Depakinum Enterik 300

General characteristics. Structure:

Contains in 1 tablet covered with a kishechnorastvorimy cover: kernel:
active ingredient: sodium Valproatum - 300 mg;
excipients: K-90 povidone (поливидон K-90) - 8 mg, silicate calcium
hydrate - 15 mg, talc - 9 mg, magnesium stearate - 3 mg;
cover:
methacrylic acid and methylmethacrylate copolymer (1:1) - прибл. 19,63 mg, talc - прибл. 19,63 mg, Opaspry white * (K1-7000 type) - прибл. 17,79, целлацефат (cellulose ацетатфталат) - прибл. 23,22 mg, diethyl phthalate - прибл. 9,73 mg. * - Opaspry white: titanium dioxide - 17,50 mg, a hypro rod - 0,29 mg.

Description. Round biconvex tablets coated white color.

Pharmacological properties:

Faomakodinamika. The antiepileptic drug rendering central myorelaxation and
sedative action.
Shows antiepileptic activity at various types of epilepsy. The main mechanism of action, apparently, is connected with impact of valproic acid on GAMK-ergichesky system: increases contents gamma аминомаслянной acids (GAMK) in the central nervous system (CNS) and activates GAMK-ergichesky transfer.

Pharmacokinetics. Absorption. Bioavailability of valproic acid at intake is close to 100%.
Average therapeutic range of serumal concentration makes 50-100 mg/l. At reasonable need of achievement of higher concentration for a blood plasma it is necessary to weigh carefully a ratio of the expected advantage and risk of emergence of side effects, in particular dozozavisimy as at concentration of valproic acid over 100 mg/l are expected increase in side effects  up to development of intoxication. At plasma concentration of valproic acid over 150 mg/l are required a drug dose decline. At course administration of drug equilibrium concentration of valproic acid in blood serum is reached within 3-14 days.

Distribution
The volume of distribution depends on age and usually makes 0,13-0,23 l/kg of body weight or at people of young age of 0,13-0,19 l/kg of body weight.
Communication with proteins of a blood plasma of valproic acid (it is preferential with albumine) high (90-95%), dozozavisimy and saturable. At patients of advanced age, patients with a renal and liver failure communication with proteins of a blood plasma decreases. At a heavy renal failure concentration free (therapeutic active) fractions of valproic acid can increase to 8,5-20%.
At a hypoproteinemia the general concentration of valproic acid (free + connected with proteins of fraction) can not change, but can decrease because of increase in metabolism free (not connected with proteins) fractions of valproic acid.
Valproic acid gets into cerebrospinal liquid and into a brain. Concentration of valproic acid in liquor makes 10% of the corresponding concentration in blood serum.
Valproic acid gets into breast milk of nursing mothers. In a condition of achievement of equilibrium concentration of valproic acid in blood serum, its concentration in breast milk makes up to 10% of its concentration in blood serum.

Metabolism
Metabolism of valproic acid is carried out in a liver by a glyukuronirovaniye, and also beta, an omega - and omega-1-oxidations. More than 20 metabolites are revealed, metabolites after an omega oxidation possess a hepatotoxic action. Valproic acid has no the inducing effect on the enzymes entering metabolic system of P450 cytochrome: unlike the majority of other antiepileptic drugs, valproic acid does not influence degree as own metabolism, and on degree metabolism of other substances, such as estrogen, progestogens and indirect anticoagulants.

