Depakin - instructions for use, doses, side effects, contraindications

Experimental and clinical data support the existence of two mechanisms of anticonvulsant action of the drug Depakin. The first is a direct pharmacological action associated with the concentration of valproic acid in the blood plasma and brain tissues that affects the GABAergic system, causing an increase in the concentration of gamma-aminobutyric acid (GABA) in the central nervous system (CNS) and activating GABA-ergic transmission.The second, apparently, is an indirect pharmacological action associated with remaining in the brain metabolites of valproic acid, either with changes in neurotransmitters or direct exposure to cell membranes.

Pharmacokinetics:

The bioavailability of valproic acid with intravenous administration is 100%. Usually, serum concentrations of valproic acid of 40-100 mg / l (300-700 μmol / L) are effective (determined before taking the first dose of the drug within 24 hours). With the justified need to achieve higher concentrations of valproic acid in blood plasma, the ratio of expected benefit and the risk of side effects, especially dose-dependent, should be weighed carefully, since valproic acid concentrations in excess of 100 mg / l are expected to increase side effects until intoxication develops. 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 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 body weight or in young people 0.13-0.19 l / kg body weight.

The connection with blood plasma proteins (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 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 the breast milk of nursing mothers. In the state of reaching an equilibrium concentration of valproic acid in the blood serum, its concentration in breast milk is up to 10% of its serum concentration.

Metabolism

Metabolism 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 degree of both own metabolism and the degree of metabolism of other substances, such as estrogens, progestogens and antagonists of vitamin K.

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 older than 2 months of age approaches that of adults.

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

In case of an overdose, the half-life of valproic acid was increased to 30 hours.

Hemodialysis is affected only by the free fraction of valproic acid in the blood (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 reduce the serum concentrations 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:

The injection dosage form of valproic acid is indicated for the temporary replacement of its oral dosage forms, the use of which is temporarily impossible.

In adults:

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

- partial epileptic seizures: partial seizures with secondary generalization or without it (in monotherapy or in combination with other antiepileptic drugs).

Children:

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

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

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

Contraindications:

- Increased sensitivity to sodium valproate, valproic acid, valproate seminary, valmromid or to any of the components of the drug;

acute hepatitis;

- chronic hepatitis;

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

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

- hepatic porphyria;

- established mitochondrial diseases caused by mutations of a nuclear gene encoding mitochondrial enzyme γ-polymerase (POLG), for example, Alpers-Huttenlohera syndrome, and suspicion of disease, caused by γ-polymerase defects, in children younger than 2 years of age (see section "Special instructions");

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

- hemorrhagic diathesis, thrombocytopenia;

- combination with mefloquine;

- combination with preparations of St. John's wort (see section "Interaction with other drugs").

Carefully:

- In children under 3 years of age due to the increased risk of liver damage (see "Special instructions");

- with simultaneous administration of several anticonvulsants (because of the increased risk of liver damage);

- with renal failure (dosage correction is required);

- at diseases of a liver and a pancreas in the anamnesis;

- during pregnancy;

- with congenital fermentopathy;

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

- with hypoproteinemia;

- 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, butyrophenone 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), colestyramine (in connection with pharmacokinetic interactions at the level of metabolism or at the level of communication with blood plasma proteins, it is possible to change plasma concentrations of either these drugs and / or valproic acid, for more details see the 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 existing 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 represent a special 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 Depakin® during pregnancy

Experimental studies of reproductive toxicity, conducted on mice, rats and rabbits, demonstrated the presence of valproic acid teratogenic effect.

Congenital malformations

The available clinical data demonstrated a high incidencesmall and severe developmental defects, in particular, congenital neural tube defects, craniofacial deformities, developmental limb and cardiovascular malformations, hypospadias, as well as multiple developmental defects affecting different organ systems, in children born to mothers taking time of pregnancy valproate acid, in comparison with their frequency with the admission during pregnancy of a number of other antiepileptic drugs. So the risk of congenital malformations in children born to 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 of mothers with epilepsy, which were received during pregnancy monotherapy valproic acid was 10.73% (95% confidence interval 8.16-13.29). This risk is greater than the risk heavy congenital malformations in of the general population, which was 2-3%. This risk is dose-dependent, but the threshold dose, below which there is no such risk, is not established Pis possible.

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 subjected to intrauterinethe effect of valproic acid, showed that up to 30-40% of these children had early developmental delays (such as delayed walking and speech retardation), as well as lower intellectual skillsbyabilities, poor speech skills (own speech and understanding of speech) and memory problems.Coefficient of mental development (index IQ), defined in children at the age of 6 years with an anamnesis of intrauterine exposure to valproate, was on average 7-10 points lower than in children exposed to intrauterine effects of other antiepileptic drugs. Although it is impossible to exclude the role of other factors that could undesirably affect the intellectual development of children who have been exposed oututerine exposure to valproic acid, it is obvious that in such children the risk of intellectual disturbances may be independent of the index IQ mother.

