Depakin Enteric 300 - instructions for use, dose, side effects, contraindications

sheath: methacrylic acid and methyl methacrylate copolymer (1: 1) - approx. 19.63 mg, talc - approx. 19.63 mg, Oprasprey white * (type K1-7000) - approx. 17.79 mg, cellacephate (cellulose acetate phthalate) - approx. 23.22 mg, diethylphthalate - approx. 9.73 mg.

* - Opraspray white: titanium dioxide - 17.50 mg, giprolose - 0.29 mg.

Description:

Round, biconvex tablets, coated with a coat of white.

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 the action of valproic acid on the GABA -ergic system: increases the content of gamma-aminobutyric acid (GABA) incentral nervous system (CNS) and activates GABA-ergic transmission.

Pharmacokinetics:

Absorption

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

The average therapeutic range of serum concentrations is 50-100 mg / l. If the need to achieve higher plasma concentrations is warranted, the ratio of expected benefit and the risk of side effects, especially dose-dependent, should be carefully weighed, since at concentrations of valproic acid of more than 100 mg / l, an increase in side effects is expected until the development of intoxication. With a plasma concentration of valproic acid above 150 mg / l, a dose reduction is required.

With the course of taking the drug, the equilibrium concentration of valproic acid in the serum is reached within 3-14 days.

Distribution

The volume of distribution depends on the age and is usually 0.13-0.23 l / kg of mass body or in young people 0,13-0,19 l / kg body weight.

The association with blood proteins of valproic acid (mainly with albumin) is high (90-95%), dose-dependent and saturable.

In elderly patients, patients with renal and hepatic insufficiency the association with plasma proteins is reduced.

In severe renal failure the concentration of the free (therapeutically active) fraction of valproic acid can be increased to 8.5-20%.

With hypoproteinemia the total concentration of valproic acid (free + protein-bound fraction) may not change, but may also decrease due to an increase in the metabolism of free (not protein-bound) valproic acid fractions.

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

Valproic acid penetrates into the breast milk of nursing mothers. In the state of achieving an equilibrium concentration of valproic acid in the serum, its concentration in breast milk is up 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 omega-1 oxidation. More than 20 metabolites have been identified, metabolites after omega-oxidation have a hepatotoxic effect.

Valproic acid does not have an inducing effect on the enzymes that enter the metabolic system of cytochrome P450: unlike most other antiepileptic drugs, valproic acid does not affect the extent of both its own metabolism and the degree of metabolism of other substances, such as estrogens, progestogens and indirect anticoagulants.

Excretion

Valproic acid is mainly excreted by the kidneys after conjugation with glucuronic acid and beta-oxidation. Plasma clearance of valproic acid in patients with epilepsy is 12.7 ml / min.

The half-life is 15-17 hours. When combined with antiepileptic drugs that induce microsomal enzymes of the liver, the plasma clearance of valproic acid increases, and the half-life decreases, the degree of their change depends on the degree of induction of microsomal liver enzymes with other antiepileptic drugs.

Half-life in children over 2 months of age is close to that in adults.

In patients with liver disease, the half-life of valproic acid increases.

With an overdose, an increase in the half-life of up to 30 hours was observed.

Only free valproic acid in the blood is subject to hemodialysis (10%).

Peculiarities of pharmacokinetics in pregnancy

With an increase in the distribution of valproic acid in the third trimester of pregnancy, its renal and hepatic clearance increases. In this case, despite taking the drug in a constant dose, it is possible to decrease the serum concentration of valproic acid. In addition, during pregnancy, the relationship of valproic acid with plasma proteins can change, which may lead to an increase in the serum content of the free (therapeutically active) fraction of valproic acid.

Indications:

In adults:

as a monotherapy or in combination with other antiepileptic drugs:

- for the treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoclonic, atonic, Lennox-Gastaut syndrome;

- for the treatment of partial epileptic seizures: partial seizures with or without secondary generalization.

Children:

as a monotherapy or in combination with other antiepileptic drugs:

- for the treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoclonic, atonic, Lennox-Gastaut syndrome;

- for the treatment of partial epileptic seizures: partial seizures with or without secondary generalization;

- prevention of seizures at high temperature, when such prophylaxis is necessary.

