per kg of body weight (600-1200 mg);

- for adolescents (body weight 40-60 kg) - 25 mg of valproic acid per kg of body weight (1000-1500 mg);

- for adults and elderly patients (body weight from 60 kg and above) - an average of 20 mg of valproic acid per kg of body weight (1200-2100 mg).

Despite the fact that calculating the daily dose of the drug takes into account the age and body weight of the patient, a wide range of individual sensitivity to valproate should be taken into account.

If epilepsy is not amenable to control when the above doses are prescribed, they can be increased by providing medical control over the patient's condition and determining the concentration of valproic acid in the blood plasma.

In some cases, the full therapeutic effect of valproic acid is not immediately apparent, but develops within 4-6 weeks. Given this circumstance, do not increase the daily dose above the recommended average daily dose before the specified time.

The daily dose of the drug can be divided into 1-2 administrations, preferably during meals.

One-time use of the drug is possible with well-controlled epilepsy. Most patients who are already taking valproic acid in the form of dosage forms neprolongirovannogo actions can be translated into sustained-release tablets (simultaneously or within a few days), the patients should take previously picked up the daily dose.

For patients who have previously taken other antiepileptic drugs, a gradual transfer to valproic acid is recommended for about 2 weeks. In this case, it is necessary to immediately reduce the dose of the antiepileptic drug previously taken, especially phenobarbital. Do not abruptly stop taking another antiepileptic drug.

Since other antiepileptic drugs can reversibly induce the activity of microsomal liver enzymes followed for 4-6 weeks after the last dose of anti-epileptic drugs monitor plasma concentrations of valproic acid, andif necessary (as the inducing metabolic effect of these drugs decreases), reduce the daily dose of valproic acid.

If necessary combinations of valproic acid with other antiepileptic drugs they should be added to the treatment gradually (see section "Interaction with other drugs").

Dosing regimen for manic episodes with bipolar disorders

Adults

The recommended initial daily dose is 750 mg. In clinical trials, the initial dose, which was 20 mg of sodium valproate per kg of body weight, also showed an acceptable safety profile.

Release forms with prolonged release can be taken 1 or 2 times a day. The dose of the drug should be increased as soon as possible until the minimum therapeutic dose is reached, which causes the desired clinical effect. The average daily dose is 1000-2000 mg of sodium valproate. Patients receiving a daily dose of more than 45 mg / kg should be under constant medical supervision.

Continuation of treatment of manic episodes in bipolar disorders should be carried out by taking an individually selected minimum effective dose.

Children and teens

The efficacy and safety of the use of valproic acid in the treatment of manic episodes in bipolar disorders in patients under the age of 18 years has not been studied.

The use of the drug in patients of special groups

Children and adolescents female, women with childbearing potential and pregnant women

Treatment with drug Valproic acid should be started under the supervision of a specialist with experience in the treatment of epilepsy and bipolar disorders. Treatment should be started only if other treatments are ineffective or not tolerated (see section "Use during pregnancy and during breastfeeding", "Special instructions"), and with regular review of treatment, the ratio of benefit and risk should be carefully re-evaluated . The use of valproic acid in monotherapy and at the lowest dosage and, if possible, in sustained release dosage forms is preferred. During pregnancy, the daily dose should be divided, at least, into 2 single doses.

Elderly patients

Although elderly patients have a change in the pharmacokinetics of valproic acid, they have limited clinical relevance,and the dose of valproic acid in elderly patients should be selected in accordance with the achievement of control over epileptic seizures.

Renal insufficiency and / or hypoproteinemia

In patients with renal insufficiency and / or hypoproteinemia, the possibility of increasing the concentration of the therapeutically active (free) valproic acid fraction in blood plasma should be considered, and, if necessary, to reduce the dose of valproic acid, focusing on the dose selection, mainly on the clinical picture, and not on the total content of valproic acid in the blood plasma (free fraction and fraction associated with blood plasma proteins), in order to avoid possible errors in the selection of a dose.