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 three to five times the risk increase), 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 monotherapy with valproic acid and combination therapy with the inclusion of valproic acid are associated with an unfavorable outcome of pregnancy, but, according to available data, combined antiepileptic therapy, including valproic acid, is associated with higher risk of an unfavorable outcome of pregnancy in comparison with monotherapy of valproic acid (that is, 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 1000 mg / day (however, a lower dose does not exclude this risk), and the combination of valproic acid with other anticonvulsants.

In connection with the foregoing, Depakin® is not should be applied when pregnancy and in women with childbearing potential without extreme necessity, that is, its use is possible in situations where others antiepileptic drugs are ineffective or the patient does not tolerate them.

The question of the need application of the drug Depakin® or options refusal to use it should be resolved before the drug is used orto be reviewed in case a woman, host drug Depakin^®, plans pregnancy.

Women with childbearing potential should use effective methods of contraception during treatment with Depakin®.

Women with childbearing potential should be informed about 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 reassessing the ratio of benefit and risk, treatment with Depakin® 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), so 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 identify 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 took 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 was found that these disorders of fertilityь 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 small clinical experience, breastfeeding with Depakin® monotherapy can be considered, but the profile of the side effects of the drug, especially hematologic disorders caused by it, should be taken into account.

Dosing and Administration:

Simple replacement therapy

(for example, before surgery)

After 4-6 hours after the last oral dose, the intravenous drug diluted with a sodium chloride solution for injection (0.9%) is administered:

- or in the form of continuous infusion of the previously used dose during the day;

- or in the form of 4 infusions, the duration of 1 hour (in this case with each infusion introduced 1/4 of the previously used daily dose).

The usual average dose is 20-30 mg / kg / day.

Situations requiring rapid achievement and maintenance of effective concentration of valproic acid in blood plasma

Intravenous bolus administration of the drug at a dose of 15 mg / kg for 5 minutes; then the administration is continued as a continuous intravenous infusion at a rate of 1 mg / kg / hour, with a gradual correction of the rate of administration to provide a valproic acid concentration in the blood of about 75 mg / l. Further, the rate of administration changes depending on the clinical picture.

After discontinuation of the infusion, the transition to treatment with oral forms of the drug Depakin^®can occur with the use of the previous dose or dose, adjusted to take into account the clinical condition of the patient.

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

Treatment with Depakin® 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.sections "Special instructions", "Use during pregnancy and during breastfeeding"), and with a 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 into at least 2 single doses.

Elderly patients

Although elderly patients age there are changes 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 failure and / or hypoproteinemia

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

Side effects:

To indicate the frequency of development of unwanted reactions (HP), the classification is used World Health Organization: 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 (see section "Special instructions").

Infrequent: 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 an increase in prothrombin time, an increase in activated partial thromboplastin time, increased thrombin time, increased INR [international normalized relationship]) (see the sections on "Application during 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: biotin deficiency / biotinidase deficiency.

Disturbances from the nervous system

Very often: tremor.

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

Infrequent: coma *, encephalopathy *, lethargy *, reversible parkinsonism, ataxia, paresthesia.

Rarely: reversible dementia, combined with reversible atrophy of the brain, cognitive disorders.

Frequency is unknown: sedation.

* Stupor and lethargy sometimes lead to transient coma / encephalopathy and were either isolated, or combined with increased frequency of convulsive attacks 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.

Hearing disorders and labyrinthine disorders

Often: reversible and irreversible deafness.

Disturbances on the part of the organ of sight

The frequency is unknown: diplopia.

Disturbances from the respiratory, thoracic and mediastinal organs

Infrequent: pleural effusion.

Disorders from the digestive system

Very often: nausea (observed a few minutes after intravenous administration of the drug with its spontaneous disappearance in a few minutes).

Often: 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.

Infrequently: pancreatitis, sometimes fatal (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").

The frequency is unknown: abdominal cramps, anorexia, increased appetite.

Disorders from the kidneys and urinary tract

Infrequent: renal failure.

Rarely: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (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 development mechanism of which is still unclear.

Disturbances from the skin and subcutaneous tissues

Often: hypersensitivity reactions, such as urticaria, pruritus; transient (reversible) and / or dose-dependent pathological hair loss (alopecia), including androgenic alopecia against the background of developed hyperandrogenia, polycystic ovaries (see below).below the subsection "Violations from the genitals and breast cancer" and "Disorders from the endocrine system"), as well as alopecia against the background of developed hypothyroidism (see below section "Disorders from the endocrine system"), violations from the nails and the nail bed .

Infrequent: 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]), hirsutism, acne.

Rarely: toxic epidermal necrolysis, Stevens-Johnson syndrome, multi-form erythema, drug-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 long-acting Depakin® preparations. The mechanism of the effect of Depakin® preparations on the metabolism of bone tissue is not established.

Rarely: systemic lupus erythematosus (see section "Special instructions"), rhabdomyolysisSee "Precautions", "Special instructions".

