Депакин® Hrono

General characteristics. Structure:

Contains in 1 tablet Депакин®Хроно 300 of mg:
Sodium Valproatum - 199,8 mg and valproic acid - 87,0 mg (that corresponds to 300 mg of Valproatum of sodium on 1 tablet).
Excipients: methylhydroxypropyl cellulose 4000 мПа.с (gipromelloza), ethyl cellulose (20 мПа.с), saccharinate of sodium, silicon dioxide colloid hydrated.
Tablet cover: methylhydroxypropyl cellulose 6 мПа.с (gipromelloza), a macrogoal 6000, talc, titanium dioxide, 30% dispersion of polyacrylate at expression in dry extract.
Contains in 1 tablet Депакин®Хроно 500 of mg:
Sodium Valproatum - 333 mg and valproic acid - 145 mg (that corresponds to 500 mg of Valproatum of sodium on 1 tablet).
Excipients: methylhydroxypropyl cellulose 4000 мПа.с (gipromelloza), ethyl cellulose (20 MPas. c), saccharinate of sodium, silicon dioxide colloid anhydrous, silicon dioxide colloid hydrated.
Tablet cover: methylhydroxypropyl cellulose of 6 MPas. from (gipromelloz), a macrogoal 6000, talc, titanium dioxide, 30% dispersion of polyacrylate at expression in dry extract.

Description. Oblong tablets, coated, almost white color, with risky on both sides, inodorous or with a slight smell.

Pharmacological properties:

The antiepileptic drug having the central myorelaxation and sedative effect.
He shows antiepileptic activity at various types of epilepsies. The main mechanism of its action, apparently, is connected with impact of valproic acid on GABA-ergic system: increases the content of piperidic acid (GAMK) in the central nervous system (CNS) and activates GABA-ergic transfer.
The therapeutic effectiveness begins with the minimum concentration of 40-50 mg/l and can reach 100 mg/l. At concentration over 200 mg/l are necessary a dose decline.

Pharmacokinetics. Bioavailability of Valproatum in blood at oral administration is close to 100%.
- The volume of distribution is preferential limited to blood and rapidly changing extracellular liquid. Valproatum gets into cerebrospinal liquid and into a brain.
- The elimination half-life makes 15 - 17 hours.
- The minimum concentration in serum of 40 - 50 mg/l fluctuating within 40 - 100 mg/l is necessary for therapeutic effect. At levels over 200 mg/l the dose decline is required.
- Steady concentration in plasma is reached by 3-4 day,
- Communication with proteins high, dozo-dependent and saturable.
- Valproatum is preferential removed with urine in the form of a glyukoronid and way a beta - oxidations.
Valproatum has no the inducing effect on the enzymes entering metabolic system of P450 cytochrome: unlike the majority of other antiepileptic drugs, Valproatum does not influence degree of both own biotransformation, and other substances, such as estroprogestagena and antagonists of vitamin K.
In comparison with the form covered with an enterosoluble cover, the form of the slowed-down release in equivalent doses is characterized by the following:
- lack of a delay time of absorption after reception;
- the prolonged absorption;
- identical bioavailability;
- smaller value of Smaks, (decrease in Smaks approximately for 25%), but with stabler phase of the plateau from 4 to 14 hours after reception;
- more linear correlation between a dose and concentration of drug in plasma.

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 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.

Route of administration and doses:

Депакин® Hrono represents a form of the slowed-down release of active ingredient of group of the drugs Depakinum which leads to decrease in the maximum concentration of active ingredient in plasma and provides more uniform concentration within a day.

This drug is intended only for adults and children weighing more than 17 kg! This dosage form is not recommended for children by age more young than 6 years (risk of hit in respiratory tracts when swallowing)!