Removal
Valproic acid is preferential removed by kidneys after conjugation with glucuronic acid and beta oxidations.
The plasma clearance of valproic acid at patients with epilepsy makes 12,7 ml/min.
The elimination half-life makes 15-17 hours. At a combination with the antiepileptic drugs inducing microsomal enzymes of a liver, the plasma clearance of valproic acid increases, and the elimination half-life decreases, extent of their change depends on extent of induction of microsomal enzymes of a liver other antiepileptic drugs. The elimination half-life at children is more senior than 2-month age is close to that at adults.
At patients with liver diseases the elimination half-life of valproic acid increases.
At overdose increase in an elimination half-life was observed till 30 o'clock. Only the free fraction of valproic acid in blood (10%) is exposed to a hemodialysis.
Features of pharmacokinetics at pregnancy.
At increase in volume of distribution of valproic acid in the third trimester of pregnancy, increase its renal and hepatic clearance. At the same time, despite administration of drug in  a constant dose,  decrease in serumal concentration of valproic acid is possible. Besides at pregnancy communication of valproic acid with proteins of plasma can change that can lead to increase in content in blood serum free (therapeutic active) fractions of valproic acid.

Indications to use:

At adults: as monotherapy or in a combination with other antiepileptic means:
- For treatment of generalized epileptic attacks: clonic, tonic, toniko-clonic, absentias epileptica, miokonichesky, atonic; Lennox-Gasto's syndrome;
- For treatment of partial epileptic attacks: partial attacks with secondary generalization or without it.
At children: as monotherapy or in a combination with other antiepileptic means:
- For treatment of generalized epileptic attacks: clonic, tonic, toniko-clonic, absentias epileptica, miokonichesky, atonic; Lennox-Gasto's syndrome;
- For treatment of partial epileptic attacks: partial attacks with secondary generalization or without it.
- Prevention of spasms at high temperature when such prevention is necessary.

Route of administration and doses:

This dosage form is not recommended for children up to 6 years (risk of hit of a tablet in respiratory tracts when swallowing). Up to 11 years it is preferable to children to apply a dosage form - syrup to intake.
Депакин® Enterik 300 is intended for intake preferably during meal.
The dose should be selected taking into account age and the body weight of the patient.
At monotherapy the initial daily dose for adults and children makes usually 5k10 mg/kg, then it is raised on 5 mg/kg by each 4-7 days to achievement of a dose with optimum effect.
Average daily dose:
- for children of 6-14 years (body weight of 25-40 kg) - 30 mg/kg of body weight (600-1200 mg);
- for teenagers of 14-18 years (body weight of 40-60 kg) - 25 mg/kg of body weight (1000-1500 mg);
- for adults (body weight is from 60 kg and above) - 20 mg/kg of body weight (1200-2100 mg). The daily dose is recommended to be divided into 2-3 receptions.
The average daily dose can be increased under control of concentration of valproic acid in blood.
In certain cases the full therapeutic effect of valproic acid appears not at once, and develops within 4-6 weeks. Therefore it is not necessary to increase a daily dose above the recommended average daily dose before this term.
For the patients accepting earlier antiepileptic means, transfer into administration of drug of Depakin® Enterik 300 it is necessary to carry out gradually, reaching an optimum dose of drug approximately within 2 weeks. At the same time the dose of the being accepted earlier antiepileptic drug, especially phenobarbital decreases at once. If earlier being accepted antiepileptic drug is cancelled, then its cancellation has to be carried out gradually.
As other antiepileptic drugs can induce reversibly microsomal enzymes of a liver, follows within 4-6 weeks after reception of the last dose of these antiepileptic drugs to monitorirovat concentration of valproic acid in blood and if necessary (in process of reduction of the effect of these drugs inducing metabolism) to reduce a daily dose of valproic acid.
At patients with a renal failure and or a hypoproteinemia it is necessary to consider a possibility of increase in concentration free (therapeutic active) fractions of valproic acid in blood serum, and if necessary to reduce a valproic acid dose, being guided at selection of a dose, mainly by a clinical picture, but not by the general content of valproic acid in blood serum (free fraction and the blood plasma of fraction connected with proteins together) to avoid possible mistakes in selection of a dose.

