Депакин® Hronosfera

General characteristics. Structure:

Contains in 1 bag of Депакин®Хроносфера™ 100 mg:
active ingredient: sodium Valproatum - 66,66 mg and valproic acid - 29,03 mg (all in terms of sodium Valproatum - 100 mg);
excipients: hard paraffin - 101,26 mg, a glitserola дибегенат 106,05 mg,
silicon dioxide colloid водный*.
Contains in 1 bag of Депакин®Хроносфера™ 250 mg:
active ingredient: sodium Valproatum - 166,76 mg and valproic acid - 72,61 mg (all in terms of sodium Valproatum - 250 mg);
excipients: paraffin of firm 253,32 mg, a glitserola дибегенат - 265,30 mg,
silicon dioxide colloid водный*.
Contains in 1 bag of Depakin® of Хроносфера™ 500 mg:
active ingredient: sodium Valproatum - 333,30 mg and valproic acid - 145,14 mg (all in terms of sodium Valproatum - 500 mg);
excipients: paraffin of firm 506,31 mg, a glitserola дибегенат - 530,25 mg,
silicon dioxide colloid водный*.
Contains in 1 bag of Депакин®Хроносфера™ 750 mg:
active ingredient: sodium Valproatum - 500,06 mg and valproic acid - 217,75 mg (all in terms of sodium Valproatum - 750 mg);
excipients: paraffin of firm 759,64 mg, a glitserola дибегенат - 795,55 mg,
silicon dioxide colloid водный*.
Contains in 1 bag of Деникин®Хроносфера™ 1000 mg:
active ingredient: sodium Valproatum - 666,60 mg and valproic acid - 290,27 mg (all in terms of sodium Valproatum - 1000 mg);
Excipients: hard paraffin - 1012,63 mg, a glitserola дибегенат-1060,50 mg, silicon dioxide colloid водный*.
* - add spraying after process of cooling of fusion and express  percentage of  quantity  of four  other  components:  0,7%  (the approximate quantity absorbed on granules: 0,56%). DESCRIPTION
Waxy microgranules of almost white or slightly yellowish color, easily loose without formation of agglomerates.

Pharmacological properties:

The antiepileptic drug having the central myorelaxation and sedative effect.
Shows antiepileptic activity at various types of epilepsies. The main mechanism of action, apparently, is connected with impact of valproic acid on GAMK-ergichesky system: increases the content of piperidic acid (GAMK) in the central nervous system (CNS) and activates GAMK-ergichesky transfer.

Pharmacokinetics. Absorption
Bioavailability of valproic acid at intake is close to 100%. Meal does not influence a pharmacokinetic profile of drug.
The maximum concentration of valproic acid in a blood plasma (Stakh) after administration of drug of Depakin® Hronosfera™ is inside reached approximately in 7 hours. In comparison by the dosage form covered with an enterosoluble cover, equivalent doses of the drug Depakin® Hronosfera™ it is characterized by longer absorption, identical bioavailability, more linear correlation between doses and plasma concentration of valproic acid (the general concentration and concentration of free fraction). Besides Stakh and the maximum plasma concentration of free fraction of valproic acid are lower (decrease makes about 25%), but at the same time there is rather stabler phase of the plateau of plasma concentration from 4 to 14 hours after reception, the size of fluctuations of plasma concentration at administration of drug of Depakin® Hronosfera™ in comparison with the dosage form covered with an enterosoluble cover decreases twice therefore valproic acid is more evenly distributed in fabrics within a day.
At course administration of drug equilibrium concentration of valproic acid in blood serum is reached within 3-14 days.
The serumal concentration of valproic acid making 40 - 100 mg/l (300 - 700 µmol/l) (are defined before reception of the drug dose first within a day) At serumal concentration of valproic acid are usually effective over 100 mg/l increase in side effects up to development of intoxication is expected. 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. Due to the reduction of size of fluctuations of plasma concentration at administration of drug of Depakin® Hronosfera™, valproic acid is more evenly distributed in fabrics within a day in comparison with a dosage form of valproic acid with immediate release.
Communication of valproic acid with proteins of a blood plasma (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 a blood plasma of fraction) can not change, but can decrease because of increase in metabolism free (the blood plasma which is 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, that is, is close to concentration of free fraction of valproic acid 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 omegas-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 extent of 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.
At use of valproic acid in monotherapy its elimination half-life makes 12-17 hours. At a combination with the antiepileptic drugs inducing microsomal enzymes of a liver (such as Primidonum, Phenytoinum, phenobarbital and carbamazepine), 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 is exposed to a hemodialysis (5k10%).
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 a blood 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.
- Treatment and prevention of bipolar affective disorders
At babies (since 6th month of life) and 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:

Depakin® Hronosfera™ is a dosage form which especially well is suitable for treatment of children (if they are capable to swallow soft food) or adults with the complicated swallowing.
Depakin® Hronosfera™ represents the granules of the prolonged action providing more uniform concentration of valproic acid in blood and, respectively, more uniform within a day its distribution in fabrics. Dosing mode
Bipolar affective disorders
The dose has to be selected and controlled by the attending physician individually. The daily dose has to be established taking into account age and the body weight of the patient. The recommended initial dose makes 20 mg (in terms of sodium Valproatum) on body weight kg. The dose has to be whenever possible quickly increased to the minimum dose providing required therapeutic effect.
The recommended maintenance dose for treatment of bipolar disorders is in range between 1000 mg and 2000 mg (in terms of sodium Valproatum) in days. The dose has to be selected according to the individual clinical answer of the patient.        It is necessary  to apply  individually picked up minimum clinically effective dose to prevention of maniacal states. Epilepsy
In monotherapy the initial daily dose makes usually 5-10 mg (in terms of sodium Valproatum) on body weight kg, then it is raised on 5 mg/kg by everyone 4-7 to achievement of the optimum dose allowing to prevent emergence of attacks of epilepsy.
Average daily dose:
- for children (up to 14 years) - 30 mg/kg of body weight;
- for teenagers of 14-18 years - 25 mg/kg of body weight;
- for adults and patients of advanced age (body weight is from 60 kg and above) - 20 mg/kg of body weight.
Thus, the daily doses given below are recommended.

Age                                     Body weight                       Average daily dose * (mg/days)
Babies from 6 to 12 months.      About 7,5-10               kg 150-300 mg
Children from 1 to 3 years                       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                     About 25-40                kg 750-1200 mg
Teenagers of 14 years                    About 40-60                 kg 1000-1500 mg
Adults                                    From 60 kg and                it is higher than 1200-2100 mg
* - a dose in terms of the number of milligrams of Valproatum of sodium
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. Though the daily dose is defined depending on age and the body weight of the patient, it is necessary to take into account a wide range of individual sensitivity to valproic acid.
To accurate correlation between a daily dose, concentration of valproic acid in blood serum and therapeutic effect it is not established. Therefore the optimum dose of drug has to be selected, mainly, on the basis of the clinical answer. Definition of concentration of valproic acid can serve in blood serum as addition to clinical observation if epilepsy does not give in to control or development of side effects is suspected. Doses, providing the serumal concentration of valproic acid making 40 - 100 mg/l (300 - 700 µmol/l) are usually effective. At reasonable need of achievement of higher concentration for blood serum it is necessary to weigh carefully a ratio of the expected advantage and risk of emergence of side effects, in particular dozozavisimy as at serumal concentration of valproic acid over 100 mg/l are expected increase in side effects up to development of intoxication.
Therefore the serumal concentration defined before reception of the first dose in days should not exceed 100 mg/l.

