Klopidogrel-Pharmex tab. of p/o of 75 mg No. 30

Translation of the instruction Mose

tablet KLOPIDOGREL-FARMEKS, coated 75 mg

Instruction

On medical use of medicine

Klopidogrel-pharmex

(clopidogrel-pharmex)

Ingredients:

Active ingredient: clopidogrel;

1 tablet contains klopidogrelya bisulphate in terms of klopidogrel 75 mg;

excipients: a mannitol (E 421), cellulose microcrystalline, hydroxypropyl cellulose, a macrogoal 6000, the castor oil hydrogenated krospovidon, silicon dioxide colloidal anhydrous;

cover: opadray II pink (gipromeloza, lactoses monohydrate, titan dioxide (E 171), triacetin, ferrous oxide red (E 172)).

Dosage form.

Tablet, coated.

Main physical and chemical properties: tablets of round shape, with a biconvex surface, coated pink color.

Pharmacotherapeutic group.

Inhibitors of aggregation of thrombocytes, except heparin.

ATX B01A C04 Code.

Pharmacological properties.

Pharmacodynamics.

Klopidogrel selectively oppresses linking of adenosinediphosphate (ADF) with a receptor on surfaces of a thrombocyte and the subsequent activation of the GPIIb/IIIa complex under the influence of ADF and, thus, suppresses aggregation of thrombocytes. Biotransformation klopidogrelya is necessary for formation of an active ingibition of aggregation of thrombocytes. Klopidogrel also oppresses the aggregation of thrombocytes induced by other agonists by blocking of increase in activity of thrombocytes the released ADF. Klopidogrel it is irreversible modifies ADF-receptors of thrombocytes. Thus, the thrombocytes interacting with klopidogrely change until the end of their life cycle. Normal function of thrombocytes is restored with a speed, the corresponding speed of updating of thrombocytes.

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From the first day of use of medicament in repeated daily doses of 75 mg shows significant delay ADF-indutsirovannoy of aggregation of thrombocytes. This action amplifies progressively and stabilized between the 3rd and 7th days. At a stable state the average level of oppression of aggregation under the influence of a daily dose of 75 mg is from 40% to 60%. Aggregation of thrombocytes and duration of bleeding return to initial level on average in 5 days after the treatment termination.

Pharmacokinetics.

Absorption. After oral administration single and repeated doses of 75 mg a day klopidogrel it is quickly soaked up. Average peak concentration in plasma not changed klopidogrelya (about 2.2-2.5 ng/ml after a single dose of 75 mg orally) were reached approximately in 45 minutes after reception of a dose. Absorption is not less than 50% according to excretion of metabolites klopidogrelya with urine.

Distribution. Klopidogrel and the main (inactive) metabolite circulating in blood, in vitro reversibly contact proteins of plasma of the person (98% and 94% respectively). This communication remains to not saturable in vitro within the wide range of concentration.

Metabolism. Klopidogrel is extensively metabolized in a liver. In vitro and in vivo exists two main ways of his metabolism: one happens to participation of esterases and leads to hydrolysis with education inactive derivative carboxylic acid (which makes 85% of all metabolites circulating in plasma), and enzymes of a system of P450 cytochrome are attracted to another. At first klopidogrel turns into an intermediate metabolite 2-oxo-klopidogrel. As a result of further metabolism 2-oxo-klopidogrelya thiol derivative — an active metabolite is formed. In vitro this metabolic way mediated by CYP3A4, CYP2C19, CYP1A2 and CYP2B6 enzymes. Active metabolite klopidogrelya (thiol derivative) which was allocated to in vitro, quickly and it is irreversible contacts receptors on thrombocytes, that interfering with aggregation of thrombocytes.

Removal. In 120 hours after intake of marked ¹⁴ C-klopidogrelya at the person about 50% of a tag was removed with urine and about 46% with a stake. After oral administration of a single dose of 75 mg the elimination half-life klopidogrelya makes about 6 hours. Elimination half-life of the main (inactive) metabolite circulating in blood makes 8 hours after single and repeated use of drug.

Pharmacogenetics.

Knows that klopidogrel is activated by several polymorphic CYP450 enzymes. CYP2C19 takes part in formation of both an active metabolite, and an intermediate metabolite 2-oxo-klopidogrelya. Pharmacokinetics of an active metabolite klopidogrelya and antithrombocytic effects, according to measurement of aggregation of thrombocytes of ex Vivo, differ depending on CYP2C19 genotype. The allele of CYP2C19*1 corresponds to completely functioning metabolism whereas alleles of CYP2C19*2 and CYP2C19*3 correspond to nonfunctioning metabolism. Alleles of CYP2C19*2 and CYP2C19*3 are responsible for the majority of alleles which weaken function, at patients Caucasian (85%) and Mongoloid (99%) races with the lowered metabolism. Other alleles associated with the absent or weakened metabolism, meet much less often. CYP2C19*4, * 5, * 6, * 7 and * 8 belong to them, however they meet at the population much less often.

Special categories of patients. Pharmacokinetics of an active metabolite klopidogrelya were not investigated in the below-stated patients of special categories.

Renal failure. After regular use of 75 mg klopidogrelya in day the patients with a heavy renal failure (clearance of creatinine of 5-15 ml / in a minute) had less expressed inhibition ADF-indutsirovannoy of aggregation of thrombocytes (25%) in comparison with the same effect at healthy volunteers, and the bleeding time was prolonged almost as well as at the healthy volunteers receiving 75 mg klopidogrelya in day. All patients had a good clinical tolerance.