Features of use:

Severe damage of a liver
The contributing factors
Clinical experience shows that patients of risk group are the patients receiving at the same time several antiepileptic drugs, children are younger than three-year age with heavy convulsive attacks, especially against the background of damage of a brain, a delay of intellectual development and/or inborn metabolic or degenerative diseases.
After  three-year  age  the risk  of damage  of a liver  considerably  decreases  and progressively decreases in process of increase in age of the patient. In most cases such damage of a liver arose within the first 6 months of treatment. Symptoms, suspicious on damage of a liver
For early diagnosis of damage of a liver clinical observation of patients is obligatory. In particular it is necessary to pay attention to emergence of the following symptoms which can precede developing of jaundice, especially patients have risk groups (see above):
- the nonspecific symptoms which especially suddenly began, such as adynamy, anorexia, a lethargy, drowsiness which sometimes are followed by the repeating vomiting and abdominal pains;
- resuming of convulsive attacks at patients with epilepsy.
It is necessary to warn patients or members of their families (at drug use by children) that they have to report about emergence of any of these symptoms to the attending physician immediately. Patients should conduct immediately clinical examination and a laboratory research of indicators of function of a liver. Identification
Definition of functional trials of a liver should be carried out before an initiation of treatment and then periodically within the first 6 months of treatment. Among ordinary researches the researches reflecting a condition of proteinaceous and synthetic function of a liver, especially prothrombin ratio are most informative. Confirmation of an aberration of a prothrombin ratio, especially in combination with aberrations of other laboratory indicators (considerable decrease in content of fibrinogen and blood-coagulation factors, increase in concentration of bilirubin and increase in activity of transaminases) demands phase-out of the drug Depakin® of Hronosfer of TM. For the purpose of precaution if patients received at the same time salicylates, their reception has to be also stopped as they are metabolized on the same metabolic way, as valproic acid. Pancreatitis
Children of younger age are in group of the increased risk of development of pancreatitis, with increase in age of the child the risk decreases. Heavy spasms, neurologic disturbances or anticonvulsant therapy can be risk factors of development of pancreatitis. The liver failure which is combined with pancreatitis increases risk of a lethal outcome.
Patients who have severe pains in a stomach nausea, vomiting and/or anorexia, have to be immediately inspected. In case of confirmation of pancreatitis, in particular at a superactivity of enzymes of a pancreas in blood, use of valproic acid the corresponding treatment has to be stopped and begun. Suicide thoughts and attempts
It was reported about emergence of suicide thoughts or attempts at the patients receiving antiepileptic drugs according to some indications. Meta-analysis of randomized placebos - controlled researches of antiepileptic drugs also showed small increase in risk of suicide thoughts and attempts. The mechanism of this effect is unknown.
Therefore the patients receiving Depakin® Hronosferatm should be controlled constantly regarding suicide thoughts or attempts, and in case of their emergence it is necessary to carry out the corresponding treatment. It is recommended to patients and persons who are looking after them at emergence in the patient of suicide thoughts or attempts to see immediately a doctor. Karbapenema
