Valproatum Orion

General characteristics. Structure:

Active ingredient: 300 mg or 500 mg of sodium of Valproatum.

Excipients: коповидон, gipromelloza, silicon dioxide, magnesium stearate, gipromelloza6 cps., stearic acid, опадрай V-28920: polyvinyl alcohol, titanium E-171 dioxide, talc, lecithin, gum xanthane.

The anti-epileptic drug of the first line which is applied at various types of attacks and forms of epilepsy.

Pharmacological properties:

Pharmacodynamics. Sodium Valproatum is antiepileptic means. In the chemical relation it is fatty acid with a branched chain. The mechanism of effect of sodium of Valproatum is up to the end not defined. It is considered that the mechanism of effect of drug is connected, first of all, with increase in concentration of an inhibitory neurotransmitter of piperidic acid (GAMK) in the central nervous system (CNS). Besides, sodium Valproatum can directly influence natrium and potassium channels neuro нальных membranes.

Pharmacokinetics. Absorption. After oral administration of sodium it valproatprevrashchatsya in a stomach and a small bowel in valproic acid which is quickly and almost completely absorbed. Absolute bioavailability makes 90-100%. Time of achievement of peak concentration in a blood plasma (Tmax) depends on the used dosage form. After a single dose of tablets of Valproatum Orion with the modified release of Tmax makes 8,6±2,5 hours (average value ± a standard deviation). Meal can reduce speed, but not extent of absorption.

Distribution. About 90-95% of sodium of Valproatum contact serum proteins (mainly albumine). The share of untied substance increases at elderly people, patients with a hypoalbuminemia, a renal or liver failure and at high concentration of sodium of Valproatum in blood serum (bolee80-85 mg/l). Distribution volume
(Vd) at adults makes 0,1-0,2 l/kg. High Vd values (0,2-0,4 l/kg) were observed at children and teenagers. Concentration of sodium of Valproatum in cerebrospinal fluid averages 10% of level in blood serum, but noticeable individual distinctions can be noted.

Metabolism and removal. Sodium Valproatum is metabolized mainly in a liver before removal with urine. The main part is metabolized by conjugation with glucuronic acid. The rest is metabolized by a beta, an epsilon and an epsilon-1 of oxidation. There are no data on autoinduction, but other drugs can strengthen metabolism by induction of liver microsomal enzymes. The plasmatic clearance at healthy volunteers made about 6-8 ml/kg an hour; at the patients accepting the drugs inducing enzymes it is higher (about 15-20 ml/kg an hour). The elimination half-life (T1/2) at healthy volunteers usually reached 12-16 h; at the patients accepting the inducing enzymes, T1/2 made about 9 h. Some metabolites (such kak2-en-valproic acid) can have antiepileptic effect, but their clinical value at the person so far is completely not established.

Indications to use:

Generalized epileptic seizures, such as toniko-clonic attacks (big convulsive attacks), absentias epileptica (small attacks), myoclonic and atonic attacks. As supportive application at treatment of partial, focal attacks.

Route of administration and doses:

As to accurate correlation between a daily dose, concentration in blood serum and therapeutic effect it is not shown, the dosage has to be selected depending on clinical reaction. The lowest dose providing sufficient control over attacks, especially at pregnancy is recommended.

There can sometimes be reasonable a definition of concentration in blood serum, for example, if the patient at the same time takes medicine which changes clearance of sodium of Valproatum, or at suspicion to side effects. Range of concentration in blood serum of 40-100 mg/l (300-700 µmol/l) is considered therapeutic, but at many patients good therapeutic reaction is reached and at other concentration. The risk of undesirable effects increases if concentration in blood serum (measured before acceptance of the first dose of the current days) prevyshayet100 mg/l.

The pill "Valproatum Orion" with the modified release should be taken whole, washing down with enough liquid (for example, a glass of water). The concomitant use of food can reduce speed, but not extent of absorption. Tablets with the modified release appoint one or two times a day. Most of patients who were not treated by a dosage form with the modified release earlier can be transferred directly to drug with the modified release and continue to accept a former dose.

Monotherapy.
Adults. For adults the initial dose of 600 mg a day with increase in a dose each 3-7 days is offered until attacks stop. The usual maintenance dose makes 1000-2000 mg a day (20-30 mg/kg/days). The maximum dose makes 2500 mg a day.

