Depakin Chronosphere - instructions for use, dose, side effects, contraindications

* - added by spraying after the melt cooling process and expressed in percent of the number of the other four components: 0.7% (approximate amount absorbed on pellets: 0.56%).

Description:

Easily free-flowing, without the formation of agglomerates, waxy microgranules of almost white or slightly yellowish color.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.G.01 Valproic acid

Pharmacodynamics:

Antiepileptic drug, which has central muscle relaxant and sedative effect. It shows antiepileptic activity in various types of epilepsy.

The main mechanism of action, apparently, is associated with the action of valproic acid on the GABA -ergic system: increases the content of gamma-aminobutyric acid (GABA) in the central nervous system(CNS) and activates GABA-ergic transmission.

Pharmacokinetics:

Absorption

The bioavailability of valproic acid when administered is close to 100%. The intake of food does not affect the pharmacokinetic profile of the drug.

The maximum concentration of valproic acid in the blood plasma (C_m_Oh) after taking the drug Depakin® Chronosphere inside is reached after about 7 hours.

Compared to the enteric coated form, equivalent doses of the Depakin® Chronosphere product are characterized by longer absorption, identical bioavailability, a more linear correlation between doses and plasma concentrations of valproic acid (total concentration and free-fraction concentration). In addition, C_m_Oh and the maximum plasma concentration of the free fraction of valproic acid is lower (Reduction of about 25%), but it has a relatively more stable phase plateau plasma concentration from 4 to 14 hours after ingestion, the magnitude of fluctuations of plasma concentrations while taking the drug Depakin® Chronosphere compared with the dosage formulation, enteric coated tablets, decreases in two as a result valproic acid more evenly distributed in the tissues during the day.

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

Usually, serum concentrations of valproic acid of 40-100 mg / l (300-700 μmol / L) (determined before the first dose of the drug during the day) are effective. Valvular concentrations of valproic acid of more than 100 mg / l are expected to increase side effects up to development of intoxication.

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. In connection with the decrease in the magnitude of fluctuations in plasma concentrations with the administration of the drug Depakin® Chronosphere, valproic acid more evenly distributed in the tissues during the day compared with the immediate release dosage form of valproic acid.

The association of valproic acid 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 the free (therapeutically active) fraction of valproic acid may increase to 8.5-20%.

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

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, that is, close to the free valproic acid concentration in serum.

Valproic acid penetrates the breast milk of nursing mothers. In the state of reaching an equilibrium concentration of valproic acid in the serum, its concentration in breast milk is up to 10% of its serum concentration blood.

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 P 450: unlike most others antiepileptic drugs, valproic acid does not affect the degree 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.

When valproic acid is used in monotherapy, its half-life is 12-17 hours. When combined with antiepileptic drugs that induce microsomal liver enzymes (such as primidon, phenytoin, phenobarbital and carbamazepine), 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 by other antiepileptic drugs.

Half-life in children over 2 months of age is close to that of 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. Hemodialysis is affected only by the free fraction of valproic acid in the blood (5-10%).

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 blood plasma proteins can change, which may lead to an increase in the serum content of the free (therapeutically active) fraction of valproic acid.

Indications:

Have of adults: as a monotherapy or in combination with other antiepileptic means:

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

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

- lPrevention and prevention of bipolar affective disorders.

In infants (starting from the 6th month of life) and children: as monotherapy or in combination with other antiepileptic drugs:

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

- dFor 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:

- 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;

- severe violations of the liver or pancreas;

- 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;

- Children under 6 months.

Carefully:

- With liver and pancreatic disease in history;

- during pregnancy;

- with congenital fermentopathy;

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

- with renal failure (dosage correction is required);

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

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

- with the 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 insufficiency carnitine palmitoyltransferase (CBT) type II (a 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 Depakin® Chronosphere 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 defects of limbs and cardiovascular system, hypospadias, as well as multiple developmental defects affecting different organ systems in children born to mothers taking valproic acid during pregnancy, compared to their frequency with the intake of a number of other antiepileptic drugs during pregnancy.