Side effects:

The incidence of adverse events following the use of the drug is classified according to WHO recommendations: very frequent - ≥10%; frequent - ≥1% and <10%; infrequent - ≥0.1% and <1%; rare - ≥0.01% and <0.1%; very rare - <0.01%; unknown frequency - based on available data, the frequency can not be estimated.

Congenital, hereditary and genetic disorders: teratogenic effect (see section "Application during pregnancy and during breast-feeding").

Benign, malignant and unspecified neoplasms (including cysts and polyps): rare - myelodysplastic syndrome.

Violations of the blood and lymphatic system: frequent - anemia, thrombocytopenia (see section "Special instructions"); infrequent - pancytopenia, leukopenia, neutropenia (leukopenia and pancytopenia can be with or without bone marrow depression.) After the drug is discontinued, the blood picture returns to normal); rare - disorders of bone marrow hemopoiesis, including isolated aplasia / hypoplasia of erythrocytes, agranulocytosis, macrocytic anemia, macrocytosis, reduction in the content of clotting factors (at least one), deviation from the norm of blood clotting parameters (such as increased prothrombin time, increased activated partial thromboplastin time , an increase in thrombin time, an increase in INR (the international normalized ratio) (see the sections on "Use during pregnancy and during pectorum th-feeding "," Cautions ").

The emergence of spontaneous ecchymosis and bleeding indicates the need to discontinue the drug and conduct a survey.

Disorders from the endocrine system: infrequent - the syndrome of inadequate secretion of antidiuretic hormone (SNSADG), hyperandrogenism (hirsutism, virilization, acne, alopecia in masculine type and / or increasing concentrations of androgens in the blood); rare - hypothyroidism (see the section "Application during pregnancy and during breastfeeding").

Disorders from the metabolism and nutrition: frequent - hyponatremia, weight gain (the dynamics of body weight should be carefully monitored, as its increase is a factor contributing to the development of the polycystic ovary syndrome); rare - hyperammonemia (isolated and moderate without changes in liver function parameters, which do not require discontinuation of treatment), as well as the occurrence of hyperammonemia accompanied by manifestations of neurologic symptoms: encephalopathy, vomiting, ataxia and other neurological symptoms - which required the discontinuation of valproic acid and additional examination ) (see section "Special instructions").

Disorders of the psyche: frequent - a state of confusion, hallucinations, aggressiveness^*), agitation^*), impaired attention, depression (when combining valproic acid with other anticonvulsant drugs); rare - behavioral disorders^*), psychomotor hyperactivity^*), impaired ability to learn^*), depression (with monotherapy with valproic acid).

Disturbances from the nervous system: very frequent - a tremor; frequent - extrapyramidal disorders, stupor^**), drowsiness, convulsions^**), memory impairment, headache, nystagmus; infrequent - coma^**), encephalopathy^**), lethargy^**), reversible parkinsonism, ataxia, paresthesia; rare - reversible dementia, combined with reversible cerebral atrophy, cognitive disorders; the unknown frequency is sedation.

Hearing disorders and labyrinthine disorders: frequent - reversible or irreversible deafness.

Disturbances on the part of the organ of sight: the unknown frequency is diplopia.

Vascular disorders: Frequent - bleeding and hemorrhage (see "Pregnancy and lactation", "Cautions."); infrequent - vasculitis.

Disturbances from the respiratory system, chest and mediastinal organs: infrequent - pleural effusion.

Disorders from the digestive system: very frequent - nausea; frequent - vomiting, gum changes (mainly, gingival hyperplasia), stomatitis, epigastric pain, diarrhea, which often occur in some patients at the beginning of treatment, but usually disappear after a few days and do not require discontinuation of therapy (frequent reactions from the side of the digestive system can be reduced by taking the drug during or after a meal); infrequent - pancreatitis, sometimes with a fatal outcome (development of pancreatitis is possible during the first 6 months of treatment.) In case of acute pain in the abdomen, it is necessary to control the activity of serum amylase, see section "Special instructions"); unknown frequency - abdominal cramps, anorexia, increased appetite.