Elderly patients. Concentration of untied sodium of Valproatum in blood serum at elderly patients are higher, than at younger adults, but the general concentration of drug does not change. The dose should be determined by therapeutic reaction.

Children with body weight more than 20 kg. For children with body weight more than 20 kg are offered an initial dose of 300 mg a day irrespective of body weight, then the dose is raised on 100-200 mg by each 3-7 days until attacks stop. For exact selection of a dose it is necessary to use other dosage form of sodium of Valproatum. The usual maintenance dose makes 15-30 mg/kg a day. The maximum dose makes 35 mg/kg a day.

Patients with a liver or renal failure or a hypoalbuminemia. At patients with a liver or renal failure or a hypoalbuminemia an untied part of sodium of Valproatum increases in blood serum. The dosage has to be based on therapeutic reaction.

Combination therapy. Upon transition from other medicine to the tablets "Valproatum Orion" with the modified release or at addition of tablets with the modified release to earlier carried out treatment the dose is raised gradually to achievement of optimum level. At the same time the dose of other medicines is reduced and gradually cancelled. If it is necessary to use other antiepileptic drug, it is entered into the scheme of treatment gradually.

Features of use:

Preventions. Use of antiepileptic medicine in rare cases leads to a new attack or development of new types of attacks in the patient.

Cases of severe damage of a liver which can lead to death are noted. The risk at children under three years with heavy epilepsy is highest. It concerns in particular to mentally retarded children, damage of a brain, genetically caused degenerative or metabolic diseases or diseases of a liver in the anamnesis. The risk increases at the patients accepting at the same time and other antiepileptic drugs.

In the presence of at the same time hepatitis and pancreatitis the risk of a lethal outcome increases. In the majority of cases a hepatotoxic was noted during pervykh6 months of treatment, usually the между2nd-y the и12th-y for weeks. starshe3 years a hepatotoxic occurs at children much less often, and the risk decreases with age.

Prior to treatment it is necessary to collect the anamnesis and to conduct laboratory researches. Regularly inspect a clinical condition of the patient and watch laboratory indicators, in feature within the first six months of treatment.

The early diagnosis of a hepatotoxic is based on a clinical picture. In particular, it is necessary to consider the following symptoms which can precede jaundice. The patient and/or his family needs to be informed about need to ask immediately for medical care at emergence at it of the 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, abdominal pains, vomiting, bleeding and hypostasis;
- a recurrence of epileptic seizures, despite observance of doctor's instructions.

If there is a suspicion on a hepatotoxic, it is necessary to inspect at once the patient and to conduct the corresponding laboratory researches. As blood parameters not in all cases deviate norm and levels of liver enzymes in some cases can be raised and in the absence of an abnormal liver function, at assessment of the situation it is necessary to consider the anamnesis of the patient and a clinical picture. If there is a suspicion on a hepatotoxic, use of sodium of Valproatum should be stopped immediately.

Cases of acute pancreatitis which can lead to death are noted. They can be observed irrespective of age of the patient or duration of treatment. Pancreatitis from the failure is usually observed at small children and patients with heavy epilepsy, damage of a brain or the accepting several antiepileptic drugs.

The accompanying liver failure increases risk of a lethal outcome.
The patient and/or his family there have to be poinformirovana about need of the immediate request for medical care at emergence of symptoms of pancreatitis (such as stomach pain, nausea and vomiting). In the presence of the symptoms testimonial of pancreatitis, medical examination, including determination of levels of a lipase and/or amylase in blood serum has to be conducted. At suspicion of pancreatitis use of sodium of Valproatum should be stopped immediately.

Precautions when using. Patients with the established disturbance of a cycle of an ureapoiesis or suspicion on it. Sodium Valproatum increases risk of a giperammoniyemiya at patients with disturbances of a cycle of an ureapoiesis. Valproatum sodium use by such patients should be avoided.

Disturbances of a cycle of an ureapoiesis should be excluded prior to treatment at the patients having in the anamnesis: 1) an inexplicable lethargy or a coma, or increase in level of ammonium in blood serum; 2) inexplicable hepato gastrointestinal symptoms (anorexia, vomiting, cytolysis); 3) existence in the family anamnesis of death in newborn or children's age.

In the presence of symptoms (such as apathy, drowsiness, vomiting or hypotension) or at increase of frequency of attacks it is necessary to watch levels of ammonium and sodium of Valproatum in blood serum and if necessary to stop treatment or to lower a dose.

