Valprok hrono

General characteristics. Structure:

Active ingredient: Valproatum sodium/valproic acid;

1 tablet of Valprokom 300 hrono contains Valproatum of sodium 200 mg and valproic acid of 87 mg (that corresponds to 300 mg of Valproatum of sodium on 1 tablet);

1 tablet of Valprokom 500 hrono contains Valproatum of sodium 333 mg and valproic acid of 145 mg (that corresponds to 500 mg of Valproatum of sodium on 1 tablet);

Excipients: ethyl cellulose, ammonium and methacrylate copolymer, silicon dioxide colloid anhydrous, a covering for drawing a cover (a gipromelloza, glycerin, ammonium and methacrylate copolymer, polyacrylate dispersion, polyethyleneglycol, talc).

Pharmacological properties:

Pharmacodynamics. Anticonvulsant drug of the prolonged action. Inhibits GAMK-transferase, brakes biotransformation of GAMK (inactivation), stabilizes and increases its contents in TsNS. Stimulates the central GABA-ergic processes (including brake a stress - limiting), reduces excitability and convulsive readiness of motor zones of a brain.

Shows tranquilizing properties, reduces sensation of fear, improves a mental condition and mood of patients, has antiarrhytmic activity. Highly effective at absentias epileptica and temporal pseudo-absentias epileptica, ineffective at psychomotor attacks.

Pharmacokinetics. Bioavailability of drug - about 100%. The prolonged form is characterized by the slowed-down absorption, lower (approximately for 25%), but stabler concentration in a blood plasma between 4 and 14 hours thanks to what concentration of valproic acid is within a day more uniform.

The therapeutic effectiveness of drug is shown at its concentration in a blood plasma from 40 to 100 mg/l. At regular reception equilibrium concentration is established on 3 - the 4th day of therapy. More than 96% of drug are exposed to intensive metabolism in a liver, 90-95% contact proteins of plasma, mainly, albumine. Drug gets through a blood-brain barrier, through a placental barrier, in insignificant quantities comes to maternal milk at a lactation. It is removed generally with urine in the conjugated look. The elimination half-life makes 8-20 hours.

Indications to use:

For adults and children: as monotherapy or in a combination with other antiepileptic drugs:
· for treatment of generalized epileptic seizures (clonic, tonic, toniko-clonic attacks, absentias epileptica, myoclonic and atonic attacks); Lennox-Gasto's syndrome;
· for treatment of partial epileptic seizures (partial attacks with secondary generalization or without).
Treatment of a maniacal syndrome at bipolar disturbances.

Route of administration and doses:

The dose of drug and duration of treatment are defined by the doctor according to age and body weight of the patient, taking into account a wide range of individual sensitivity to Valproatums.

The adult the initial daily dose of Valprokom hrono makes 10-15 mg/kg of body weight, then the dose is gradually increased before achievement of an optimum dose. The usual maintenance dose makes 20-30 mg/kg of body weight a day. However if epilepsy at such doses is uncontrollable, they can be increased on condition of careful observation of a condition of the patient.

If the patient does not accept any other antiepileptic drugs, the dose should be increased gradually at an interval of 2-3 days to reach an optimum dosage approximately in a week.

At the patients accepting other anticonvulsant drugs, treatment by Valprokom is hrono begun gradually to reach clinically effective dose approximately within 2 weeks then, depending on efficiency of treatment, reduce doses of the drugs accepted at the same time.

In need of use of a combination of Valprokom hrono with other antiepileptic means they should be entered into the scheme of treatment gradually.

Patients of advanced age should establish a dose depending on the level of control over epilepsy.

To children the usual maintenance dose makes 30 mg/kg of body weight a day.

The optimum dose of Valprokom is hrono established on the basis of the clinical answer. There can sometimes be reasonable a definition of concentration of valproic acid in plasma, for example, in cases when it is not possible to reach adequate control over attacks or there is a threat of development of side effects. Range of concentration of 40-100 mg/l (300-700 µmol/l) is considered therapeutic.

The daily dose is recommended to be accepted in one or two receptions. Single use is possible in case of well controlled epilepsy. Drug is accepted inside in time or after food, without chewing a tablet and washing down with enough liquid.

Features of use:

The beginning of use of antiepileptic drug can sometimes be followed by resuming of epileptic seizures or developing of heavier attacks or development in the patient of new types of attacks, irrespective of spontaneous flukluation that are observed at some epileptic states. In case of Valprokom's use hrono it first of all concerns the made changes in the scheme of a combination therapy antiepileptic drugs or pharmacokinetic interaction, toxicity or overdose.

Sodium Valproatum, one of active ingredients of Valprokom hrono, in a human body turns into valproic acid therefore it is not necessary to use at the same time other drugs which are exposed to the same transformation in order to avoid valproic acid overdose (for example, divalproatum, вальпромид).