Simultaneous use of karbapenem is not recommended (see the section "Interaction with Other Medicines and Other Forms of Interaction").
Women of childbearing age
At use of drug for women of childbearing age it is necessary to exclude pregnancy and to make sure that the woman uses a reliable way of contraception.
Control methods of safety of treatment by the drug Depakin® Hronosfera™
Before use of the drug Depakin® Hronosfera™ and periodically within the first 6 months of treatment, especially patients from risk group have development of damage of a liver, it is necessary to conduct a research of function of a liver. As well as at use of the majority of antiepileptic drugs, perhaps slight increase of activity of "hepatic" enzymes, especially in an initiation of treatment which proceeds without clinical manifestations and is passing. At these patients carrying out more detailed research of laboratory indicators, including a prothrombin ratio is necessary, and drug dose adjustment, and if necessary, both repeated clinical and laboratory inspection can be required. Before therapy or surgery, in case of spontaneous developing of hypodermic hematomas or bleedings, it is recommended to carry out hematologic blood test (to define a leukocytic blood count, including quantity of thrombocytes; bleeding time and koagulogramma). Children
At children uses of drug are younger than three-year age in case of need its use in monotherapy and in the dosage form recommended for children is recommended. At the same time before an initiation of treatment it is necessary to weigh a ratio of potential advantage of use of valproic acid and risk of damage of a liver and development of pancreatitis at its use.
At children more young than 3 years it is necessary to avoid simultaneous use of salicylates in connection with risk of a hepatotoxic and bleedings. Renal failure
The valproic acid dose decline in connection with increase in concentration of its free fraction in blood serum can be required. In case of impossibility of monitoring of plasma concentration of valproic acid, the dose of drug should be adjusted on the basis of clinical observation of the patient. Insufficiency of enzymes of a carbamide cycle
At suspicion on insufficiency of enzymes of a carbamide cycle, use of valproic acid is not recommended. At such patients several cases of a giperammoniyemiya with a stupor or a coma were described. In these cases of a research
metabolism it is necessary to carry out prior to treatment by valproic acid.
At children with inexplicable gastrointestinal symptoms (anorexia, vomiting, cases
cytolysis), a lethargy or a coma in the anamnesis, with a delay of intellectual development or at
the family anamnesis of death of the newborn or child, prior to treatment of valproyevy
metabolism researches, in particular definition have to be conducted by acid
ammoniyemiya (presence of ammonia and its connections at blood) on an empty stomach and after reception
food.
Patients with a system lupus erythematosus
Though it is shown that in the course of treatment by the drug Depakin® Hronosfera™ of disturbance of functions of immune system meet exclusively seldom, the potential advantage of its use needs to be compared with potential risk at purpose of drug to patients with a system lupus erythematosus. Increase in body weight
Patients should be warned about risk of increase in body weight in an initiation of treatment, and it is necessary to take measures, generally dietary, for data of this phenomenon to a minimum. Ethanol
During treatment valproic acid does not recommend the ethanol use.