Laboratory monitoring. Except ordinary researches, prior to treatment it is necessary to conduct a research of function of a liver and pancreas and coagulability of blood. In four weeks after an initiation of treatment again laboratory researches, including the general blood test with calculation of thrombocytes and definition of coagulability of blood, levels of aminotransferase, an alkaline phosphatase, bilirubin and amylase. Concerning function of a liver the researches reflecting protein synthesis, in particular prothrombin levels are most informative. It is necessary to watch change of levels of fibrinogen, other factors of coagulation, bilirubin and liver enzymes.

If laboratory parameters are normal or are a little changed also a clinical condition of the patient normal, other researches are not required. It is recommended to estimate a clinical condition and laboratory parameters each 1-2 months during pervykh6 months of treatment.

If at patients with a normal clinical state the laboratory indicators deviating norm are noted significantly, the research is repeated by three times with an interval no more than two weeks, and then once a month within the first six months of treatment. If the level of transaminases (ASAT/ALAT) exceeds an upper limit of norm three times, it is necessary to consider seriously the possibility of the termination of treatment even if at the patient clinical symptoms are not noted. If abnormal laboratory indicators are found in the patient with clinical symptoms, treatment should be stopped immediately.

After the first six months it is recommended to carry out laboratory monitoring two or three times a year. If sodium Valproatum was applied within several years without problems, laboratory researches can be conducted once a year.

Before surgical intervention and in case of hematomas or spontaneous bleedings in addition conduct hematologic researches (the general blood test including calculation of thrombocytes, and also a bleeding time and coagulability). If the quantity of thrombocytes are repeatedly lower than 100 x 10 l or if bleeding is observed, Valproatum sodium dose decline is recommended. In case of severe bleeding or considerable decrease in quantity of thrombocytes it is necessary to consider the possibility of the termination of treatment.

Children. At babies and children more young than three years it is necessary to estimate carefully therapeutic advantage concerning risk of a hepatotoxic and pancreatitis. In this age group monotherapy is recommended. In particular children of derivative salicylates as at the same time the risk of a hepatotoxic and bleeding increases should avoid co-administration.

Increase in body weight. Sodium Valproatum often causes to the uvelichena of body weight, sometimes considerable and progressing. Patients should be informed on it in an initiation of treatment and to resort to the measures aimed at minimization of increase in body weight.

Women and girls. Prior to sodium treatment by Valproatum women of childbearing age should address the specialist as drug represents potential teratogenic risk for a fruit. Also there are data that sodium Valproatum can increase risk of a syndrome of a polycystosis of ovaries.

Patients with damage of marrow. Patients with damage of marrow have to be under careful observation.

System lupus erythematosus. To patients with symptoms which can demonstrate existence of a system lupus erythematosus this medicine is appointed with care.

Patients with suspicion of ketoacidosis. As sodium Valproatum is allocated with urine partially in the form of ketones, it can cause pseudo-positive takes at an urine research on ketones.

Renal failure. It is necessary to consider a possibility of increase in concentration of untied valproic acid in blood serum of patients with a renal failure and to respectively reduce a dose.

HIV-positive patients. It agrees some issledovaniyamin vitro, sodium Valproatum can stimulate replication of HIV, however when studying mononuklear of peripheral blood of HIV-positive patients any mitogenopodobny influence of sodium of Valproatum concerning induction of replication of HIV is noted. This effect is not confirmed at vivo forehead-vekain. However these data should be taken into account when determining virus loading at HIV-positive patients.

Pregnancy and feeding by a breast. Pregnancy. Women of childbearing age need to be informed in detail on importance of planning and monitoring of pregnancy prior to sodium treatment by Valproatum.

The risk connected with epilepsy and antiepileptic drugs in general. At the children born by mothers having epilepsy who accept any antiepileptic drugs the general level of malformations approximately в23 time (about 3%) is higher, than in general at the population. Despite an established fact of the increased frequency of malformations at the children born at treatment of epilepsy, the corresponding role of drugs and the disease in developing of malformations it is formally not established. The most often found malformations are the labium leporium, defects of cardiovascular system and a neurotubule.