The initial daily dose makes usually 10 - 15 mg/kg, then it is raised to achievement of an optimum dose.
The average daily dose makes 20 - 30 mg/kg. However, if epilepsy does not give in to control at such doses, they can be increased, at careful control of a condition of the patient.
For children the usual dose makes 30 mg/kg a day.
For adults the usual dose makes 20-30 mg/kg a day.
At elderly patients the dose should be established according to their clinical state.
The daily dose is defined depending on age and the body weight of the patient; however, it is necessary to take into account a wide range of individual sensitivity to Valproatum.
Good correlation between a daily dose, concentration of drug in blood serum and therapeutic effect is established: the dose should be established on the basis of the clinical answer. Determination of level of valproic acid can serve in plasma as addition to clinical observation if epilepsy does not give in to control or there is a suspicion on side effects. Range of a therapeutic effectiveness usually makes 40 - 100 mg/l (300 - 700 µmol/l). Депакин® Hrono is intended for intake. The daily dose is recommended to be accepted in one or two receptions, are preferable during food. Use is in one step possible at well controlled epilepsy. A pill is taken, without crushing and without chewing them. Initiation of treatment.
Upon transition from tablets of immediate release of Valproatum which provided necessary control over a disease to a form of the slowed-down release (Hrono's Depakin®), it is necessary to keep a daily dose. Replacement of other antiepileptic drugs on Depakin Hrono should be made gradually, reaching an optimum dose of Valproatum approximately within 2 weeks. At the same time depending on a condition of the patient, the dose of the previous drug decreases.
For the patients who are not accepting other antiepileptic drugs, doses should be increased in 2-3 days to reach an optimum dose approximately within a week.
In need of a combination with other antiepileptic means, they should be entered gradually (see. "Interaction with other medicinal substances and other forms of interaction").

Features of use:

Liver dysfunction:
There are rare messages on hard and lethal cases of diseases of a liver. The group of the increased risk is made by babies and children up to 3 years with heavy epilepsy, especially the epilepsy connected with injury of a brain, a delay of intellectual development and/or inborn metabolic or degenerative diseases. 3 years are aged more senior the frequency of such complications considerably decreases and gradually decreases with age.
In most cases the abnormal liver function was observed within the first 6 months of treatment, usually between 2 and 12 weeks, and most often at the combined antiepileptic treatment.
Early diagnosis is based preferential on clinical inspection. In particular, two factors which can precede jaundice, especially at the patients making risk group have to be taken into account.
- On the one hand, the nonspecific general symptoms which are usually appearing suddenly, such as adynamy, the anorexia, extreme fatigue, drowsiness which sometimes are followed by the repeating vomiting and abdominal pains.
- On the other hand, a recurrence of epileptic seizures against the background of antiepileptic therapy
It is recommended to inform the patient and if it is the child, then his family that at development of such clinical symptoms it is necessary to see immediately a doctor, Krom of clinical inspection, it is necessary to carry out the urgent analysis of function of a liver.
Within the first 6 months of treatment it is necessary to check function of a liver periodically. Among classical tests the tests reflecting protein synthesis by a liver and, especially, prothrombin ratio are most important. In case of detection of abnormally low level of a prothrombin, considerable lowering of the level of fibrinogen and factors of coagulation, increase in level of bilirubin and hepatic transaminases - treatment of Depakin® of Hrono has to be suspended. It is also necessary to interrupt treatment with salicylates if they were included in the scheme of treatment as they use the ways of metabolism, general with Valproatum.

Pancreatitis
Severe forms of pancreatitis, sometimes with a lethal outcome were in rare instances noted. These cases observed irrespective of age of the patient and duration of treatment though, the risk of development of pancreatitis decreased with increase in age of patients.
Insufficiency of function of a liver at pancreatitis increases risk of a lethal outcome. It is necessary  to carry out  definition  of function  of a liver   prior to treatment    and periodically within the first 6 months of treatment, especially patients have risk groups.
It is necessary to emphasize that at treatment by both Hrono's Depakin®, and other antiepileptic drugs, the small, isolated and temporary increase in level of transaminases, especially in an initiation of treatment, in the absence of any clinical symptoms can be observed.
In this case it is recommended to conduct fuller laboratory examination (including, in particular, definition of a prothrombin ratio) to reconsider a dosage if it is required, and to repeat analyses depending on change of parameters.
For children 3 years are younger use of Valproatum (in the recommended dosage form) in monotherapy is recommended, but prior to treatment it is necessary to estimate potential advantage of treatment by drug in relation to risk of development of diseases of a liver or pancreatitis.