Influence on ability to manage vehicles or to be engaged in other potentially opsny types in deyatelnost.
During treatment it is necessary to be careful during the driving of motor transport and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions (risk of development of drowsiness, especially in cases of the combined antiepileptic therapy and in combination with benzodiazepines).

Side effects:

For the indication of frequency of development of the undesirable side reactions (USR) classification of the NPR of World Health Organization is used: very frequent> 10%; frequent> 1 and <10%; infrequent> 0,1 and <1%; rare> 0,01 and <0,1%; very rare <0,01%, unknown frequency (when according to the available data it is not possible to estimate the frequency of development of the NPR).
Inborn, inherited and genetic disorders
Teratogenic risk (see "see the section "Pregnancy and Period of Feeding by a Breast"). Disturbances from blood and lymphatic system
Frequent
Thrombocytopenia. Rare
Pancytopenia,  anemia,  leukopenia,  disturbances of a marrowy hemopoiesis, including the isolated aplasia of cells of a red blood sprout. Unknown frequency
Agranulocytosis,  isolated decrease in content of fibrinogen in the blood and lengthening of a prothrombin time which are usually not followed by clinical manifestations and especially at use of high doses ( valproic acid has an inhibiting effect on the second phase of aggregation of thrombocytes). Disturbances from a nervous system Frequent
Passing and/or dozozavisimy easy postural tremor and drowsiness.
Infrequent
Ataxy.
Rare
Extrapyramidal  frustration  which  can be  irreversible,  including reversible parkinsonism. Very rare
Dementia which is combined with a brain atrophy, reversible within several weeks or months after drug withdrawal.
Several cases of development of a stupor and lethargy sometimes leading to a passing coma / encephalopathy. They can be isolated or be combined with increase of the frequency of convulsive attacks (despite treatment) decreasing at drug withdrawal or reduction of its dose. These cases, mainly, were observed during a combination therapy (in particular with phenobarbital or topiramaty) or after sharp increase in a dose of valproic acid. Giperammoniyemiya who is combined with neurologic symptomatology (in this case the patient needs additional inspection) (see the section "Special Instructions"). Disturbances from an acoustic organ and labyrinth disturbances Rare
Reversible or irreversible deafness. Disturbances from an organ of sight
Unknown frequency
Diplopia, nystagmus, flashing of "front sights" before eyes. Disturbances from digestive tract
Frequent
In  an initiation of treatment nausea, vomiting, pains in epigastriums, diarrhea which at the continuing administration of drug usually disappear in several days. Very rare
Pancreatitis, sometimes with a lethal outcome.
Disturbances from kidneys and urinary tract
Very rare
Enuresis, there were several separate messages on development of a reversible syndrome of Fankoni which mechanism of development is still not clear. Disturbances from skin and hypodermic fabrics
Frequent
Passing or dozozavisimy alopecia. Very rare
Toxic epidermal necrolysis, Stephens-Johnson's syndrome, mnogoformny erythema, rash.
Disturbances from a metabolism and food
Frequent
The isolated and moderate giperammoniyemiya in the absence of changes of indicators
functional trials of a liver and neurologic manifestations, not demanding cancellation
drug.
Very rare
Hyponatremia.
Unknown frequency
Syndrome of disturbance of secretion of antidiuretic hormone.
Disturbances from vessels
Rare Vasculitis.
The general frustration and disturbances in an injection site
Frequent
Increase in body weight. As obesity is risk factor for development of a syndrome of polycystic ovaries, it is necessary to watch carefully patients with increase in body weight. Very rare
Small peripheral hypostases.
Disturbances from immune system
Frequency is unknown
Quincke's disease, syndrome of medicinal rash with an eosinophilia and system symptoms (DRESS syndrome), allergic reactions, for example, a small tortoiseshell.
Disturbances from a liver and biliary tract
Rare
Damages of a liver (see the section "Special Instructions").
Disturbances from generative organs and a mammary gland
Rare
Amenorrhea and dysmenorrhea. Unknown frequency Male infertility. Disturbances of mentality
Infrequent
Irritability, hyperactive condition, confusion of consciousness, especially at the beginning
treatments.
Rare
Changes of behavior, mood, depression, feeling of fatigue, aggression,
psychoses, unusual excitement, motive concern, dysarthtia.
Unknown frequency
Hallucinations.

Interaction with other medicines:

Influence of valproic acid on other drugs.
Neuroleptics, inhibitors of a monoaminooxidase (MAO), antidepressants, benzodiazepines.
Valproic acid can exponentiate effect of other psychotropic drugs, such as neuroleptics, MAO inhibitors, antidepressants and benzodiazepines; therefore at their simultaneous use with valproic acid careful medical observation and, if necessary, correction of doses is recommended. Lithium drugs
Valproic acid does not influence serumal concentration of lithium. Phenobarbital
Valproic acid increases plasma concentration of phenobarbital (due to reduction of his hepatic metabolism) in this connection development of sedative action of the last, especially at children is possible. Therefore careful medical observation of the patient during the first 15 days of a combination therapy with an immediate dose decline of phenobarbital in case of development of sedative action and, if necessary, definition of plasma concentration of phenobarbital is recommended. Primidonum
Valproic acid increases plasma concentration of Primidonum with strengthening of its side effects (such as sedative action); at prolonged treatment these symptoms disappear. Careful clinical observation of the patient, especially at the beginning of a combination therapy with dose adjustment of Primidonum if necessary is recommended. Phenytoinum
Valproic acid reduces the general plasma concentration of Phenytoinum. Besides valproic acid increases concentration of free fraction of Phenytoinum with a possibility of development of symptoms of overdose (valproic acid forces out Phenytoinum from communication with proteins of plasma and slows down its hepatic catabolism). Therefore careful clinical observation of the patient and definition of concentration of Phenytoinum and its free fraction in blood is recommended. Carbamazepine
At simultaneous use of valproic acid and carbamazepine it was reported about emergence of clinical manifestations of toxicity of carbamazepine as valproic acid can exponentiate toxic effects of carbamazepine.
Careful clinical observation of such patients, especially at the beginning of  a combination  therapy  with  correction    , if necessary,  of a carbamazepine dose is recommended. Lamotridzhin
Valproic acid slows down metabolism of a lamotridzhin in a liver and increases an elimination half-life of a lamotridzhin almost twice. This interaction can lead to increase in toxicity of a lamotridzhin, in particular to development of heavy skin reactions, including a toxic epidermal necrolysis. Therefore careful clinical observation and, if necessary, correction (decrease) of a dose of a lamotridzhin is recommended. Zidovudine
Valproic acid can increase plasma concentration of a zidovudine that
leads to increase in toxicity of a zidovudine.
Felbamat
Valproic acid can lower average values of clearance of a felbamat by 16%. Nimodipin (for intake and, on extrapolations, solution for parenteral administration)
Strengthening of hypotensive effect of a nimodipin in connection with increase in its plasma concentration (inhibition of metabolism of a nimodipin valproic acid). Influence of other drugs on valproic acid
The antiepileptic drugs capable to induce microsomal enzymes of a liver (including Phenytoinum, phenobarbital, carbamazepine) reduce plasma concentration of valproic acid. In case of a combination therapy of a dose of valproic acid have to be adjusted depending on clinical reaction and concentration of valproic acid in blood. Felbamat
At a combination of a felbamat and valproic acid the clearance of valproic acid decreases by 22-50% and respectively plasma concentration of valproic acid increase. It is necessary to control plasma concentration of valproic acid. Meflokhin
Meflokhin accelerates metabolism of valproic acid and itself is capable to cause spasms therefore at their simultaneous use development of an epileptic seizure is possible.
Drugs of the St. John's Wort which is made a hole
At simultaneous use of valproic acid and drugs of the St. John's Wort which is made a hole perhaps decrease in anticonvulsant efficiency of valproic acid.
The drugs having high and strong communication with proteins of plasma (acetylsalicylic acid)
In case of the simultaneous use of valproic acid and drugs having high and strong communication with proteins of plasma (acetylsalicylic acid) increase in concentration of free fraction of valproic acid is possible. Indirect anticoagulants
At simultaneous use of valproic acid and indirect anticoagulants careful control of a prothrombin ratio is required. Cimetidinum, erythromycin
Serumal concentration of valproic acid can increase in case of simultaneous use of Cimetidinum or erythromycin (as a result of delay of her hepatic metabolism). Karbapenema (panipeny, meropeny, imipeny)
The decrease in concentration of valproic acid in blood at its simultaneous use from karbapenema leading to 60-100% to decrease in concentration of valproic acid in blood in two days of joint therapy which was sometimes combined with developing of spasms. It is necessary to avoid simultaneous use of karbapenem for patients with the picked-up valproic acid dose in connection with their ability quickly and intensively to reduce concentration of valproic acid in blood. If it is impossible to avoid treatment of a karbapenemama, it is necessary to carry out careful monitoring of concentration of valproic acid to blood. Rifampicin
Rifampicin can reduce concentration of valproic acid in blood that brings
to loss of therapeutic effect  of valproic acid. Therefore can
to be required increase in a dose of valproic acid at simultaneous use
rifampicin.
Other interactions
With topiramaty
Simultaneous use of valproic acid and topiramat was associated with encephalopathy and/or a giperammoniyemiya. The patients receiving at the same time these two drugs have to be under careful medical observation regarding development of symptoms of giperammoniyemichesky encephalopathy. About estrogen-progestogennymi drugs
Valproic acid has no ability to induce enzymes of a liver and thereof valproic acid does not reduce efficiency estrogen-progestogennykh of drugs at the women using hormonal ways of contraception.
With ethanol and other potentially gepatotoksichny drugs
At their use along with valproic acid strengthening is possible
hepatotoxic effect of valproic acid.
With clonazepam
Simultaneous use of clonazepam with valproic acid can bring in isolated cases to strengthening of expressiveness of the absansny status. With miyelotoksichny medicines
At simultaneous use with valproic acid the risk of oppression of a marrowy hemopoiesis increases.