Epidemiological researches allow communication between reception of the antiepileptic drugs in vitro and risk of an arrest of development. Many factors, including epilepsy of mother and genetic factors can strengthen this risk. Despite this potential risk, treatment of epilepsy it is impossible to interrupt sharply as it can cause the beginning of attacks that can have serious effects both for mother, and for a fruit.

The risks connected from sodium by Valproatum. Valproic acid gets through a placenta. The general risk of malformations during the first trimester of pregnancy is increased, as well as in a case using other traditional antiepileptic means. Sodium Valproatum, most likely, preferential vyzvat the defects connected with fusion of a neurotubule (such as meningomyelocele or a crevice of a backbone). Frequency of anomalies  of a neurotubule is estimated as 1-2%. Besides, the fetal valproatny syndrome was noted. This syndrome is characterized by craniofacial anomalies and a potential arrest of development. It can also include serious malformations of bodies. The genetic nature of exposure to a fetal valproatny syndrome is supposed.

The fact that the woman plans pregnancy is the basis for review of need of antiepileptic therapy. Women of childbearing age should be informed on risks and benefits of antiepileptic treatment during pregnancy.

Despite potential risks, Valproatum it is not necessary to cancel sodium without consultation of the specialist as the sharp termination of treatment or a dose decline can cause heavy attacks which can be dangerous both to mother, and to a fruit.

If sodium Valproatum nevertheless is appointed during pregnancy, it is used in the lowest effective doses, it is preferential in the form of monotherapy. For avoidance of high peak concentration in blood serum division of a daily dose into several receptions and use of a form with the modified release is recommended. Frequency of malformations of a neurotubule increases with increase in a dose, in particular if the daily dose exceeds 1000 mg.

Use of folates before and during pregnancy can reduce the frequency of malformations  of a neurotubule at children of women with high risk. Women,  not accepting contraceptives, it is necessary to inform on expediency of reception of folic acid.

For early identification of teratogenic effects prenatal monitoring is recommended (for example, ultrasonography and definition of alpha-fetoprotein).

Risks for newborns. At newborns  whose mothers received sodium Valproatum, the hemorrhagic syndrome most of which severe form could lead to death was very seldom noted. The hemorrhagic syndrome is probably connected with a hypofibrinemia. It should be distinguished from decrease in level of blood-coagulation factors the, dependent on vitamin K, connected with the antiepileptic means inducing enzymes. It is necessary to watch quantity of thrombocytes, levels of fibrinogen and factors of coagulation and to conduct a research of coagulability of blood at newborns.

Feeding by a breast. Release of sodium of Valproatum with breast milk low, concentration makes 1-10% of level in blood serum of mother. Clinical effects concerning the children who are on breastfeeding are noted. Breastfeeding during sodium treatment by Valproatum is considered safe.

Influence on ability to manage vehicles and to work with difficult mechanisms.

Sodium Valproatum can influence the central nervous system (for example, to cause dizziness) that can influence ability to control of vehicles and work with difficult mechanisms. These effects are more probable at high doses or when using along with other drugs which influence the central nervous
system (such as other antiepileptic means, benzodiazepines and alcohol).

Side effects:

Side reactions at use of the drug Valproatum Orion often dozozavisima and fast-passing.

Inborn, family and genetic frustration. Risk of teratogenic effects.

From system of a hemopoiesis and lymphatic system. Easy, the miyelosupressiya, thrombocytopenia, hemorrhages, the lowered fibrinogen level is completely reversible; usually without clinical symptoms, especially at reception of high doses (sodium Valproatum shows an inhibiting effect on the second phase of reaction of aggregation of thrombocytes). Miyelosupressiya sometimes takes severe forms, passes into an agranulocytosis, anemia and a pancytopenia, a lymphopenia, thrombocytopenia, a leukopenia, a lymphocytosis, the extended bleeding time as a result of oppression of aggregation of thrombocytes and/or a trombotsitopatiya, is caused by deficit of a factor of VIII/von Willebrand, an aplasia of red marrow or a true erythrocyte aplasia. At patients with asimptomny thrombocytopenia, whenever possible, showed simple reduction of a dose of drug taking into account levels of thrombocytes and extent of control of a disease that, as a rule, leads to disappearance of thrombocytopenia.