Disturbances from the liver and bile ducts: frequent - liver damage: deviation from the norm of indicators of the functional state of the liver, such as a decrease in the prothrombin index, especially in combination with a significant decrease in fibrinogen and clotting factors, an increase in the concentration of bilirubin and an increase in the activity of "liver" transaminases in the blood; liver failure,in exceptional cases, fatal; it is necessary to monitor patients for the development of possible violations of liver function (see section "Special instructions").

Disturbances from the skin and subcutaneous tissues: frequent reactions hypersensitivity (urticaria, pruritus), alopecia (transient and / or dose-dependent), including androgenic alopecia against the background of developed hyperandrogenism, polycystic ovary and alopecia against the background of developed hypothyroidism, disorders of the nails and the nail bed; infrequent - angioedema, rash, hair disorders (normal hair structure, hair color change, abnormal hair growth - disappearance of waviness and curly hair or, conversely, the appearance of curly hair in persons with initially straight hair), hirsutism, acne; rare - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, rash syndrome with eosinophilia and systemic symptoms (DRESS syndrome).

Disturbances of musculoskeletal and connective tissue: infrequent - reduction of bone mineral density, osteopenia,osteoporosis and fractures in patients taking valproic acid for a long time (the mechanism of the influence of valproic acid on the metabolism of bone tissue is not established); rare - systemic lupus erythematosus (see section "Special instructions"), rhabdomyolysis (see sections "With caution", "Special instructions").

Disorders from the kidneys and urinary tract: infrequent - renal failure; rare - enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (complex of biochemical and clinical manifestations of affection of proximal renal tubules with violation of tubular reabsorption of phosphate, glucose, amino acids and bicarbonate), the mechanism of development of which is not yet known.

Violations of the genitals and mammary gland: frequent - dysmenorrhea; infrequent - amenorrhea; rare - male infertility, polycystic ovary; unknown frequency - irregular menstruation, breast enlargement, galactorrhea.

General disorders: infrequent - hypothermia, not severe peripheral edema.

Laboratory and instrumental data: rare - biotin deficiency / biotinidase deficiency.

^*) Undesirable reactions, mainly observed in patients of childhood.

^**)Stupor and lethargy sometimes lead to transient coma / encephalopathy and were either isolated, or combined with increased frequency of seizures against the background of treatment, and also decreased with withdrawal of the drug or with a decrease in its dose. Most of these cases have been described against a background of combined therapy, especially with the simultaneous use of phenobarbital or topiramate, or after a sharp increase in the dose of valproic acid.

Overdose:

Symptoms

Clinically acute massive overdose usually occurs in the form of coma with muscle hypotension, hyporeflexia, miosis, respiratory depression, metabolic acidosis, excessive lowering of blood pressure and vascular collapse / shock. Single cases of intracranial hypertension associated with edema of the brain were described.

The presence of sodium in the composition of valproic acid preparations during their overdose can lead to the development of hypernatremia.

With a massive overdose, a lethal outcome is possible, but usually the prognosis is favorable.

Symptoms of overdose may vary, reported on the development of convulsive seizures with very high plasma concentrations of valproic acid.

Treatment

Emergency hospital care should be as follows: gastric lavage, which is effective within 10-12 hours after taking the drug. To reduce the absorption of valproic acid, it may be effective to administer activated carbon, including its administration through a nasogastric tube. It is required to monitor the state of the cardiovascular and respiratory systems and maintain an effective diuresis, it is necessary to monitor the functions of the liver and pancreas. If breathing is depressed, artificial ventilation may be required. In some cases, a positive effect was given by naloxone. In very severe cases, hemodialysis and hemoperfusion are used.

Interaction:

The effect of valproic acid on other drugs

Neuroleptics, MAO inhibitors, antidepressants, benzodiazepines

Valproic acid may enhance the effect of other psychotropic medications: neuroleptics, MAO inhibitors, antidepressants and benzodiazepines - in case of their simultaneous use, careful medical supervision and, if necessary, dose adjustment, are indicated.

Lithium preparations

Valproic acid does not affect serum lithium concentrations.

Phenobarbital

Valproic acid increases the plasma concentrations of phenobarbital (due to a decrease in its hepatic metabolism), in connection with which the development of sedative action of the latter, especially in children, is possible. It is recommended that the patient be constantly monitored during the first 15 days of combined therapy, with an immediate reduction in the dose of phenobarbital in case of sedation and, if necessary, determination of plasma concentrations of phenobarbital.