 Before therapy or  surgery,   in case of hematomas or spontaneous bleedings, it is recommended to carry out hematologic blood test (to define a blood count, including quantity of thrombocytes, a bleeding time and coagulative tests).
It is necessary to avoid the combined use with salicylates for children is younger than 3 years because of risk of a hepatotoxic.

At patients with a renal failure it is recommended to take into account the increased concentration of a free form of valproic acid in serum and to lower a dose.

At an acute pain abdominal syndrome and such gastrointestinal symptoms as nausea, vomiting and/or anorexia, it is necessary to be able to distinguish pancreatitis and, at the increased level of enzymes of a pancreas, to cancel drug, taking alternative therapeutic measures.

Sodium Valproatum is not recommended to patients with deficit of enzymes of a carbamide cycle. At such patients several cases of the giperammoniyemiya which is followed by a stupor and/or a coma were described.

At children with inexplicable gastrointestinal symptoms (anorexia, vomiting, cytolysis cases), 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 by Valproatum of sodium metabolism researches, especially ammoniyemiya have to be conducted at starvation and after meal.

Though it is shown that in the course of treatment of Depakin® of Hrono of disturbance of functions of immune system meet exclusively seldom, the patients suffering from a system lupus erythematosus need to compare potential advantage of its use to potential risk at purpose of drug.

Patients should be warned about risk of addition in weight in an initiation of treatment, and it is necessary to take measures, generally dietary, for data of this phenomenon to a minimum.

Influence on ability to manage vehicles or other mechanisms.
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.

Side effects:

From the central nervous system: An ataxy (from> 0,1 to <1%);
Cases of cognitive disturbances with the progressing approach (giving a full picture of a syndrome of dementia), reversible within several weeks or months after drug withdrawal (<0,01%);
Conditions of confusion of consciousness or convulsions: in several cases of treatment Valproatum described a stupor or the lethargy sometimes leading to a passing coma (encephalopathy); these cases were isolated or are connected with paradoxical increase in frequency of convulsions during therapy, their frequency decreased at suspension of process of treatment or at reduction of a dose of drug. Most often such cases are described at complex treatment (especially with phenobarbital) or after sharp increase in a dose of Valproatum. The isolated cases of reversible parkinsonism. Headache, easy postural tremor and drowsiness.

From the alimentary system:
At some patients in an initiation of treatment gastrointestinal disturbances (nausea, vomiting, a gastralgia, diarrhea) often develop, but they usually pass without therapy cancellation by drug within several days.
Pancreatitis cases, sometimes with a lethal outcome (<0,01%), the treatments demanding the early termination.
Abnormal liver function (from> 0,01 to <0,1%);
From bodies of a hemopoiesis:
Often arising dozozavisimy thrombocytopenia.
Oppression of a marrowy hemopoiesis (from> 0,01 to <0,1%), including anemia, a leukopenia or a pancytopenia.

From an urinary system:
Enuresis (<0,01%), the isolated cases of a reversible syndrome of Fankoni (genesis is not clear).

Allergic reactions:
Skin rash, small tortoiseshell, vasculitis. In some cases (<0,01%) the toxic epidermal necrolysis, Stephens-Johnson's syndrome, a multiformny erythema were described.