Contraindications:

-   Hypersensitivity  to    sodium Valproatum,    valproic acid, seven-sodium Valproatum, a valpromid or to any of drug components.
- Acute hepatitis.
- Chronic hepatitis.
- A serious illness of a liver (especially medicinal hepatitis) in the anamnesis at the patient and his close blood relatives.
- Severe damages of a liver with a lethal outcome at use of valproic acid for close blood relatives of the patient.
- Heavy abnormal liver functions or pancreas.
- Hepatic porphyria.
- Hemorrhagic diathesis, thrombocytopenia.
- A combination with meflokhiny.
- A combination with the St. John's Wort which is made a hole.
- Children's age up to 6 years (risk of hit of a tablet in respiratory tracts when swallowing).

With care
- At diseases of a liver and pancreas in the anamnesis.
- At pregnancy.
- At inborn fermentopatiya.
- At oppression of a marrowy hemopoiesis (a leukopenia, thrombocytopenia, anemia).
- At a renal failure (correction of doses is required).
- At a hypoproteinemia.
- The patients receiving several anticonvulsant drugs because of the increased risk have damages of a liver.
- At a concomitant use of the drugs provoking convulsive attacks or reducing a threshold of convulsive readiness such as tricyclic antidepressants, selection inhibitors of repeated serotonin reuptake, derivative fenotiazin, phenyl propyl ketone derivatives, chloroquine, бупропион, трамадол (risk of provoking of convulsive attacks).
- At a concomitant use of neuroleptics, inhibitors of a monoaminooxidase (MAO), antidepressants, benzodiazepines (possibility of potentiation of their effects).
- At a concomitant use of phenobarbital, Primidonum, Phenytoinum, a lamotridzhin, a zidovudine, a felbamat, acetylsalicylic acid, indirect anticoagulants, Cimetidinum, erythromycin, karbapenem, rifampicin, a nimodipin (in connection with pharmacokinetic interactions on a metabolic rate or communication with proteins of plasma change of plasma concentration or these drugs and/or valproic acid, for more details see the section "Interaction with Other Medicines" is possible).
- At simultaneous use of carbamazepine (risk of potentiation of toxic effects of carbamazepine and decrease in plasma concentration of valproic acid).
- At simultaneous use of a topiramat (risk of development of encephalopathy).