Contraindications:

- Hypersensitivity to valproate sodium, valproic acid, valproate semitriya, valpromidu or to any of the components of the drug;

acute hepatitis;

- chronic hepatitis;

- severe liver disease (especially drug-induced hepatitis) in a history of the patient and / or his close blood relatives;

- severe liver damage with lethal outcome when using valproic acid in close blood relatives of the patient;

- severe violations of the liver or pancreas;

- hepatic porphyria;

- established mitochondrial diseases caused by mutations of the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG), e.g., Alpers syndrome-Huttenlohera and suspected diseases caused by defects γ-polymerase in children under two years of age (relates to the use of dosage forms Depakin® preparation which are designed for receiving children) (see "Special instructions.");

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

- hemorrhagic diathesis, thrombocytopenia;

- combination with mefloquine;

- combination with preparations of St. John's wort;

- Children under 6 years of age (risk of falling into the airway during swallowing).

Carefully:

- In diseases of the liver and pancreas in anamnesis.

- during pregnancy;

- with congenital fermentopathy;

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

- with renal failure (dosage correction is required);

- with hypoproteinemia;

- with simultaneous reception of several Panticonvulsants (due to an increased risk of liver damage);

- with 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, butterophenone derivatives, chloroquine, bupropion, tramadol (risk of provoking convulsive seizures);

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

- with 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), colostiramine (in connection with pharmacokinetic interactions at the level of metabolism or at the level of communication with blood plasma proteins, a change in the plasma concentrations of either these drugs and / or valproic acid, section "Interaction with other drugs");

- with the simultaneous use of carbamazepine (the risk of potentiating the toxic effects of carbamazepine and reducing the plasma concentration of valproic acid);

- with simultaneous application of topiramate or acetazolamide (risk of encephalopathy);

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

Pregnancy and lactation:

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 particular risk for both the mother and the fetus, in connection with the possibility of a lethal outcome. The risk associated with the use of the drug Denikin® enteric 300 during pregnancy. Experimental studies of reproductive toxicity, conducted in mice, rats and rabbits, demonstrated the presence of teratogenic action in valproic acid.

Congenital malformations

The available clinical data demonstrated a high incidence of small and severe developmental defects, in particular, neural tube defects, craniofacial deformities, developmental limb and cardiovascular malformations, hypospadias, and multiple malformations affecting various organ systems in children , born to mothers who took valproic acid during pregnancy, compared with their frequency when taking a number of other antiepileptic drugs during pregnancy. So the risk of congenital malformations in children,born in mothers with epilepsy, who received monotherapy with valproic acid during pregnancy, was approximately 1.5, 2.3, 2.3 and 3.7 times higher, compared with monotherapy with phenytoin, carbamazepine, phenobarbital and lamotrigine, respectively.

The meta-analysis data, including register and cohort studies, showed that the incidence of congenital malformations in children born to mothers with epilepsy who received monotherapy with valproic acid during pregnancy was 10.73% (95% confidence interval of 8.16- 13.29). This risk is greater than the risk of severe congenital malformations in the general population of 2-3%. This risk is dose-dependent, but it is not possible to establish a threshold dose below which there is no such risk.

Disorders of mental and physical development

It is shown that the intrauterine effect of valproic acid can have undesirable effects on the mental and physical development of children exposed to such effects. Apparently, this risk is dose-dependent, but it is not possible to establish a threshold dose below which there is no such risk.The exact gestational period for the risk of these effects is not established, and the risk is not excluded throughout the pregnancy.

Studies of pre-school children exposed to intrauterine effects of valproic acid showed that up to 30-40% of such children had early developmental delays (such as delayed walking and speech retardation), and lower intellectual abilities, poor speech skills (their own speech and understanding of speech) and memory problems.

The coefficient of mental development (IQ index), determined in children aged 6 years with a history of intrauterine exposure to swelling of rue acid, was on the average 7-10 points lower than in children exposed to the uterine effect of other antiepileptic drugs. Although the role of other factors that could undesirably affect the intellectual development of children exposed to the intestinal effects of valproic acid can not be ruled out, it is obvious that in such children the risk of intellectual disturbances may be independent of the mother's IQ index.