Disorders from the endocrine system

Infrequently: the syndrome of inadequate secretion of the antidiuretic hormone (SNSADG), hyperandrogenism (hirsutism, virilization, acne, alopecia in masculine type and / or an 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 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 vague 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: abnormality functional state liver, such as a decrease in the prothrombin index, especially in combination with significant decline the content of fibrinogen and clotting factors, increase in concentration bilirubin and increased activity of "hepatic" transaminase in the blood; hepatic insufficiency, in exceptional cases - with a fatal outcome; it is necessary to monitor patients for possible violations of the baking 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, enlargement of mammary glands, 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 *, impaired ability to learn *; depression (with monotherapy with valproic acid).

* Undesirable reactions, mainly observed in patients of childhood.

Overdose:

Overdose Symptoms

Clinical manifestations of acute massive overdose usually occur in the form of coma with muscle hypotonia, 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, if the contents of the vial containing lyophilizate or solution for intravenous administration, if after this no more than 10-12 hours have elapsed. 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 (MAO) inhibitors, 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 observation of the patient during the first 15 days of combination therapy with immediate reduction of the dose of phenobarbital in case of development of sedative action and, if necessary, determination of plasma concentrations of phenobarbital is recommended.

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. In addition, 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 occurrence of clinical manifestations of the toxicity of carbamazepine has been reported, since valproic acid can potentiate toxic effects 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.

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

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

Temozolomide

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

The effect of other drugs on valproic acid

Antiepileptic drugs that can induce microsomal liver enzymes (including phenytoin, phenobarbital, carbamazepine) reduce 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.

ConcentrationqiI metabolites of valproic acid in the serum can be increased in case of its simultaneous use 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 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, so when they are used simultaneously, an epileptic fit may develop.

Preparations of St. John's Wort perforated

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 Valproic acid can increase in the case of simultaneous application of cimetidine or erythromycin (as a result of 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, due to their ability to rapidly and intensively 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.

Kolestyramine

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

Other interactions

With topiramate or acentnersétazolamide

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.

FROM 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 contraception.

With ethanol and other nomesocially hepatotoxic drugs

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

FROM 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® 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 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 uniform elements in 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 under the age of three with severe convulsive seizures, 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 studies reflecting the state of protein synthetic 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 cm.above), requires the discontinuation of Depakin®. 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 an attempt at 0.19% in all patients taking antiepileptic drugs (including an increase in this risk by 0.24% the 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^®, 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 neuronstheabolitesthe 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 repression, axonalьнуYu sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia or a complicated migraine with a visual (occipital) aura and others.In accordance with modern clinical practice for the diagnosis of such diseases should lead the test for mutations of the γ-polymerase gene (POLG) (see section "Contraindications").

Women with childbearing potentials, pregnant women women

Depakin® 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. It should be carefully overestimated benefit-risk ratio in the following cases: during regular revision of treatment, when the girl reaches puberty and, as a matter of urgency, if planning or pregnancy occurs, women taking valproic acid.

During treatment with valproic acid, women with childbearing potential should use reliable contraceptive methods and they should be informed about the risks associated with taking Depakin® 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 a comprehensive about information about the risks associated with taking the drug Depakin® 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 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 during pregnancy and during breastfeeding").

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

Children

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 on the basis of clinical monitoring for 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), lethargy or coma in history, with mental retardation or with a family history of death of a newborn or child, studies of metabolism should be conducted prior to treatment with valproic acid, in particular, 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 during the treatment with the drug Depakin^® disorders of the immune system are extremely rare, the potential benefit from its use should be compared with the potential risk of 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 possibility adverse effects of valproic acid on pancreas, when using 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 immunodeficiency virus human being (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 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 palm treesutoiltransferase (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 if combined anticonvulsant therapy is used or when the drug Depakin® is combined with benzodiazepines (see "Interactions with Other Drugs").

Form release / dosage:

Lyophilizate for the preparation of a solution for intravenous administration, 400 mg (complete with a solvent).

Packaging:

400 mg of lyophilizate in bottles of colorless glass (type I), ukuPorous rubber stopper, rolled up with an aluminum cap with a plastic lid type "flip-off"For 4 ml of solvent in ampoules of colorless glass (type I) with a fault line and an additional ring on the top of the ampoule.

For 1 vial and 1 ampoule in a plastic contour mesh package without coating (pallet). 1 pallet together with instructions for use in the inner cardboard pack.

4 inner cardboard packs in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

Lyophilizate - 3 years; solvent - 5 years.

Note. The shelf life of the kit corresponds to the shortest shelf life of the component included in the kit.

Terms of leave from pharmacies:On prescription

Registration number:LP-001530

Date of registration:24.02.2012

Date of cancellation:2017-02-24

The owner of the registration certificate:Sanofi-Aventis FranceSanofi-Aventis France France

Manufacturer: & nbsp

GRUPPO LEPETIT, S.R.L. Italy

Representation: & nbspSanofi Aventis GroupSanofi Aventis Group

Information update date: & nbsp11.12.2015

Illustrated instructions

Instructions

Depakin® (Depakine®)