Primidone

Valproic acid increases plasma concentrations of primidone with an increase in its side effects (such as sedation); with long-term treatment, these symptoms disappear. Clinical monitoring of patients is recommended, especially at the onset of combination therapy, if necessary, with a primidone dose adjustment.

Phenytoin

Valproic acid reduces the total plasma concentrations of phenytoin. Besides, valproic acid increases the concentration of the free fraction of phenytoin with the possibility of developing symptoms of an overdose (by displacing phenytoin from the connection with plasma proteins and slowing its hepatic catabolism).It is recommended to closely monitor the patient and determine the concentrations of phenytoin and its free fraction in the blood plasma.

Carbamazepine

With the simultaneous use of valproic acid and carbamazepine, the occurrence of clinical manifestations of carbamazepine toxicity has been reported, valproic acid can potentiate the toxic effects of carbamazepine. It is recommended to closely monitor the patient's condition, especially at the beginning of the combination therapy, and if necessary, adjust the dose of carbamazepine.

Lamotrigine

Valproic acid slows the metabolism of lamotrigine in the liver and increases its T_1/2almost 2 times. This interaction can lead to an increase in the toxicity of lamotrigine, in particular, to the development of severe skin reactions, including toxic epidermal necrolysis. A thorough clinical observation and, if necessary, a correction (reduction) of the dose of lamotrigine is recommended.

Zidovudine

Valproic acid increases plasma concentrations of zidovudine, which leads to an increase in toxicity of the latter.

Felbamat

Valproic acid can reduce the average clearance value of felbamate by 16%.

Olanzapine

Valproic acid can reduce plasma concentrations of olanzapine.

Rufinamide

Valproic acid can lead to an increase in the plasma concentration of rubinamide. This increase depends on the concentration of valproic acid in the blood plasma. Care must be taken, especially in children. this effect is more pronounced in this population.

Nimodipine (for oral administration and, for extrapolation, solution for parenteral administration)

Strengthening the hypotensive effect of nimodipine due to an increase in its plasma concentration (inhibition of the metabolism of nimodipine by valproic acid).

Temozolomide

The simultaneous administration of temozolomide with valproic acid leads to a mild, but statistically significant, decrease in the clearance of temozolomide.

Propofol

Valproic acid can lead to an increase in plasma concentrations of propofol. Consideration should be given to reducing the dose of propofol when it is used concomitantly with valproic acid.

The effect of other drugs on valproic acid

Antiepileptic drugs capable of inducing microsomal liver enzymes (including phenytoin, phenobarbital, carbamazepine)

Reduce plasma concentrations of valproic acid. In the case of combination therapy, a dose adjustment of valproic acid is required depending on the clinical response of the organism and the concentration of valproic acid in the blood plasma. The concentration of valproic acid metabolites in the blood plasma can be increased if it is used simultaneously with phenytoin or phenobarbital. Therefore, patients receiving treatment with these two drugs should be carefully monitored for signs and symptoms of hyperammonemia, some metabolites of valproic acid can inhibit the enzymes of the carbamide cycle (urea cycle).

Felbamat

When combined with felbamate and valproic acid, the clearance of valproic acid is reduced by 22-50% and, correspondingly, plasma concentrations of valproic acid are increased. Plasma concentrations of valproic acid should be monitored.

Meflokhin

Meflokhin accelerates the metabolism of valproic acid and is itself capable of causing seizures,therefore, with their simultaneous application, it is possible to develop an epileptic fit.

Preparations of St. John's Wort

With the simultaneous use of valproic acid and preparations of St. John's wort, it is possible to reduce the anticonvulsant effect of valproic acid.

Drugs that have a high and strong bond with blood plasma proteins (acetylsalicylic acid)

With simultaneous application with valproic acid, an increase in the concentration of the free valproic acid fraction is possible.

Cimetidine, erythromycin

Serum concentrations of valproic acid may increase in the case of simultaneous application of cimetidine and erythromycin (as a result of a slowing of its hepatic metabolism).