From immune system. A system lupus erythematosus, hypersensitivity reactions, a Quincke's disease, sinry DRESS (medicamentous rashes with an eosinophilia and system manifestations) or a hypersensitivity syndrome to medicine. Disturbance of metabolism and alimentary frustration. The isolated giperammoniyemiya without liver dysfunction symptoms. There is no need for drug withdrawal. Fankoni's syndrome (emergence it is still unknown), the increased testosterone level. Very exceptional cases of a hyponatremia (with or without syndrome of inadequate secretion of ADG (SNSAG)), giperammoniyemiya, being followed clinical symptoms (an enfefalopatiya, vomiting, an ataxy).

Mental disorders. A disorientation, a hyperactivity, aggression, irritability, confusion, mental disorders, including psychoses, disorders of behavior, a depression and concern.

From a nervous system. Tremor, paresthesias, headache. At a combination therapy with other antiepileptic means fatigue, drowsiness, apathy and an ataxy were observed. Hyperactivity, irritability. The confusion of consciousness, several cases of a stupor and a lethargy progressing to temporary a coma (encephalopathy) were described at sodium treatment by Valproatum. It were isolated separate cases or associated with emergence by court during treatment. Symptoms disappeared after a dose decline or cancellation of therapy. The majority of these cases were registered at a combination therapy (especially with phenobarbital) or after sharp increase in a dose.

Nystagmus and вертиго. Also giperammoniyemiya cases with neurologic symptoms are described. In such cases the further research is necessary.

Enuresis, hallucinations. It was reported about the reverse dementia connected with a reverse brain atrophy and the isolated reversible parkinsonism.

It was reported about cases of extrapyramidal frustration, including reverse parkinsonism.

From acoustic organs and balance. A hearing loss (reverse and irreversible, relationship of cause and effect is not established), a sonitus.

From a digestive tract. The nausea, vomiting, hypersalivation and gastrointestinal frustration arising, as a rule, in an initiation of treatment are also temporary, pancreatitis (sometimes with a lethal outcome), pain in a stomach, diarrhea.

From the alimentary system. Liver dysfunction, sometimes is followed by a giperammoniyemiya and drowsiness. Especially children, can have them very heavy, even with a lethal outcome. It can occur within the first six months of treatment. Liver diseases.

From skin and hypodermic cellulose. Short-term hair loss, thinning of hair, skin reactions, such, as exanthematous rash, skin vasculitis, mnogoformny erythema, toxic epidermal necrolysis, Stephens-Johnson's syndrome, discolorations of hair.

From a musculoskeletal system and connecting fabric. Decrease in mineral density of a bone tissue, osteosinging, osteoporosis, fractures.

From reproductive system and mammary glands. Irregular periods, an amenorrhea, a polycystosis of ovaries, infertility at men, a hirsutism.
The general disturbances and reactions in an injection site. Increase in weight or loss of weight, increase or loss of appetite, cases of peripheral hypostases (frivolous), stomatitis, porphyria, hypothermia.

Interaction with other medicines:

Impact of other medicines on Valproatum sodium metabolism. Carbamazepine, Phenytoinum, phenobarbital and Primidonum reduce concentration of valproyevy acid in serum. It is recommended to make clinical observation and tracking of concentration of drug in serum, especially at the beginning of a combination therapy and at cancellation of drug which causes induction of enzymes.

Felbamat can increase concentration of sodium of Valproatum. It is recommended to make clinical observation and tracking of concentration of drug in serum, especially at the beginning of a combination therapy.

The Ethosuximidum can moderately reduce Valproatum sodium level in serum.
Fluoxetine can increase Valproatum sodium level in serum.

Meflokhin, chloroquine. Meflokhin can reduce Valproatum sodium levels. Besides, meflo-hin and chloroquine can reduce a threshold of convulsive readiness. Simultaneous use is not recommended. If the combination is necessary, careful observation is necessary.

Karbapenemovy antibiotics can quickly reduce Valproatum sodium levels in serum.

At simultaneous use careful clinical observation and definition of concentration of drug in serum is required.

Rifampinum increases clearance of sodium of Valproatum and reduces Valproatum sodium level in serum.

Erythromycin and isoniazid can increase Valproatum sodium level in serum.

Acetylsalicylic acid at antipyretic doses can force out sodium Valproatum from places of linkng with proteins of plasma and inhibit Valproatum sodium metabolism.

Cimetidinum can increase Valproatum sodium level in serum.

Valproatum sodium impact on metabolism of other medicines.