Upon transition from dosage forms of the drug Depakin® of immediate release or the slowed-down release which well controlled epilepsy to Depakin® Hronosfera™ it is recommended to keep the same daily dose. For the patients accepting earlier antiepileptic means, transfer into administration of drug of Depakin® Hronosfera™ should be carried 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.
In need of a valproic acid combination with other antiepileptic means, they should be added gradually (see the section "Interaction with Other Medicines and Other Forms of Interaction").
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 the drug Depakin® Hronosfera™. Special groups of patients
Though patients of advanced age have changes of pharmacokinetics of valproic acid, they have the limited clinical importance and the valproic acid dose at patients of advanced age has to be selected according to achievement of ensuring control over epilepsy attacks.
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. Route of administration
Drug is accepted inside.
Bags of Depakin® of Хроносфера™ 100 mg are applied only at children and babies. Bags of Depakin® Hronosfera™ of 1000 mg are applied only at adults. The daily dose is recommended to be accepted in one or two receptions, are preferable during meal.
Use is in one step possible at well controlled epilepsy. The drug Depakin® Hronosfera™ has to be filled on a surface of soft food or drink, cold or room temperature (yogurt, orange juice, fruit puree etc.).
The drug Depakin® Hronosfera™ cannot be used with hot food or drinks (such as soups, coffee, tea, etc.).
The drug Depakin® Hronosfera™ cannot be filled in a small bottle with a pacifier as granules can hammer a pacifier opening.
If Depakin® Hronosfera™ is accepted with liquid, it is recommended to rinse a glass with a small amount of water and to drink this water as granules can stick to glass.
Mix always should be swallowed at once, without chewing. It should not be kept for the subsequent reception.
Considering duration of process of release of active ingredient and the nature   of excipients, the inert matrix of a granule  is not soaked up from a digestive tract, and removed with a stake  after full release of active ingredient.

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, especially at use of high doses, decrease in content of fibrinogen in the blood and lengthening of a prothrombin time which are usually not followed  by clinical  manifestations  (  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 a 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.
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 conduct examination  regarding an exception of this pathology. Very rare
Small peripheral hypostases.
Disturbances from immune system
Unknown frequency
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.
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 a blood 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 a blood plasma (acetylsalicylic acid)
In case of the simultaneous use of valproic acid and drugs having high and strong communication with proteins of a blood 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 leads to loss of therapeutic effect of valproic acid. Therefore increase in a dose of drug at simultaneous use of rifampicin can be required. 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-progestagennymi drugs
Valproic acid has no ability to induce enzymes of a liver and thereof valproic acid does not reduce efficiency estrogen-progestagennykh  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 months. 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 (dose adjustment 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, a primidin, 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 a blood plasma change of plasma concentration or these drugs and/or valproic acid, for more details see the section "Interaction with Other Medicines and Other Forms of Interaction" 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.
The risk connected with development of epileptic seizures during pregnancy
During pregnancy development of generalized toniko-clonic epileptic
attacks, the epileptic status with development of a hypoxia can 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® Hronosfera™  in  time
pregnancies.
The pilot reproductive studies 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 relationship of cause and effect 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 relationship of cause and effect with valproic acid 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 the children who underwent pre-natal influence of valproic acid.
Both monotherapy by valproic acid, and a combination therapy with valproic acid inclusion, are associated with a pregnancy failure, but according to the available data the combined antiepileptic therapy including valproic acid is associated with higher risk of a failure of pregnancy in comparison with monotherapy by valproic acid.
Due to the above, Depakin® Hronosfera™ it 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® Hronosfera™  or possibility of refusal of its use has to be solved prior to use of drug or be reconsidered if the woman receiving Depakin® Hronosfera™ plans pregnancy.
Women of childbearing age have to use effective ways of contraception during treatment by the drug Depakin® Hronosfera™.
Women of childbearing age have to be informed on risks and advantage of use of valproic acid during pregnancy.
If the woman plans pregnancy or became pregnant, then it is necessary to carry out revaluation of need of treatment by valproic acid depending on indications.
- At the indication bipolar disorders it is necessary to consider a question of the treatment termination by valproic acid.
- At the indication epilepsy a 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 drug after all has to be continued by valproic acid 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 slow release is preferable.
- Besides 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® Hronosfera™ of mother can consider a question of feeding by a breast, 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:

At a temperature not above 25 °C. Not to cool and not to freeze. To store in the place, unavailable to children. List B. Period of validity 2 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Granules of the prolonged action of 100 mg, 250 mg, 500 mg, 750 mg, 1000 mg.
On 100 mg, 250 mg, 500 mg, 750 mg and 1000 mg in bags from a three-layered complex
(paper/aluminium / ionomeric pitch).
On 30 or 50 bags together with the application instruction place in a cardboard pack.