Data on long-term outcomes are limited.

There is evidence to suggest that children exposed to intrauterine effects of valproic acid have an increased risk of developing a spectrum of autistic disorders (approximately a three to fivefold increase in risk), including childhood autism. Limited data suggest that children who have been exposed in utero to valproic acid have a high likelihood of developing Attention Deficit / Hyperactivity Disorder (ADHD). 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 there is a risk of developing fetal abnormalities less when using valproic acid in monotherapy).

The risk factors for the development of fetal malformations are: a dose of more than 1000 mg / day (however, a lower dose does not exclude this risk) and the combination of valproic acid with other anticonvulsant drugs.

In connection with the above, the drug Depakin® enteric 300 should not be used in pregnancy and in women with childbearing potential without extreme necessity, that is, its use is possible in situations where other antiepileptic drugs are ineffective or the patient does not tolerate them. The need to use the drug Depakin® enteric 300 or the possibility of refusing its use should be decided before the drug is started or revised if the woman taking the drug Depakin® enteric 300, is planning a pregnancy.

Women with childbearing potential should use effective contraceptive methods during treatment with Depakin® enteric 300.

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

If a woman with epilepsy is planning a pregnancy, or has a pregnancy, then a valuation of the need for valproic acid should be reassessed. The question of continuing treatment with valproic acid or its withdrawal is decided after a reassessment of the ratio of benefit and risk.If, after a reassessment of the benefit-risk ratio, treatment with Depakin®, enteric 300 should still be continued during pregnancy, then it is recommended to apply it in the minimum effective daily dose divided into several methods. It should be noted that during pregnancy, the use of dosage forms of the sustained release preparation is more preferable than other dosage forms. Additionally, if possible before the onset of pregnancy, you should start taking folic acid (at a dose of 5 mg per day), since folic acid can reduce the risk of developing neural tube defects. However, the data available at present do not confirm its preventive action against congenital malformations arising from the action of valproic acid. A special prenatal diagnosis should be carried out (including in the third trimester of pregnancy) to detect possible defects in the formation of the neural tube or other fetal malformations "including detailed ultrasound.

Risk for newborns

There have been reports of the development of single cases of hemorrhagic syndrome in newborns whose mothers took valproic acid during pregnancy. This hemorrhagic syndrome is associated with thrombocytopenia, hypofibrinogenemia and / or a decrease in the content of other coagulation factors. Also reported on the development of afibrinogenemii, which could lead to death. This hemorrhagic syndrome should be distinguished from the vitamin K deficiency caused by phenobarbital and other inducers of microsomal liver enzymes.

Therefore, in newborns whose mothers received treatment with valproic acid during pregnancy, coagulation tests (determine the number of platelets in the peripheral blood, plasma fibrinogen concentration, clotting factors and coagulogram) should be performed. Reported cases of hypoglycemia in newborns, whose mothers were taking valproic acid during the third trimester of pregnancy. Hypothyroidism was reported in newborns whose mothers took valproic acid during pregnancy.In newborns whose mothers took valproic acid in the last trimester of pregnancy, withdrawal can occur (in particular, the appearance of agitation, irritability, hyperreflexia, tremor, hyperkinesia, muscle tone disorders, tremors, seizures and difficulty feeding).

Fertility

In connection with the possibility of developing dysmenorrhea, amenorrhea, polycystic ovaries, an increase in the concentration of testosterone in the blood, fertility in women may decrease (see the "Side effect" section). In men valproic acid can reduce sperm motility and impair fertility (see section "Side effect"). It is established that these violations of fertility are reversible after discontinuation of treatment.

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 in breastfeeding, and therefore the use of the drug in this period is not recommended. Based on literature data and a small clinical experience,you can consider breastfeeding with monotherapy with Depakin® enteric 300, but you should take into account the profile of the side effects of the drug, especially the hematologic disorders caused by it.

Dosing and Administration:

This dosage form is not recommended for children under 6 years of age (risk of ingestion of the tablet in the respiratory tract when swallowed). Children under 11 years of age are advised to use a medicinal form - oral syrup.