There are single messages about heavy or sometimes and lethal damages of a liver. The early diagnosis of a hepatotoxic is based on a clinical picture. In particular, it is necessary to consider symptoms which can precede jaundice, and other symptoms testimonial of a hepatotoxic:

• the general symptoms and signs (usually appear suddenly): for example, drowsiness, an adynamy, confusion of consciousness, the excited state, anorexia, an abdominal pain, vomiting, bleeding and hypostasis;

• a recurrence of epileptic seizures, despite observance of doctor's instructions.

Due to the existing risk of development of abnormal liver functions within the first 6 months of treatment (usually during 2 - the 12th week) during treatment it is regularly necessary to control functional trials of a liver (level of aminotransferases, bilirubin, crude protein), coagulability of blood (a prothrombin time, fibrinogen, a factor of VIII), quantity of thrombocytes, activity of a lipase and alpha amylase in urine. At identification of abnormally low level of the prothrombin which is especially followed by considerable decrease in level of fibrinogen and factors of coagulability of blood, increase in level of bilirubin and transaminases treatment by Valproatum has to be suspended. The risk of development of side effects from a liver is increased at a combination therapy with other anti-epileptics.

It is recommended to inform the patient (and if it is the child, then his parents) that at emergence of the described clinical symptoms, it is necessary to see a doctor immediately. Except clinical inspection, it is necessary to carry out functional hepatic trials urgently.

At treatment by this drug, especially in the beginning, temporary moderate increase in level of transaminases without any manifestations can be observed. It is recommended to conduct full laboratory examination (in particular, to determine the level of a prothrombin and, perhaps, to reconsider a dosage of drug and to carry out retests).

Pancreatitis cases which sometimes came to an end letalno were seldom observed. These cases did not depend on age of the patient and duration of treatment. Pancreatitis is most often observed at children of younger age or at patients with heavy epilepsy, injury of a brain or at patients who accept complex antiepileptic therapy. If pancreatitis is followed by a liver failure, the risk of emergence of lethal cases considerably increases.

The patient and/or his family have to ask immediately for medical care at emergence of symptoms of pancreatitis (such as abdominal pain, nausea and vomiting). In the presence of the symptoms testimonial of pancreatitis, medical examination, including determination of level of a lipase and/or amylase in a blood plasma has to be conducted. At suspicion of pancreatitis Valprokom's use hrono should be stopped immediately.

Before therapy or surgery, in case of spontaneous hematomas or bleedings, it is recommended to carry out blood test (to define a blood count, including quantity of thrombocytes, a bleeding time and coagulative tests).

Meta-analysis of randomized placebos - controlled clinical tests of antiepileptic medicines revealed slight increase of risk of suicide thoughts and behavior. The mechanism of this increase is unknown, and available data do not exclude a possibility of increase in risk of a suicide at Valprokom's reception hrono.

It is necessary to watch a condition of patients attentively for the purpose of early detection of symptoms of a depression, tendency to self-damage, suicide thoughts or behavior.

It is necessary to control free concentration of valproic acid in blood of patients with a renal failure and at its increase respectively to reduce a drug dose.

Valproatum of sodium increases risk of a giperammoniyemiya at patients with disturbance of a cycle of an ureapoiesis. Use of Valproatum of sodium by such patients should be avoided.

At such patients giperammoniyemiya cases which were followed by a stupor or a coma were described.

Though in the course of treatment disturbances of functions of immune system arise Valproatums exclusively seldom, hrono patients need to compare possible advantage of Valprokom's use to potential risk at purpose of drug with a system lupus erythematosus.

Patients should be warned about a possibility of increase in body weight in an initiation of treatment, and, in order to avoid it, need to keep to a diet.

As Valproatum of sodium is removed with urine partially in the form of ketones, it can cause pseudo-positive takes at an urine research on availability of acetone.

At patients with acute abdominal pain or such gastrointestinal symptoms as nausea, vomiting and/or anorexia, it is necessary to carry out differential diagnosis with pancreatitis and at increase in levels of transaminases immediately to cancel drug and to host alternative therapeutic actions.

At children with the obscure symptoms from a liver and a digestive tract (anorexia, vomiting, cytolysis cases), a lethargy or a coma in the anamnesis, with a delay of intellectual development, in case of the death of the baby or the child in the family anamnesis prior to treatment by Valprokom it is hrono necessary to conduct a metabolism research, especially the test for an ammoniyemiya on an empty stomach and after meal.

During treatment by Valprokom alcohol intake is hrono contraindicated.

Ability to influence speed of response at control of motor transport or work with other mechanisms. At drug use by Valprok it is not allowed to manage vehicles hrono and to be engaged in other types of activity requiring special attention, ability to concentrate and accurate coordination of movements.