Indirect anticoagulants, including warfarin and other coumarin derivatives

With the simultaneous use of valproic acid and indirect anticoagulants, careful monitoring of the prothrombin index is required.

Carbapenems (panipenem, meropenem, imipenem)

Causes rapid and intensive decrease in the concentration of valproic acid in blood plasma by 60-100% for 2 days of joint therapy, which sometimes leads to seizures.Carbapenems should not be used concomitantly in patients with a selected dose of valproic acid. If carbapenem treatment can not be avoided, careful monitoring of plasma concentrations of valproic acid should be carried out.

Rifampicin

Rifampicin lowers plasma concentrations of valproic acid, leading to a loss of its therapeutic effect. Therefore, it may be necessary to increase the dose of valproic acid with simultaneous application of rifampicin.

Inhibitors of proteases

Protease inhibitors, such as lopinavir, ritonavir, reduce the plasma concentration of valproic acid with simultaneous use with it.

Kolestyramine

Kolestiramin can lead to a decrease in plasma concentrations of valproic acid with simultaneous use with it.

Other interactions

Topiramate or acetazolamide

The simultaneous use of valproic acid and topiramate or acetazolamide was associated with encephalopathy and / or hyperammonemia. Patients are advised to be under careful medical supervision for the development of hyperammonemic encephalopathy.

Quetiapine

The simultaneous use of valproic acid and quetiapine may increase the risk of developing neutropenia / leukopenia.

Estrogen-progestogen preparations

Valproic acid does not have the ability to induce liver enzymes, and therefore does not reduce the effectiveness of estrogen-progestogen drugs in women using hormonal methods of contraception.

Ethanol and other potentially hepatotoxic drugs

With their combined use, it is possible to increase the hepatotoxic effect of valproic acid.

Clonazepam

Simultaneous application can result in occasional increases in the expression of the absences status.

Myelotoxic drugs

With simultaneous use, the risk of oppression of bone marrow hematopoiesis is increased.

Special instructions:

Before starting valproic acid and periodically during the first 6 months of treatment, especially in patients at risk of developing liver disease, liver function tests should be performed.

As with most antiepileptic drugs, when using valproic acid,there may be a slight increase in the activity of "hepatic" enzymes, especially at the beginning of treatment, which occurs without clinical manifestations and is transient. These patients need to conduct a more detailed study of biological indicators, including a prothrombin index, may also require a dose adjustment, and if necessary, a repeated clinical and laboratory examination.

Before the start of therapy or before surgery, with spontaneous subcutaneous hematoma or bleeding, it is recommended to determine the time of bleeding, the number of elements in the peripheral blood, including platelets.

Severe liver damage

Predisposing factors

Clinical experience has shown that patients at risk are:

- patients receiving simultaneously several antiepileptic drugs;

- children younger than 3 years of age with severe convulsive seizures, especially against the background of brain damage, mental retardation and / or congenital metabolic or degenerative diseases;

- patients taking salicylates concomitantly (salicylates are metabolized along the same metabolic pathway as valproic acid).

Typically, liver damage occurs during the first 6 months of treatment, usually between 2 and 12 weeks of treatment and is usually observed with the use of valproic acid as part of a combination antiepileptic therapy. Upon reaching children of 3 years of age, the risk of developing liver damage is significantly reduced and progressively decreases as the patient's age increases.

Symptoms Suspected of Liver Damage

For early diagnosis of liver damage, clinical monitoring of patients is mandatory. In particular, attention should be paid to the appearance of the following symptoms, which may precede the onset of jaundice, especially in patients at risk:

- nonspecific symptoms, especially those that started suddenly, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain;

- resumption of convulsive seizures in patients with epilepsy.

It is necessary to warn patients or members of their families (when the drug is used by children)that they should immediately inform the attending physician about the occurrence of any of the above symptoms. Patients should immediately carry out a clinical examination and a laboratory study of liver function indicators.