Lamotridzhin. Sodium Valproatum inhibits metabolism of a lamotridzhin and increases an elimination half-life, concentration in serum and toxicity of a lamotridzhin. Simultaneous use is not recommended. If use of a combination is necessary, then it is necessary to apply a reduced dose of a lamotridzhin. Careful clinical observation and tracking of concentration of drug in serum is necessary. In particular, it is necessary to monitor serious skin reactions and at their emergence immediately to stop use of a lamot-ridzhin.

Carbamazepine. Sodium Valproatum can inhibit metabolism of carbamazepine and carbamase-pin-10,11-epoxide. There are messages on clinical toxicity at  Valproatum sodium use together with carbamazepine.

Fenotoin. Sodium Valproatum forces out Phenytoinum from places of its linkng with proteins that considerably increases concentration of untied Phenytoinum in serum and fabrics. At prolonged use concentration of untied Phenytoinum usually is returned to initial level.

Besides, sodium Valproatum can inhibit metabolism of Phenytoinum. When determining levels of Phenytoinum it is necessary to estimate an untied form.

Phenobarbital, Primidonum. Sodium Valproatum inhibits metabolism of phenobarbital and Primidonum. At emergence of sedation or other symptoms of intoxication barbiturates the phenobarbital dose (or Primidonum) should be reduced immediately.

Felbamat, Ethosuximidum. Sodium Valproatum can inhibit metabolism of a felbamat and Ethosuximidum and, thus, to increase their levels in blood serum.

Zidovudine. Sodium Valproatum inhibits metabolism of a zidovudine that can result in hypertoxity of a zidovudine.

Lorazepam, amitriptyline, нортриптилин. Sodium Valproatum inhibits metabolism and increases levels in blood serum of lorazepam, amitriptyline and a nortriptilin.

Nimodipin. Sodium Valproatum inhibits metabolism of a nimodipin that can cause hypotension.

Others. It is recommended to use with care of Valproatum sodium in a combination with new antiepileptic drugs which pharmakodinamichesky and pharmacokinetic properties can be still insufficiently studied. At simultaneous use topirama-that and Valproatum sodium risk of a giperammoniyemiya or encephalopathy can increase. It is necessary to watch a clinical condition of the patient and level of ammonium in blood serum, especially at the beginning of the combined treatment and at emergence of evokativny symptoms.

Sodium Valproatum can cause thrombocytopenia, dysfunction of thrombocytes or to reduce levels of blood-coagulation factors. It can increase risk of the bleeding connected with anticoagulants (such as warfarin) and the drugs inhibiting aggregation of thrombocytes (such as acetylsalicylic acid). Sodium Valproatum can also inhibit warfarin metabolism. At simultaneous use with anticoagulants regular monitoring of coagulability of blood is recommended.

Sodium Valproatum can exponentiate sedations of other medicines (such as neuroleptics, MAO inhibitors, antidepressants and benzodiazepines).

Absentia epileptica cases at simultaneous use of clonazepam and sodium of Valproatum were noted.

Potentially gepatotoksichny medicines and medicinal plants, and also alcohol can strengthen Valproatum sodium hepatotoxic.

Sodium Valproatum does not reduce efficiency of hormonal contraceptives as has no essential enzimindutsiruyushchy potential.

Contraindications:

Hypersensitivity to sodium to Valproatum or any of excipients. Chronic or acute hepatitis. Heavy dysfunction of a liver, in particular medicinal (also in the anamnesis). Heavy dysfunction of a pancreas. Porphyria. Tendency to bleedings.

Overdose:

Symptoms. At overdose the most common symptoms are drowsiness, a lethargy, nausea, vomiting, dizziness and tachycardia, also symptoms can include a coma, respiratory depression, a metabolic acidosis, thrombocytopenia and a leukopenia, arterial hypotension, spasms, a hypoglycemia, increase in intracranial pressure and electrolytic disturbances.

Therapy. There is no specific antidote. Clinical actions have to be directed to treatment of noted symptoms. It is necessary to resort to the numerous reception of absorbent carbon and other measures reducing absorption. It is necessary to watch vital signs and if necessary to undertake the supporting measures. At cases of overdose the hemodialysis was successfully used. Sometimes also Naloxonum was applied intravenously.

Storage conditions:

To store at the room temperature (15–25 °C) in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 30 or 100 tablets in a bottle with the water-absorbing capsule; in a cardboard box.