So the risk of congenital malformations in children born to mothers with epilepsy who received monotherapy Balepduring 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 valproic acid monotherapy during pregnancy was 10.73% (95% confidence interval 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. Coefficient of mental development (index IQ), defined in children aged 6 years with a history of intrauterine exposure to valproic acid, was on average 7-10 points lower than in children exposed to intrauterine effects of other antiepileptic drugs.Although the role of other factors that could undesirably affect the intellectual development of children exposed to intrauterine effects of valproic acid can not be ruled out, it is obvious that in such children the risk of intellectual disorders 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 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 monotherapy with valproic acid and combination therapy with valproic acid 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 monotherapy 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 anticonvulsant drugs. In connection with the foregoing, the drug Depakin® Chronosphere should not be used in pregnancy and in women with childbearing potential without extreme necessity, that is, its use is possible in situations when other antiepileptic drugs are ineffective or the patient does not tolerate them.

The need to use the drug Depakin® Chronosphere or the possibility of not using it should be decided before the drug is started or revised if the woman taking the drug Depakin® Chronosphere is planning a pregnancy.

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

Women with childbearing potential should be informed of the risks and benefits of using valproic acid during pregnancy.If a woman is planning a pregnancy, or if she has a pregnancy, then a reassessment of the need for valproic acid in depending on the readings (see below).

- When bipolar disorder is indicated, consideration should be given to stopping treatment with valproic acid.

- When epilepsy is indicated, the question of continuing treatment with valproic acid or its withdrawal is decided after a reassessment of the benefit-risk ratio. If after a reassessment of the ratio of benefit and risk, treatment with Depakin^® Chronosphere still should be continued during pregnancy, it is recommended to apply it in the minimum effective daily dose divided into several methods. It should be noted that in pregnancy it is more preferable to use dosage forms of the sustained release preparation than other dosage forms.

If possible, even before the onset of pregnancy, you should also start taking folic acid (at a dose of 5 mg per day), since folic acid can reduce the risk of developing neural tube defects. but 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), including a detailed ultrasound study, to identify possible defects in the formation of the neural tube or other malformations of the fetus.

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,must necessarily carry coagulation tests (to determine the number of platelets in peripheral blood, the plasma concentration of fibrinogen, coagulation factors and coagulation).

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 have taken 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 in 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 data from the literature and little clinical experience, it is possible to consider breastfeeding when monotherapy Depakin^®Chronosphere, but it should take into account the profile of side effects of the drug, especially caused by hematological disorders.

Dosing and Administration:

The drug Depakin^® The chronosphere is a dosage form that is particularly suitable for treatment of children (if they are able to swallow soft food) or adults with difficulty swallowing.

Preparation Depakin® Chronosphere represents granules of prolonged action, ensuring a more uniform concentration of valproic acid in blood and, respectively,more uniform throughout the day, its distribution in tissues.

Dosing regimen

Bipolar affective disorders

The dose should be selected and monitored by the attending physician individually. The daily dose should be set taking into account the age and body weight of the patient.

The recommended initial dose is 20 mg (in terms of sodium valproate) per kg of body weight. The dose should be as quickly as possible to the minimum dose providing the desired therapeutic effect. The recommended maintenance dose for the treatment of bipolar disorders is in the range between 1000 mg and 2000 mg (in terms of sodium valproate) per day. The dose should be selected according to the individual clinical response of the patient.

For the prevention of manic conditions, an individually selected minimum clinically effective dose should be used.

Epilepsy

In monotherapy initial daily dose is usually 5.10 mg (in terms of sodium valproate) per kg body weight, is then raised to 5 mg / kg every 4-7 days until the optimal dose, allowing to prevent the occurrence of epileptic seizures.

Average daily dose:

- for children (up to 14 years) - 30 mg / kg of body weight;

- for adolescents aged 14-18 - 25 mg / kg of body weight;

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

Thus, the daily doses presented below are recommended.

Age	Body mass	*Average daily dose (mg / day)**
Breast children from 6 to 12 months.	About 7.5-10 kg	150-300 mg
Children from 1 to 3 years old	About 10-15 kg	300-450 mg
Children from 3 to 6 years	About 15-25 kg	450-750 mg
Children from 7 to 14 years old	About 25-40 kg	750-1200 mg
Teens from 14 years old	About 40-60 kg	1000-1500 mg
Adults	From 60 kg and above	1200-2100 mg

* - dose in terms of the number of milligrams of sodium valproate

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.

Although the daily dose is determined depending on the age and body weight of the patient, a wide range of individual sensitivity to valproic acid should be taken into account.