Pregnancy and period of an ormleniye breast.
The risk connected with development of epileptic seizures during pregnancy
 During pregnancy development of generalized toniko-clonic
epileptic seizures, the epileptic status with development of a hypoxia can
to represent extra risk, both for mother, and for a fruit in connection with a possibility of a lethal outcome.
The risk connected using the drug Depakin® Enterik 300 during pregnancy.
The pilot studies of reproductive toxicity conducted on mice, rats and rabbits showed existence at valproic acid of teratogenic action.
The available clinical data confirm that at the children who were born at mothers with epilepsy receiving valproic acid the increased frequency of occurrence of disturbances of pre-natal development of varying severity is observed (neurotubule malformations; craniofacial deformations; malformations of extremities, cardiovascular system; and also the multiple defects of pre-natal development mentioning different systems of bodies) in comparison with the frequency of their occurrence at reception by pregnant women of some other antiepileptic drugs.
The available data assume existence of interrelation between pre-natal influence of valproic acid and risk of an arrest of development (especially speech development) in the children who were born at mothers with epilepsy accepting valproic acid. The arrest of development is often combined with malformations and the phenomena of a dismorfizm. However in cases of an arrest of development at such children it is difficult to establish precisely valproic acid relationship of cause and effect because of a possibility of simultaneous influence of other factors, such as low I.Q. of mother or both parents; genetic, social factors, environmental factors; insufficient efficiency of the treatment directed to prevention of epileptic attacks at mother during pregnancy.
Also it was reported about development of various autistic frustration in children,
undergone pre-natal influence of valproic acid.
Both monotherapy by valproic acid, and a combination therapy with inclusion
valproic acid, are associated with a pregnancy failure, but on
to the available data the combined antiepileptic therapy including
valproic acid, is associated with higher risk of adverse
the result of pregnancy in comparison with monotherapy by valproic acid.
Due to the above, Depakin® Enterik 300 should not be applied at pregnancy and at women of childbearing age without emergency. Its use is possible, for example, in situations when other antiepileptic drugs are inefficient or the patient does not transfer them.
The question of need of use of the drug Depakin® Enterik 300 or possibilities of refusal of its use has to be solved prior to use of drug or be reconsidered if the woman receiving Depakin® Enterik 300 plans pregnancy.
Women of childbearing age have to use effective ways of contraception during treatment by the drug Depakin® Enterik 300. Women of childbearing age have to be informed on risks and advantage of use of valproic acid during pregnancy.
If the woman with epilepsy plans pregnancy or became pregnant, the question of treatment continuation by valproic acid or its cancellation is solved after revaluation of a ratio of advantage and risk. If after revaluation of a ratio of advantage and risk treatment by the drug Depakin® Enterik 300 after all has to be continued during pregnancy, then it is recommended to apply it in the smallest effective daily dose divided into several receptions. It should be noted that at pregnancy use of dosage forms of drug of slow release is preferable.
A month before conception and within 2 months after it it is necessary to add folic acid to antiepileptic treatment (in a dose of 5 mg a day) as it can minimize risk of malformations of a neurotubule.
It is necessary to exercise constant special prenatal control for detection of possible defects of formation of a neurotubule or other malformations of a fruit. Risk for newborns
It was reported about development of isolated cases of a hemorrhagic syndrome in newborns whose mothers accepted valproic acid during pregnancy. This hemorrhagic syndrome, is connected with a hypofibrinogenemia and perhaps caused by decrease in maintenance of blood-coagulation factors. Also it was reported about development of an afibrinogenemiya with a lethal outcome. This hemorrhagic syndrome should be distinguished from deficit of the vitamin K caused by phenobarbital and other inductors of microsomal enzymes of a liver.
Therefore at the newborns born by mothers receiving valproic acid it is necessary  to define surely quantity of thrombocytes in blood, plasma concentration of fibrinogen, blood-coagulation factors and a koagulogramma. It was reported about hypoglycemia cases at newborns whose mothers accepted valproic acid during the third trimester of pregnancy. Feeding period breast
Valproic acid excretion in breast milk low, its concentration in milk makes 1-10% of its concentration in blood serum.
Proceeding from data of literature and brief clinical experience, at monotherapy by the drug Depakin® Enterik 300 mothers can plan breastfeeding, but at the same time it is necessary to take a profile of side effects of drug, the hematologic disturbances which are especially caused by it into account.

Overdose:

Clinical manifestations of acute massive overdose usually proceed in the form of a coma with hypotonia of muscles, a hyporeflexia, a miosis, respiratory depression, a metabolic acidosis. Cases of the intracranial hypertensia connected with brain hypostasis were described.
At massive overdose the lethal outcome, however usually the forecast is possible at overdose favorable.
Symptoms of overdose can vary, was reported about development of convulsive attacks at very high plasma concentration of valproic acid. Acute management at overdose in a hospital has to be following: a gastric lavage which is effective within 10-12 hours after administration of drug, observation of a condition of cardiovascular and respiratory system and maintenance of an effective diuresis. In some cases with success Naloxonum was applied. In very hard cases of massive overdose the hemodialysis and hemoperfusion were effective.

Storage conditions:

In the dry place at a temperature not above 25 °C. To store in the place, unavailable to children! Period of validity 3 years. Not to take medicine after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

The tablets covered with a kishechnorastvorimy cover on 300 mg.
On 10 tablets in the blister from the PVC/ave of 10 blisters together with the instruction on a medical use place in a cardboard pack.