Depakin® enteric 300 is intended for oral administration, preferably during meals.

The dose should be selected taking into account the age and body weight of the patient.

In monotherapy, the initial daily intake for adults and children is usually 5-10 mg / kg, then it is increased by 5 mg / kg every 4-7 days until a dose with an optimal effect is achieved.

Average daily dose:

- for children 6-14 years old (body weight 25-40 kg) - 30 mg / kg body weight (600-1200 mg);

- for adolescents 14-18 years (body weight 40-60 kg) - 25 mg / kg body weight (1000-1500 mg);

- for adults (body weight from 60 kg and above) - 20 mg / kg body weight (1200-2100 mg).

The daily dose is recommended to be divided into 2-3 doses.

The average daily dose can be increased by monitoring the concentration of valproic acid in the blood.

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

For patients who have previously taken antiepileptic drugs, the transfer to the drug Depakin® enteric 300 should be carried out gradually, reaching the optimal dose of the drug for about 2 weeks. At the same time, the dose of an antiepileptic drug previously taken, especially phenobarbital, is immediately reduced. If previously taken antiepileptic drug is canceled, then its cancellation should be carried out gradually.

Since other antiepileptic drugs can reversibly induce microsomal liver enzymes, monitor the concentrations of valproic acid in the blood within 4-6 weeks after the last dose of these antiepidemic drugs and, if necessary (as the metabolic-inducing effect of these drugs decreases), reduce the daily dose valproic acid.

The use of the drug in patients of special groups

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

Treatment with Depakin® Enteric 300 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 types of treatment are ineffective or not tolerated (see "Special instructions", "Use during pregnancy and during breastfeeding"), and with regular review of treatment, the benefit / risk ratio should be carefully reassessed .

Preferably, Depakin® is used in monotherapy and at the lowest effective doses and, if possible, in sustained release dosage forms. During pregnancy, the daily dose should be divided, at least, into 2 single doses.

Elderly patients

Although elderly patients have changes 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

Patients with renal insufficiency and or hypoproteinemia should take into account the possibility of increasing the concentration of the free (therapeutically active) fraction of valproic acid in the blood serum and, if necessary, reduce the dose of valproic acid, focusing on the dose selection, mainly on the clinical picture, and not on the total valproic acid content in the blood serum (free fractions and fractions associated with plasma proteins, together) to avoid possible errors in the selection of a dose.

Side effects:

The classification of the World Health Organization is used to indicate the frequency of unwanted reactions (HP): very often ≥ 10%; often ≥ 1% and <10%; infrequently ≥0.1% and <1%; rarely ≥0.01% and <0.1%; very rarely <0.01%; frequency is unknown (when it is not possible to estimate the frequency of development of HP according to the available data).

Congenital, hereditary and genetic disorders

Teratogenic risk (see section "Application during pregnancy and during breastfeeding").

Violations of the blood and lymphatic system

Often: anemia, thrombocytopenia (seesection "Special instructions").

Infrequently: pancytopenia, leukopenia, neutropenia. Leukopenia and pancytopenia can be, with or without bone marrow depression.

After the drug is stopped, the blood picture returns to normal.

Rarely: disorders of bone marrow hematopoiesis, 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 increase in prothrombin time, increase in activated partial thromboplastin time, increase in thrombin time, increase in INR [International Normalized Ratio]) (see " pregnancy and during breastfeeding "and" Special instructions ").

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

Laboratory and instrumental data

Rarely: deficit biotin / insufficiency of biotinidase.

Disturbances from the nervous system

Often: tremor.

Often: extrapyramidal disorder, stupor *, drowsiness, convulsions *, memory impairment, headache, nystagmus; dizziness (with intravenous administration, dizziness may occur within a few minutes and pass spontaneously within a few minutes).

Infrequently: * coma, encephalopathy *, lethargy *, reversible parkinsonism, ataxia, paresthesia, increased frequency and severity of seizures (including the development of status epilepticus), or the emergence of new types of seizures (see. section "Special instructions").

Rarely: reversible dementia, combined with reversible cerebral atrophy, cognitive disorders.