A clear correlation between the daily dose, the concentration of valproic acid in the blood serum and the therapeutic effect is not established.Therefore, the optimal dose of the drug should be selected, mainly, on the basis of a clinical response. Determination of the concentration of valproic acid in the blood serum can serve as a supplement to clinical observation in cases where epilepsy is not susceptible to control or suspected of the development of side effects. It is usually effective doses providing plasma concentrations of valproic acid comprising 40-100 mg / L (300-700 micromol / L). If the need to achieve higher concentrations in the serum is warranted, the ratio of expected benefit and the risk of side effects, especially dose-dependent, should be weighed carefully, since with the serum concentrations of valproic acid above 100 mg / l, the side effects are expected to increase until the intoxication develops. Therefore, the serum concentration, determined before taking the first dose per day, should not exceed 100 mg / l.

In the transition from medicinal forms of the drug Depakin^® immediate release or sustained release that have well controlled epilepsy, it is recommended that the Depakine® Chronosphere product continue to receive the same daily dose.

For patients who had previously taken antiepileptic drugs, a transfer to the drug Depakin® Chronosphere 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.

If necessary, combinations of valproic acid with other antiepileptic drugs should be added gradually (see section "Interaction with other drugs and other forms of interaction").

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 antiepileptic drugs and, if necessary (as the metabolic-inducing effect of these drugs decreases), reduce the daily dose preparation Depakin® Chronosphere.

Application of the drug the patients of special groups

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

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

Elderly patients

Although elderly patients age there are changes in the pharmacokinetics of valproic acids, they have limited clinical significance and the dose of valproic acid in elderly patients should be selected in accordance with the achievement of control over epileptic seizures.

Renal insufficiency and / or hypoproteinemia

In patients with renal insufficiency and / or hypoproteinemia, consider the possibility of increasing the concentration of the free (therapeutically active) valproic acid fraction 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 content of valproic acid in the blood serum (free fraction and fractions associated with plasma proteins, together) to avoid possible errors in the selection of a dose.

Mode of application

The drug is taken internally.

Packages Depakin® Chronosphere 100 mg are used only in children and infants.

Packages Depakin® Chronosphere 1000 mg are used only in adults.

The daily dose is recommended to be taken in one or two doses, preferably at the time of admission food.

Use in one dose is possible with well-controlled epilepsy. The Depakin® Chironosphere should be poured onto the surface of soft food or a drink, cold or at room temperature (yoghurt, orange juice, fruit puree, etc.). Depakine® Chronosphere preparation apply with hot food or drinks (such as soups, coffee, tea, etc.).

Preparation Depakin® Chronosphere can not be poured into a bottle with a pacifier, as the granules can clog the orifice of the nipple.

If Depakin® Chronosphere is taken with a liquid, it is recommended to rinse the glass with a little water and drink this water, as the granules can stick to the glass.

The mixture should always be swallowed immediately, without chewing. It should not be stored for later use.

Side effects:

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

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 the clotting parameters (such as an increase in prothrombin time, increased activated partial thromboplastin time, an increase in thrombin time, an increase in MHO [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: biotin deficiency / biotinidase deficiency.

Disturbances from the nervous system

Often: tremor.

Often: extrapyramidal disorders, 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 in the chest and mediastinum

Infrequently: pleural effusion.

Disorders from the 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: abdominal cramps, anorexia, increased appetite.

Disorders from the kidneys and urinary tract

Infrequently: renal insufficiency.

Rarely: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (complex of biochemical and clinical manifestations of affection of proximal tubule tubules with 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, 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").

Disorders from the 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 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 sections "Special instructions" and "Use during pregnancy and during breastfeeding").

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 "liver" transaminases in the blood; liver failure,in exceptional cases, fatal; it is necessary to monitor patients for possible violations of liver function (see section "Special instructions").

Violations of the genitals and mammary gland

Often: dismenorrhea.

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 hypotension muscles, hyporeflexia, miosis, respiratory depression, metabolic acidosis. Cases of intracranial hypertension associated with edema of the brain were described.

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.

Emergency assistance for overdose in a hospital should be as follows: gastric lavage, which is effective within 10-12 hours after taking the drug, monitoring the state of the cardiovascular and respiratory system and maintaining effective diuresis. 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, inhibitors monoamine oxidase (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 observation of the patient during the first 15 days of combination therapy with immediate reduction of the dose of phenobarbital is recommended, in case of sedation and, if necessary, determination of plasma concentrations of phenobarbital.