Laboratory indicators:
Often the isolated and moderate giperammoniyemiya without changes in analyses of functions of a liver meets, especially at polytherapy. Drug withdrawal in this case is not required.
However, also the giperammoniyemiya connected with neurologic symptoms is described. This state demands further inspections. Increase in level of hepatic transaminases is possible.
Separate cases of lowering of the level of fibrinogen or increase in a bleeding time, usually without the related clinical manifestations are described and especially at high doses (Valproatum of sodium possesses an inhibiting effect on the second stage of aggregation of thrombocytes). Hyponatremia (<0,01%)

Others:
Teratogenic risk (see. "Pregnancy and breastfeeding").
Hair loss, rare messages on a hearing loss (from> 0,01 to <0,1%) as
reversible, and irreversible, very exceptional cases of not heavy peripheral hypostases
(<0,01%),  an increase in weight as addition of body weight is a factor
risk of a polycystic syndrome of ovaries, careful control such is recommended
patients.
There are also messages on an amenorrhea and disturbance of a regularity of a menstrual cycle.

Interaction with other medicines:

Contraindicated combinations: Meflokhin
Risk of epileptic seizures at patients with epilepsy in connection with the strengthened metabolism of valproic acid and konvulsantny effect of a meflokhin.

St. John's Wort
Danger of decrease in concentration of valproic acid in a blood plasma.

Not recommended combinations: Lamotridzhin
The increased risk of heavy skin reactions (toxic epidermal necrolysis). Besides, increase in concentration of a lamotridzhin in plasma (his metabolism in a liver is slowed down by sodium Valproatum). If the combination is necessary, careful clinical and laboratory control is required.

The combinations demanding special precautions: Carbamazepine
Increase in concentration of an active metabolite of carbamazepine in plasma with overdose signs. Besides, the decrease in concentration of valproic acid in plasma connected with increase in hepatic metabolism of the last under the influence of carbamazepine.
It is recommended: clinical observation, definition of concentration of drugs in plasma and review of their dosage, especially in an initiation of treatment.

Karbapenema, monobaktama: meropeny, panipeny, and, on extrapolation, azreona, imipeny.
Danger of emergence of spasms, in connection with decrease in concentration of valproic acid in serum.
It is recommended: clinical observation, definition of concentration of drugs in plasma and, perhaps, review of a dosage of valproic acid during treatment by the antibacterial agent and after his cancellation.

Felbamat
Increase in concentration of valproic acid in serum, with danger of overdose.
Clinical control, laboratory control and, perhaps, review of a dosage of valproic acid during treatment felbamaty and after its cancellation.

Phenobarbital, Primidonum
Increase in concentration of phenobarbital or Primidonum in plasma with overdose signs, usually at children. Besides, the decrease in concentration of valproic acid in plasma connected with strengthening of hepatic metabolism by phenobarbital or Primidonum.
Clinical monitoring during the first 15 days of the combined treatment with immediate reduction of a dose of phenobarbital or Primidonum at emergence of signs of sedation; determination of level of both antikonvulsant in blood.

Phenytoinum
Changes of concentration of Phenytoinum in plasma, danger of the decrease in concentration of valproic acid connected with strengthening of hepatic metabolism of the last Phenytoinum.
Clinical monitoring, determination of level of two anti-epileptics in plasma is recommended, it is possible - modification of their doses.

Topiramat
The danger of a giperammoniyemiya or encephalopathy which is usually attributed to valproic acid at a combination with topiramaty.
The strengthened clinical and laboratory control within the first month of treatment and in case of symptoms of an ammoniyemiya.

Neuroleptics, inhibitors of a monoaminooxidase (MAO), antidepressants, benzodiazepines.
Valproatum potentsiirut effect of psychotropic drugs, such as: neuroleptics, MAO inhibitors, antidepressants and benzodiazepines.
Clinical monitoring and, if necessary, correction of a dose of drug is recommended.

Cimetidinum and erythromycin
Serumal level of Valproatum increases.

Zidovudine
Valproatum can increase concentration of a zidovudine in plasma that leads to increase in toxicity of the last.

Combinations which should be taken into account: Nimodipin (orally, and, on extrapolation, parenterally)
Strengthening of hypotensive effect of a nimodipin in connection with increase in its concentration in plasma (metabolism reduction by valproic acid).