Frequency unknown: sedation.

* Stupor and lethargy sometimes led to transient coma / encephalopathy and were either isolated or combined with an increase in seizures during the treatment, and decreased to remove the drug or reducing 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.

Hearing disorders and labyrinthine disorders

Often: reversible and irreversible deafness.

Disturbances on the part of the organ of sight

Frequency unknown: diplopia.

Disturbances from the respiratory organs, chest and the mediastinum

Infrequently: pleural effusion.

Infringements from digestive system

Often: nausea.

Often: vomiting, gum changes (mainly gum 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 digestive system can be reduced by taking the drug during or after a meal.

Infrequently: pancreatitis, sometimes with a fatal outcome (development of pancreatitis is possible during the first 6 months of treatment, in the case of acute pain in the abdomen, it is necessary to monitor the activity of serum amylase, see section "Special instructions").

Frequency unknown: spasms in abdomen, anorexia, increased appetite.

Disorders from the kidneys and urinary tract

Infrequently: renal insufficiency.

Rarely: enuresis, tubulointerstitial nephritis,reversible Fanconi syndrome (a complex of biochemical and clinical manifestations of affection of proximal renal tubules with a violation of tubular reabsorption of phosphate, glucose, amino acids and bicarbonate), the mechanism of development of which is still unclear.

Disturbances from the skin and subcutaneous tissues

Often: hypersensitivity reactions, for example, urticaria, pruritus; transitory (reversible) and / or dose-dependent pathological hair loss (alopecia), including androgenic alopecia against the background of developed hyperandrogenism, polycystic ovary (see below subsections "Infringements on the part of the genitals and the breast" and "Endocrine system disorders"), as well as alopecia against the background of developed hypothyroidism (see below section "Endocrine system disorders"), disorders from the nails and the nail bed.

Infrequently: angioedema, rash, hair disorders (such as abnormal hair structure, hair color changes, abnormal hair growth [disappearance of waviness and curly hair, or vice versa, appearance of curly hair in persons with initially straight hair]).

Rarely: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, rash syndrome with eosinophilia and systemic symptoms (DRESS-syndrome).

Disturbances from musculoskeletal and connective tissue

Infrequently: reduction of bone mineral density, osteopenia, osteoporosis and fractures in patients taking Depakin® for a long time. The mechanism of the influence of Depakin® preparations on the metabolism of bone tissue is not established.

Rarely: systemic lupus erythematosus (see section "Special instructions"), rhabdomyolysis (see "With caution", "Special instructions").

Infringements from endocrine system

Infrequently: syndrome of inadequate secretion of antidiuretic hormone (SNSADG), hyperandrogenism (hirsutism, virilization, acne, alopecia in masculine type and / or increase in androgen concentrations in the blood).

Rarely: hypothyroidism (see section "Application during pregnancy and during breast-feeding").

Disorders from the metabolism and nutrition

Often: hyponatremia, weight gain (the increase in body weight should be carefully monitored, since weight gain is a factor contributing to the development of the polycystic ovary syndrome).

Rarely: hyperammonemia * (see below).section "Special instructions"), obesity.

* There may be cases of isolated and moderate hyperammonemia without changing liver function indicators that do not require discontinuation of treatment. There was also reported the occurrence of hyperammonemia, accompanied by the appearance of neurological symptoms (for example, the development of encephalopathy, vomiting, ataxia and other neurologic symptoms), which required the cessation of valproic acid intake and additional examination (see section "Special instructions").

Benign, malignant and Uncertain tumors (including cysts and polyps)

Rarely: myelodysplastic syndrome.

Vascular disorders

Often: bleeding and hemorrhage (see. Forums "Cautions" and "Pregnancy and lactation").

Infrequently: vasculitis.

General disorders and changes in the site of administration

Infrequently: hypothermia, minor peripheral edema.

Disturbances from the liver and bile ducts

Often: liver damage: abnormal liver function indicators, 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 "hepatic" transaminases in the blood; hepatic insufficiency, in exceptional cases - with fatal outcome; it is necessary to monitor patients for possible violations of liver function (see section "Special instructions").

Violations of the genitals and mammary gland

Often: dysmenorrhea.