Primidone

Valproic acid increases plasma concentrations of primidone with an increase in its side effects (such as sedation); with long-term treatment, these symptoms disappear. 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 occurrence of clinical manifestations of the toxicity of carbamazepine has been reported, 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 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.

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 is reduced by 22-50% and, correspondingly, plasma concentrations of valproic acid are increased. Plasma concentrations of valproic acid should be monitored.

Meflokhin

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

Preparations of St. John's Wort 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 (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 use withcarbapenemami: for two days of joint therapy there was a 60-100% decrease in the concentration of valproic acid in the blood, which was sometimes associated with the onset 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.

Kolestyramine

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.

FROM 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 simultaneous application with valproic acid, the risk of oppression of bone marrow hematopoiesis increases.

Special instructions:

Before beginning the use of the drug Depakin® Chronosphere 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, as well as 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 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 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 cm.above), requires the discontinuation of Depakin® Chronosphere. 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 thoughts 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® Chronosphere 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, valproic acid was associated with a higher incidence of acute hepatic impairment and liver-related deaths.

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 for the diagnosis of such diseases should test the test for mutations of the γ-polymerase gene (POLG) (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 other antiepileptic drugs, with the intake of 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 seizures was observed, instead of improving. In case of increased seizures, patients should consult the doctor immediately (see "Side effect").

Children and teenagers of a female, women with childbearing potential and pregnant women

The drug Depakin^® The chronosphere 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 restriction is associated with a high risk of teratogenic and mental andphysical development in children who have been in utero exposed to valproic acid. The benefit / risk ratio should be carefully reassessed in the following cases: during regular revision of treatment, when the girl achieves puberty and, as a matter of urgency, in the case of planning or pregnancy from a woman taking valproic acid.

During treatment with valproic acid, women with childbearing potential should use reliable methods of contraception and be informed about the risks associated with taking the drug Depakin^® Chronosphere during pregnancy (see section "Application 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 the drug Depakin^® Chronosphere 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 risks of teratogenic effects,as well as the risks of mental and physical development of the child;

- 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 the dosage form of 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),lethargy or coma in a history, with a delay in mental development or with a family history of death of a newborn or child, studies of metabolism should be carried out before treatment with valproic acid, in particular, the determination of ammonium (the presence of ammonia and its compounds in the blood) on an empty stomach and after meals see the section "Contraindications").

Patients with systemic lupus erythematosus

Although it has been shown that in the process of treatment with Depakin® Chronosphere the disturbances in the functions of the immune system are extremely rare, the potential benefit from its use must 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 the maximum suppressive antiretroviral therapy. However, these data should be taken into account when interpreting the results of continuous monitoring of viral load in HIV-infected patients taking valproic acid.

Patients with existing insufficiency carnitine palmitoyltransferase (CBT) type II

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

Ethanol

During treatment with valproic acid, ethanol is not recommended.

Other special instructions

The inert matrix of the drug Depakin® Chronosphere (sustained release preparation) due to the nature of its excipients is not absorbed in the gastrointestinal tract; After the release of the active substances, the inert matrix is excreted with caloric masses.

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

Patients should be have been warned of the risk of drowsiness, especially if combined anticonvulsant therapy, or with the combination of Depakin® Chronosphere with benzodiazepines (see "Interaction with other drugs and other forms of interaction").

Form release / dosage:

Granules of prolonged action, 100 mg, 250 mg, 500 mg, 750 mg and 1000 mg.

Packaging:

For 100 mg, 250 mg, 500 mg, 750 mg and 1000 mg in sachets from a three-layer complex (paper / aluminum / ionomer resin).

For 30 or 50 bags together with the instructions for use are placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C. Do not chill or freeze.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-005197/08

Date of registration:03.07.2008

Expiration Date:Unlimited

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

Manufacturer: & nbsp

SANOFI WINTHROP INDUSTRIE France

Representation: & nbspSanofi Aventis GroupSanofi Aventis Group

Information update date: & nbsp23.04.2017

Illustrated instructions

Instructions

Depakin® Chronosphere (Depakine® Chronosphere)