Identify

Determination of functional liver samples should be performed before treatment and then periodically during the first 6 months of treatment. The most informative are studies that reflect the state of protein-synthetic liver function, especially the prothrombin index. The deviation from the norm of the prothrombin index, especially in combination with deviations from the norm of other laboratory indicators (a significant decrease in fibrinogen and clotting factors, an increase in bilirubin concentration and an increase in the activity of "liver" transaminases), and the appearance of other symptoms indicative of liver damage (see. above), requires the discontinuation of valproic acid. For the purpose of precaution, if patients receive concomitant salicylates, their administration should also be discontinued.

Pancreatitis

There are registered rare cases of severe forms of pancreatitis in children and adults developing regardless of age and duration of treatment.Several cases of hemorrhagic pancreatitis have been observed with a rapid progression of the disease from the first symptoms to the fatal outcome.

Severe convulsions, concomitant neurological disorders and anticonvulsant therapy may be risk factors for pancreatitis. Liver failure in combination with pancreatitis increases the risk of death.

Children are at increased risk for developing pancreatitis, but with increasing age, this risk is reduced.

Patients who experience severe abdominal pain, nausea, vomiting, and / or anorexia should be examined immediately. In case of confirmation of pancreatitis, in particular, with increased activity of pancreatic enzymes in the blood, the use of valproic acid should be discontinued and appropriate treatment prescribed.

Suicidal thoughts and attempts

There have been reports of suicidal thoughts and attempts in patients taking antiepileptic drugs for certain indications.

A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs showed,that on the background of taking drugs in patients, there is an increased risk of suicidal thoughts and attempts by 0.19% (including an increase of 0.24% in patients taking antiepileptic drugs for epilepsy), compared with their frequency in patients taking a placebo . The mechanism of this effect is unknown.

Patients taking valproic acid should be monitored continuously for suicidal thoughts or attempts, and, if they occur, appropriate treatment should be provided. Patients and caregivers when suicidal thoughts or attempts should immediately contact the doctor in charge.

Women with childbearing potential, pregnant women

The drug should not be used in children and adolescent females, women with childbearing potential and pregnant women, unless alternative treatments are ineffective or not tolerated. This limitation is associated with a high risk of teratogenic effects and mental and physical developmental disorders in children who have been in utero exposed to valproic acid.

The benefit / risk ratio should be carefully reassessed in the following cases: during regular revision of treatment, when the girl achieves puberty and, as a matter of urgency, in the case of planning or pregnancy from a woman taking valproic acid.

During treatment with valproic acid, women with childbearing potential should use reliable methods of contraception, and they should be informed about the risks associated with taking the drug during pregnancy (see section "Use during pregnancy and during breastfeeding"). To help the patient understand these risks, the doctor who prescribes valproic acid should provide the patient with information about the risks associated with taking the drug during pregnancy.

In particular, the physician prescribing valproic acid should make sure that the patient understands:

- the nature and magnitude of the risks associated with the use of valproic acid during pregnancy, particularly the risks of teratogenic effects, as well as the risks of mental and physical developmental disorders;

- the need to use effective contraception;

- the need for regular revision of treatment;

- the need for urgent consultation with his or her attending physician if she suspects she has become pregnant, or when she suggests the possibility of pregnancy. A woman planning a pregnancy should definitely try, if possible, to switch to alternative treatment before she attempts to conceive (see "Application in pregnancy and during breastfeeding").

Treatment with valproic acid should be continued only after a doctor who has experience in the treatment of epilepsy and bipolar disorders, will reassess her the relationship between benefit and risks from treatment.

Carbapenems

Simultaneous use of carbapenems is not recommended (see section "Interaction with other drugs").

Patients with established mitochondrial diseases or suspected of them

Valproic acid can initiate or weight the manifestations of the patient's mitochondrial diseases caused by mitochondrial DNA mutations, as well as the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG).In particular, in patients with congenital neurometabolic syndromes caused by mutations of a gene encoding γ-polymerase (POLG); e.g., in patients with syndrome, Alpers Huttendohera using valproic acid associated higher incidence of acute liver failure and liver disease related deaths. Diseases caused by defects γpolymerase may be suspected in patients with a family history of such diseases or symptoms suggestive of their availability, including unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus, delayed mental and physical development, psychomotor regression axonal sensorimotor neuropathy, myopathy , ophthalmoplegia or complicated migraine with visual (occipital aura) and others. In accordance with current clinical practice for the diagnosis of such diseases must be straight lead testing for gene mutations in the polymerase (POLG) (see. section "Contraindications").