Acetylsalicylic acid
At a concomitant use of Valproatum and acetylsalicylic acid strengthening of effects of Valproatum, owing to increase in concentration of Valproatum in serum is observed.
Antagnoista vitamins K
Careful monitoring of a prothrombin ratio at joint appointment with vitamin-to-dependent anticoagulants is necessary.

Other forms of interactions Oral contraceptives
Valproatum does not possess enzyme - the inducing effect and therefore does not influence estrogen-progesterone at the women applying hormonal contraceptives.

Contraindications:

- Hypersensitivity to Valproatum, divalproatum, a valpromid or to any of medicine components;
- Acute hepatitis;
- Chronic hepatitis;
- Cases of heavy hepatitis at the patient   or   in his family anamnesis, especially caused by medicines;
- Porphyria;
- A combination with meflokhiny;
- A combination with a St. John's Wort;
- This   drug      is not recommended   to be used   in   a combination   with lamotridzhiny.
- Children's age up to 6 years (risk of hit in respiratory tracts when swallowing). PREGNANCY AND BREASTFEEDING
    During    pregnancy    development    of generalized    toniko-clonic epileptic seizures, the epileptic status with development of a hypoxia can bear risk of death both for mother, and for a fruit. The risk connected with Valproatum.
At animals: pilot studies on mice, rats and rabbits showed teratogenic action.
At people: according to the available data Valproatum preferential causes disturbance of development of a neural tube: myelomeningocele, backbone crevice (1-2%). Several cases of a front dismorfiya and malformations of extremities (in particular, shortening of extremities), and also malformations of cardiovascular system are described.
The risk of malformations is higher at the combined antiepileptic therapy, than at monotherapy by sodium Valproatum. However, it is quite difficult to establish relationship of cause and effect between malformations of a fruit and other factors (genetic, social, environmental factors, etc.)

Due to the above:
Use of drug at pregnancy can be appointed by the doctor only when the expected advantage for the pregnant woman exceeds possible risk for a fruit.
If the woman plans pregnancy, it is necessary to revise indications for antiepileptic treatment.
During pregnancy it is not necessary to interrupt antiepileptic treatment with Valproatum if it is effective. In such cases monotherapy is recommended; which minimum effective day dose should be divided into several receptions in day.
In addition to antiepileptic therapy drugs of folic acid (in a dose of 5 mg a day) can be added as they allow to minimize risk of developing of malformations of a neurotubule. However, irrespective of whether the patient of a foliata receives or not, anyway it is necessary to carry out special antenatal control of a neural tube or other malformations.

Newborns
Valproatum can cause a hemorrhagic syndrome in newborns. In case of Valproatum this syndrome, apparently, is connected with a hypofibrinogenemia. Cases of development of an afibrinogenemiya from the death were noted. Perhaps, it is connected with reduction of a number of blood-coagulation factors.
At the newborn carry surely out definition of number of thrombocytes, fibrinogen level in plasma and blood-coagulation factors.
Feeding by a breast
Valproatum excretion in milk low, with concentration between 1% and 10% of the serumal level of drug.
According to literature and brief clinical experience of mother can plan breastfeeding during treatment by this drug in the form of monotherapy, taking into account a profile of its safety (in particular, hematologic frustration).

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 wet brain were described.
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 very hard cases carry out dialysis. Usually the forecast at overdose is favorable, however several cases of a lethal outcome were described.

Storage conditions:

At a temperature below 25 °C in the dry place. 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:

Hrono's Depakinum - tablets of the prolonged action, coated 300 mg. 50 tablets in  a polypropylene bottle with a polyethylene stopper with a moisture absorber.
On 2 bottles together with the application instruction in a cardboard box.

Hrono's Depakinum - tablets of the prolonged action, coated 500 mg. 30 tablets in   a polypropylene bottle with a polyethylene stopper with a moisture absorber. On 1 bottle together with the application instruction in a cardboard box.