Infrequently: amenorrhea.

Rarely: male infertility, polycystic ovary.

Frequency unknown: irregular menstruation, breast enlargement, galactorrhea.

Disorders of the psyche

Often: a state of confusion, hallucinations, aggressiveness *, agitation *, attention violation *; Depression (when combining valproic acid with other anticonvulsants).

Rarely: behavioral disorders *, psychomotor hyperactivity *, learning disabilities *; depression (with monotherapy with valproic acid).

* Undesirable reactions, mainly observed in patients of childhood.

Overdose:

Clinical manifestations of acute massive overdose usually occur in the form of coma with hypotonia of the muscles, hyporeflexia, miosis, respiratory depression, metabolic acidosis, excessive lowering of arterial pressure, and vascular collapse / shock. 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 when overdosed.

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

Treatment of overdose

Emergency care for overdose in the hospital 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 receive activated charcoal, including its administration through a nasogastric tube. It is required to monitor the state of the cardiovascular and respiratory system, maintain an effective diuresis, and carry out symptomatic therapy.

It is necessary to monitor the liver and pancreas. If breathing is depressed, artificial ventilation may be required. In some cases, naloxone. In very severe cases of massive overdose, hemodialysis and hemoperfusion were effective.

Interaction:

The effect of valproic acid on other drugs

Neuroleptics, monoamine oxidase inhibitors (MAO), antidepressants, benzodiazepines

Valproic acid may potentiate the effects of other psychotropic drugs, such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, when they are used simultaneously with valproic acid, careful medical supervision and, if necessary, dosage adjustment are recommended.

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. Therefore, careful medical supervision of the patient induring the first 15 days of combined therapy with immediate reduction in the dose of phenobarbital in the 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. A thorough clinical observation of the patient is recommended, especially at the beginning of the combination therapy, with correction of the dose of primidone, if necessary.

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 (valproic acid expels phenytoin from the connection with plasma proteins and slows down its hepatic catabolism). Therefore, careful clinical observation of the patient and the determination of the concentrations of phenytoin and its free fraction in the blood are recommended.

Carbamazepine

With the simultaneous use of valproic acid and carbamazepine, the emergence of clinicalmanifestations of the toxicity of carbamazepine, since valproic acid can potentiate the toxic effects of carbamazepine. A thorough clinical observation of such patients is recommended, especially at the beginning of the combination therapy with correction, if necessary, a dose of carbamazepine.

Lamotrigine

Valproic acid slows the metabolism of lamotrigine in the liver and increases the half-life of lamotrigine by almost 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. Therefore, careful clinical observation and, if necessary, correction (reduction) of the dose of lamotrigine is recommended.

Zidovudine

Valproic acid can increase plasma concentrations of zidovudine, which leads to an increase in zidovudine toxicity.

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. Care should be taken, especially in children, since this effect is more pronounced in this population.

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.

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.

The effect of other drugs on valproic acid

Antiepileptic drugs capable of inducing microsomal liver enzymes (including phenytoin, phenobarbital, carbamazepine) reduce the plasma concentrations of valproic acid. In the case of combination therapy, doses of valproic acid should be adjusted depending on the clinical response and the concentration of valproic acid in the blood.

The concentration of valproic acid metabolites in the serum 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, since some valproic acid metabolites can inhibit urea enzymes (urea cycle).

Felbamat

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

Meflokhin

Meflokhin accelerates the metabolism of valproic acid and is itself capable of causing seizures, so when they are used simultaneously, an epileptic fit may develop.

Preparations of St. John's Wort

With the simultaneous use of valproic acid and preparations of St. John's wort, a possible reduction in anticonvulsant efficacy of valproic acid is possible.

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

In the case of concomitant use of valproic acid and preparations having a high and strong bond with plasma proteins (acetylsalicylic acid), it is possible to increase the concentration of the free valproic acid fraction.

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.