Renal insufficiency

In renal failure may require dose reduction of valproic acid due to the increase in the concentration of its free fractions in plasma.If it is not possible to monitor plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient.

Insufficiency of urea enzymes (urea cycle)

When suspicion of the insufficiency of the enzymes of the carbamide cycle, the use of valproic acid is contraindicated. Such patients described several cases of hyperammonemia accompanied by a stupor or coma. In these cases, metabolic studies should be performed prior to the initiation of valproic acid therapy (see "Contraindications").

In children with unexplained gastrointestinal symptoms (anorexia, vomiting, cytolysis cases), lethargy or coma in a history, with mental retardation or a family history of death of a newborn or child, studies of metabolism should be conducted prior to the initiation of valproic acid therapy, determination of ammonia (the presence of ammonia and its compounds in the blood) on an empty stomach and after eating (see "Contraindications").

Patients with systemic lupus erythematosus

Although it is shown,that in the course of treatment with valproic acid, immune system dysfunctions are extremely rare, and the potential benefit of using it should be compared with the potential risk in appointing valproic acid to patients with systemic lupus erythematosus.

Weight gain

Patients should be warned about the risk of weight gain at the beginning of treatment, and measures, mostly dietary, should be taken to minimize this phenomenon.

Patients with diabetes mellitus

Given the potential for adverse effects of valproic acid on the pancreas, the use of the drug in patients with diabetes should carefully monitor the concentration of glucose in the blood. In the study of urine for the presence of ketone bodies in patients with diabetes mellitus, it is possible to obtain false-positive results, since valproic acid is excreted by the kidneys, partially in the form of ketone bodies.

Patients, infected with the human immunodeficiency virus (HIV)

In studies in vitro it was found that valproic acid stimulates HIV replication under certain conditions. The clinical significance of this fact is unknown.In addition, the significance of these data is not established for patients receiving the maximum suppressive antiretroviral therapy. However, these data should be taken into account when interpreting the results of continuous monitoring of viral load in HIV-infected patients taking valproic acid.

Patients with existing insufficiency carnitine palmitoyltransferase (CBT) type II

Patients with existing type II CPT deficiency should be warned about a higher risk of developing rhabdomyolysis with valproic acid.

Ethanol

During treatment with valproic acid, the use of ethanol is not recommended.

Other special instructions

Inert matrix of the preparation Valproic acid prolonged action of communication with the nature of its excipients is not absorbed in the digestive tract; After the release of the active substances, the inert matrix is excreted with caloric masses.

Effect on the ability to drive transp. cf. and fur:

When taking valproic acid, patients should be warned about the potential for developing drowsiness, especially if combined anticonvulsant therapy is used or when valproic acid is combined with benzodiazepines(see section "Interaction with other drugs"). In connection with the above, patients should be especially careful in situations where a fast psychomotor reaction may be required.

Form release / dosage:

Tablets with prolonged release, film-coated, 300 mg and 500 mg.

Packaging:

For 10 tablets in a planar cell package.

For 20, 30, 40, 50 or 100 tablets in a polymer canister for medicines with the control of the first opening, sealed with a cap with silica gel.

1, 2, 3, 4, 5, 6 or 10 contour mesh packages of polyvinylchloride / polyvinylidene chloride film and aluminum foil printed lacquered along with instruction for use in a cardboard package.

On 1 bank together with the instruction on application in a pack from a cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004165

Date of registration:28.02.2017

Expiration Date:28.02.2022

The owner of the registration certificate:Life Sainses OHCFLife Sainses OHCF Russia

Manufacturer: & nbsp

OBNINSKAYA CHEMICAL - PHARMACEUTICAL COMPANY, CJSC Russia

Information update date: & nbsp31.03.2017

Illustrated instructions

Instructions

Valproic acid (Valproic acid)