Side effects:

From the alimentary system: nausea, vomiting, pain in epigastriums, diarrhea and other dispeptic disturbances - develop in an initiation of treatment more often and, as a rule, pass independently within several days without drug withdrawal; decrease or increase in appetite; an abnormal liver function (tranzitorny increase in level of hepatic transaminases and level of bilirubin in blood serum) and a pancreas (pancreatitis).
From the central nervous system: obnubilation; a lethargy, the isolated struporous states; reversible dementia, the isolated reversible parkinsonism, a tremor, drowsiness, a headache, an ataxy, decrease in hearing, a hearing loss both reversible, and irreversible.
From system of a hemopoiesis: thrombocytopenia, anemia, macrocytosis, leukopenia, pancytopenia.
From system of a blood coagulation: in some cases, is more often at use in high doses - decrease in level of fibrinogen or increase in a bleeding time.
From an urinary system: seldom - disturbance of functions of kidneys, a reversible syndrome of Fankoni; very seldom - enuresis, an urine incontience.
Allergic reactions: exanthematous rash, in some cases - a toxic epidermal necrolysis, Stephens-Johnson's syndrome, a multiformny erythema.
Metabolic disturbances: the isolated and moderately expressed giperammoniyemiya, increase in body weight, it is very rare - a hyponatremia.
Reproductive disturbances: amenorrhea, disturbance of a regularity of periods, risk of emergence of a polycystic syndrome of ovaries; very seldom - a gynecomastia.
Others: in some cases - a hair loss, a vasculitis, not heavy peripheral hypostases.
Teratogenic risk (see the section "Use during Pregnancy").

Interaction with other medicines:

Simultaneous use with drugs which can cause spasms or reduce a convulsive threshold, it has to be considered or it is not recommended or in general it is contraindicated. The majority of antidepressants (Imipraminums, the selection inhibitors of serotonin reuptake), neuroleptics (fenotiazina and phenyl propyl ketones), мефлохин, бупроприон, трамадол belong to such drugs.
Contraindicated combinations:

with meflokhiny - risk of developing of epileptic seizures at patients with epilepsy in connection with strengthening of metabolism of valproic acid and konvulsantny effect of a meflokhin;

with St. John's Wort drugs - risk of decrease in concentration of valproic acid in a blood plasma and efficiency of drug.

Not recommended combinations:
it is necessary to avoid simultaneous use of Valprokom hrono and salicylates, considering that these drugs are metabolized in the same way, at the same time there is a replacement of valproic acid from communication with proteins and strengthening of its action is possible.
The concomitant use of Valprokom hrono with anticoagulants and acetylsalicylic acid can lead to strengthening of a tendency to bleeding. It is recommended to control a bleeding time and quantity of thrombocytes during treatment.

The combinations demanding extra care at use:
with Phenytoinum - the general concentration of Phenytoinum in plasma changes; there is a danger of decrease in concentration of valproic acid in a blood plasma because of strengthening of her metabolism in a liver under the influence of Phenytoinum.
With phenobarbital, Primidonum and carbamazepine - drugs accelerate Valprokom's removal hrono from an organism and thus reduce its efficiency. Besides, there is an increase in concentration of phenobarbital or Primidonum in plasma with the advent of signs of their overdose, usually at children. Clinical observation of a condition of the patient for the first 15 days the combined treatments and immediate reduction of a dose of phenobarbital or Primidonum with the advent of sedation symptoms, and also determination of levels of both antiepileptic drugs in blood is recommended. Increase in concentration of an active metabolite of carbamazepine in plasma, emergence of symptoms of its overdose is observed. At combined use of Valprokom hrono with carbamazepine clinical observation of a condition of the patient, definition of concentration of both drugs in a blood plasma also correction of their dosing is recommended.

With karbapenemam, monobaktamam (meropeny, panipeny, to aztreona, imipeny) - danger of emergence of spasms because of decrease in concentration of valproic acid in a blood plasma. Clinical observation of a condition of the patient, definition of concentration in a blood plasma and dose adjustment of anticonvulsant drug is necessary.

With topiramaty - danger of emergence of a giperammoniyemiya or encephalopathy under the influence of the valproic acid accepted in a combination with topiramaty. The strengthened clinical and laboratory control in an initiation of treatment and in case of any symptoms indicating emergence of these phenomena is recommended.

With felbamaty - increase in concentration of valproic acid in blood serum and risk of overdose. Clinical observation of a condition of the patient, definition of concentration of a felbamat in plasma and, perhaps, correction of a dosage of Valprokom is recommended hrono during treatment felbamaty and after its cancellation.