Cimetidine, erythromycin

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

Carbapenems (panipenem, meropenem, imipenem)

Reduction of valproic acid concentrations in the blood with its simultaneous application with carbapenems: for two days of joint therapy, a 60-100% reduction in valproic acid in the blood was observed, which was sometimes associated with the occurrence of seizures. Carbapenems should not be used concomitantly in patients with a selected dose of valproic acid because of their ability to rapidly and rapidly reduce valproic acid concentrations in the blood.If carbapenem treatment can not be avoided, careful monitoring of valproic acid concentrations in the blood should be performed.

Rifampicin

Rifampicin can reduce the concentration of valproic acid in the blood, which leads to a loss of the therapeutic effect of valproic acid. 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.

Kolyactiramin

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

Other interactions

With topiramate or acetazolamide

The simultaneous use of valproic acid and topiramate or acetazolamide was associated with encephalopathy and / or hyperammonemia. Patients taking these drugs concomitantly with valproic acid should be carefully monitored for symptoms of hyperammonemic encephalopathy.

With quetiapine

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

With estrogen-progestogen drugs

Valproic acid does not have the ability to induce liver enzymes, and, as a result, valproic acid does not reduce the effectiveness of estrogen-progestogen drugs in women who use hormonal methods of contraception.

With ethanol and other potentially hepatotoxic drugs

When used simultaneously with valproic acid, it is possible to increase the hepatotoxic effect of valproic acid.

With clonazepam

The simultaneous use of clonazepam with valproic acid may lead in a few cases to an increase in the expression of absent status.

With myelotoxic drugs

With their simultaneous use with valproic acid, the risk of oppression of bone marrow hematopoiesis increases.

Special instructions:

Before beginning the use of Depakin® enteric 300 and periodically during the first 6 months of treatment, especially in patients at risk of developing liver damage, a study of liver function should be performed.

As with the majority of antiepileptic drugs, with the use of valproic acid, a slight increase in the activity of "liver" enzymes is possible, especially at the beginning of treatment, which occurs without clinical manifestations and is transient. These patients need a more detailed study of biological indicators, including a prothrombin index, and a dose adjustment of the drug may be required, and if necessary, a re-clinical and laboratory examination.

Before starting 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 shows that patients at risk are patients who take several antiepileptic drugs at the same time; Children younger than three years of age with severe convulsive attacks, especially against the background of brain damage,mental retardation and / or congenital metabolic or degenerative diseases; patients taking salicylates at the same time (since salicylates are metabolized along the same metabolic pathway as valproic acid).

After three years of age, the risk of liver damage is significantly reduced and progressively decreases as the patient's age increases. In most cases, this liver damage occurred during the first 6 months of treatment, most often between 2 and 12 weeks of treatment, and usually with the use of valproic acid in combination antiepileptic therapy.

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 that may precede the onset of jaundice, especially in patients at risk (see above):

- nonspecific symptoms, especially sudden onset, 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 their families (when using the drug by children) that they should immediately report the occurrence of any of these symptoms to the treating doctor. 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. Among the usual studies, the most informative are studies that reflect the state of the protein-synthetical function of the liver, especially the definition of the prothrombin index.

Confirmation of 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 coagulation 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 the drug Depakin® enteric 300.For the purpose of precaution, if patients take concomitant salicylates, their administration should also be discontinued.

Pancreatitis

There are registered rare cases of severe forms of pancreatitis in children and adults that developed 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.

Children are at increased risk of developing pancreatitis, with increasing age of the child, this risk is reduced. Risk factors for pancreatitis can be severe seizures, neurological disorders, or anticonvulsant therapy. Hepatic insufficiency, combined with pancreatitis, increases the risk of death.

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 should be started.

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 also showed an increased risk of suicidal ideation and attempts at 0.19% in all patients taking antiepileptic drugs (including an increase in this risk by 0.24% in patients taking antiepileptic drugs for epilepsy), compared with their frequency in patients taking placebo. The mechanism of this effect is unknown.

Therefore, patients taking the drug Depakin® enteric 300 should be constantly monitored for suicidal thoughts and attempts, and, if they occur, it is necessary to conduct appropriate treatment. Patients and caregivers are advised when the patient has suicidal thoughts or attempts to immediately consult a doctor.