At simultaneous use with lamotridzhiny there is an increased risk of heavy skin reactions (a syndrome of a toxic necrolysis of epidermis). Increase in concentration of a lamotridzhin in a blood plasma because of delay of his metabolism in a liver under the influence of Valproatum. If such combination is necessary, careful observation of a condition of the patient is required.

Combinations which should be taken in attention:
with nimodipiny - strengthening of hypotensive effect of a nimodipin because of increase in its concentration in a blood plasma (weakening of metabolism by valproic acid).

Other types of interaction:
action of hormonal contraceptives does not decrease at Valprokom's use hrono.

Contraindications:

- Hypersensitivity to Valproatums and other components of drug;
- the acute hepatitis, chronic hepatitis, cases of heavy hepatitis in the individual or family anamnesis of the patient which are especially caused by medicines; 
- hepatic porphyria;
- a combination with meflokhiny and St. John's Wort drugs (see the section "Interaction with Other Medicines and Other Types of Interactions");
- the body weight of children is up to 17 kg;
- children's age up to 6 years (in this dosage form).

Use during pregnancy or feeding by a breast.

Pregnancy
It is not recommended to apply Valproatums during the entire period of pregnancy, and also to women of childbearing age who do not use effective methods of contraception.

The risk of developing of the inborn malformations of a fruit caused by Valproatums, at the pregnant women accepting them is 3-4 times higher, than among the general population (about 3%). Most often the defects connected with disturbance of closing of an embryonal neurotubule (about 2-3%) meet: a myelomeningocele, splitting of a backbone which can be diagnosed in the prenatal period; dismorfiya of the person, splitting of a lip and sky, craniostenosis, malformations of heart and bodies of urinogenital system, extremities (especially shortening of extremities). Special prenatal inspection of the patient for the purpose of identification of disturbances of fusion of a neurotubule or other anomalies of fetation within the first months of pregnancy is necessary. Reception of Valproatums in the doses exceeding 1000 mg a day and the combined use with other anticonvulsants was the most important risk factors of developing of collateral inborn malformations.

At children whose mothers accepted Valproatums during pregnancy insignificant delay of development of the speech is recorded and/or more frequentation of the logopedist or use of the adjusting actions is considerable. Several cases of autism and the disturbances connected with it at children whose mothers during pregnancy accept Valproatums are described.

If the woman plans pregnancy, it is necessary to consider the possibility of use of other methods of treatment.

If it is impossible to avoid use of Valproatum of sodium (or not alternatives), it is recommended to accept drug in the minimum effective daily dose and to give preference to use of forms of the prolonged action and if it is impossible, then to divide a dose into several receptions to avoid achievement of the maximum concentration of valproic acid in a blood plasma.
The evidence confirming efficiency of additional use of folic acid for women who during pregnancy accepted Valproatums is not obtained. However, considering its positive impact in other clinical situations, the foliyeva acid can be appointed in a dosage of 5 mg / in days a month before and for the first two months after fertilization. Irrespective of, the patient accepts folic acid or not, special inspection on existence of malformations of a fruit will be identical.
During pregnancy if treatment by Valproatums continues, it is recommended to accept drug in the minimum effective daily dose and, whenever possible, to avoid the doses exceeding 1000 mg a day.
At mother before childbirth and at the newborn it is necessary to carry out coagulative tests, in particular to define quantity of thrombocytes, fibrinogen level in plasma and a blood clotting time (the activated partial tromboplastinovy time (aChTV).
At newborns whose mothers during pregnancy accepted Valproatums emergence of the hemorrhagic syndrome which is not connected with deficit of vitamin K is possible.
It was reported about hypoglycemia cases at newborns for the first week of life at reception by mothers of Valproatums.

Feeding period breast
Excretion of Valproatums in breast milk very low. However, taking into account data on delay of development of the speech in children of chest age which mothers during pregnancy accepted Valproatums it is better for patients to refuse feeding by a breast.

Children. Drug is appointed in general to children with body weight by over 17 kg. This dosage form is not appointed to children up to 6 years because of risk of its hit in respiratory tracts when swallowing.

Overdose:

Symptoms. At considerable overdose there can be a coma which is followed by hypotonia of muscles, a hyporeflexia, a miosis, oppression of function of breath and the phenomena of a metabolic acidosis, a heart block, the intracranial hypertensia connected with wet brain is possible.

Treatment. The specific antidote does not exist. Symptomatic treatment: a gastric lavage if after administration of drug there passed no more than 10-12 hours; providing an osmotic diuresis; monitoring and correction of a functional condition of cardiovascular and respiratory systems. If necessary carry out dialysis.

Storage conditions:

To store in original packaging, in the place, unavailable to children, at a temperature not above 25 °C. Not to cool and not to freeze!

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in the blister; on 1, 3 or 10 blisters Valprok 300 hrono in a pack cardboard; on 1 or 3 blisters Valprok 500 hrono in a pack cardboard.