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 the gene encoding the γ-polymerase (POLG); for example, in patients with Alpers-Huttenlohera syndrome, the use of valproic acid was associated with a higher incidence of acute hepatic insufficiency and liver-related fatalities. Diseases due to γ-polymerase defects can be suspected in patients with a family history of such diseases or with suspicious symptoms, including unexplained encephalopathy, refractory epilepsy (focal, myoclonic), epileptic status, mental and physical retardation, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia or complicated migraine with visual (occipital) aura and others.In accordance with modern clinical practice, the test for mutation of the γ-polymerase gene (POLG) should be used to diagnose such diseases (see the section "Contraindications").

The paradoxical increase in the frequency and severity of seizures (including the development of epileptic status) or the appearance of new types of seizures

As with the use of other antiepileptic drugs, when receiving valproic acid in some patients, a reversible increase in the frequency and severity of convulsive seizures (including the development of epileptic status) or the appearance of new types of convulsions was observed, instead of improving. In case of increased seizures, patients should consult the doctor immediately (see "Side effect").

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

The drug Depakin® enteric 300 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 overestimated in the following cases: during regular revision of treatment, when the girl reaches puberty and, as a matter of urgency, if she is planning or becoming pregnant with a woman taking valproic acid.

During treatment with valproic acid, women with childbearing potential should use reliable methods of contraception and be informed of the risks associated with taking the drug Depakin® enteric 300 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 comprehensive information about the risks associated with taking Depakin® enteric 300 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, in particular, the risk 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 your doctor 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 physician with experience in the treatment of epilepsy and bipolar disorders will reassess the benefit / risk ratio from treatment with the drug to the patient.

Children (information refers to dosage forms Depakin®, which can be taken by children under the age of three)

Children under the age of three years, if necessary, use the drug, its use in monotherapy and in the recommended dosage form for children is recommended. In this case, before the start of treatment should weigh the ratio of the potential benefits of valproic acid and the risk of liver damage and the development of pancreatitis when it is used.

Children under 3 years of age should avoid the simultaneous use of valproic acid and salicylates due to the risk of toxic effects on the liver.

Renal insufficiency

It may be necessary to reduce the dose of valproic acid due to an increase in the concentration of its free fraction in the blood serum. In case of impossibility of monitoring plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient.

Enzyme insufficiency of carbamide cycle (urea cycle)

If the enzyme deficiency of the carbamide cycle is suspected, the use of valproic acid is contraindicated. Such patients described several cases of hyperammonemia with a stupor or coma. In these cases, metabolic studies should be performed prior to treatment with valproic acid (see "Contraindications").

In children with unexplained gastrointestinal symptoms (anorexia, vomiting, cytolysis cases), a history of lethargy or coma, a mental retardation or a family history of the death of a newborn or child prior to treatment with valproic acid, studies of metabolism should be conducted,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 has been shown that during the treatment with the drug Depakin® enteric 300, the disturbances in the functions of the immune system are extremely rare, the potential benefit of using it should be compared with the potential risk when using the drug in 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)

AT in vitro it was found that valproic acid stimulates HIV replication under certain experimental conditions.

The clinical significance of this fact, if any, is unknown. In addition, the value of these data obtained in the studies in vitro, for patients receiving 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 the current 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, ethanol is not recommended.

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

Patients should be warned about the risk of developing drowsiness, especially in the case of combined anticonvulsant therapy or with the combination of Depakin^® Enteric 300 with benzodiazepines (see section "Interaction with other drugs").

Form release / dosage:

Intestine-soluble film coated tablets, 300 mg.

Packaging:

For 10 tablets in a blister of PVC / Al.

10 blisters together with instructions for medical use are placed in a cardboard box.

Storage conditions:

In a dry place, at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not take the medicine after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N013995 / 01

Date of registration:02.04.2008 / 08.12.2015

Expiration Date:Unlimited

The owner of the registration certificate:Sanofi Winthrop IndustrySanofi Winthrop Industry France

Manufacturer: & nbsp

SANOFI WINTHROP INDUSTRIE France

Representation: & nbspSanofi Aventis GroupSanofi Aventis Group

Information update date: & nbsp23.04.2017

Illustrated instructions

Instructions

Depakin® Enteric 300 (Depakine® enteric 300)