Liver failure. After regular reception of 75 mg klopidogrelya in day within 10 days at patients with a heavy liver failure inhibition ADF-indutsirovannoy of aggregation of thrombocytes was the same, as well as at healthy volunteers. Average increase in a bleeding time also was identical in both groups.

Race. The prevalence of alleles of CYP2C19 which cause intermediate and weak metabolic activity of CYP2C19 differs depending on racial/ethnic origin (see the section "Pharmacogenetics"). There are limited data on patients of Mongoloid race who allow to estimate clinical value of genotyping of this CYP.

Clinical characteristics.

Indication.

Prevention of manifestations of an aterotromboz at adults:

• at the patients who had a myocardial infarction (an initiation of treatment — in several days, but not later than in 35 days after emergence), an ischemic stroke (an initiation of treatment — in 7 days, but not later than in 6 months after emergence) or for which the disease of peripheral arteries is diagnosed (damage of arteries and aterotromboz vessels of the lower extremities);
• at patients with a sharp coronary syndrome:
• with a sharp coronary syndrome without raising of a segment of ST (unstable stenocardia or a myocardial infarction without tooth Q), including at patients to whom the stent was established during performing transdermal coronary angioplasty, in a combination with acetylsalicylic acid (ASK);
• with an acute myocardial infarction with raising of a segment of ST in a combination with acetylsalicylic acid (at the patients receiving standard medicament treatment and to which thrombolytic therapy is shown).

Prevention of aterotrombotichesky and thromboembolic events at fibrillation of auricles. Klopidogrel in a combination with ASK is shown to adult patients with fibrillation of auricles which have at least one risk factor of emergence of vascular events which have contraindications to treatment by the antagonists of vitamin K (AVK) and which have low risk of developing of bleedings, for prevention of aterotrombotichesky and thromboembolic events, including a stroke.

Contraindication.

Hypersensitivity to active ingredient or to any component of drug. heavy liver failure. acute bleeding (for example, round ulcer or intracraneal hemorrhage).

Interaction with other medicines and other types of interactions.

Medicines which use is followed by increase in risk of bleedings. through potential additive effect there is an increased risk of hemorrhagic complications therefore simultaneous use of such medicines with klopidogrely demands care (see the section of "feature of use").

Oral anticoagulants. Simultaneous use of the medicament Klopidogrel-Pharmex with oral anticoagulants is not recommended as such combination can enhance intensity of bleeding (see the section "Features of Use"). Though use klopidogrelya in a dose of 75 mg a day does not change a pharmacokinetic profile of S-warfarin or the international normalized ratio (INR) at patients who throughout a long time receive treatment by warfarin, simultaneous use klopidogrelya and warfarin increases risk of bleeding because of existence of independent influence on a hemostasis.

Inhibitors of glycoprotein receptors IIb/IIIa. Klopidogrel should appoint with care the patients receiving inhibitors of glycoprotein receptors IIb/IIIa (see the section "Features of Use").

Acetylsalicylic acid (ASK). Acetylsalicylic acid does not change inhibitory action klopidogrelya on ADF-indutsirovannuyu aggregation of thrombocytes, but klopidogrel strengthens action of ASK on the aggregation of thrombocytes induced by collagen. However simultaneous use of 500 mg of ASK 2 times a day within one day did not cause significant increase in the bleeding time extended owing to reception klopidogrelya. As perhaps pharmakodinamichesky interaction between klopidogrely and acetylsalicylic acid with increase in risk of bleeding, simultaneous use of these medicaments demands care (see the section "Features of Use"). Despite this, klopidogrel and ASK it is in common possible to apply till 1 year (see the section "Pharmacological Properties").

Heparin. There are data that klopidogrel did not demand correction of a dose of heparin and did not change effect of heparin to coagulation. Simultaneous use of heparin did not change inhibiting effect klopidogrelya to aggregation of thrombocytes. As perhaps pharmakodinamichesky interaction between klopidogrely and heparin with increase in risk of bleeding, simultaneous use of these medicaments demands care.

Thrombolytic means. At patients with an acute myocardial infarction at simultaneous use klopidogrelya, fibrinospetsifichesky or fibrinonespetsifichesky thrombolytic means and heparins the frequency of cases of clinically significant bleedings is similar to that which is observed on condition of introduction of thrombolytic means and heparin along with ASK.

Non-steroidal anti-inflammatory medicaments (NPVP). Simultaneous use klopidogrelya and Naproxenum increases quantity of the concealed gastrointestinal hemorrhages. However due to the lack of researches on interaction of medicament with other NPVP it is still not found out whether the risk of gastrointestinal bleedings at use with all NPVP increases. Therefore the care at simultaneous use of NPVP is necessary, in particular TsOG-2 inhibitors, with klopidogrely (see the section "Features of Use").

Selective Serotonin Reuptake Inhibitors (SSRI). It is necessary to apply with care at the same time of SIOZS with klopidogrely because SIOZS influence activation of thrombocytes and increase risk of developing of bleedings.

Simultaneous use of other drugs. As klopidogrel turns into the active metabolite partially under the influence of CYP2C19, use of the medicaments reducing activity of this enzyme, most likely, will lead to decrease in concentration of an active metabolite klopidogrelya in plasma and also to decrease in clinical performance. It is necessary to avoid simultaneous use of medicaments which suppress activity of CYP2C19.

omeprazolum, esomeprazole, fluvoksamin, fluoxetine, moklobemid, vorikonazol, flukonazol, tiklopidin, carbamazepine and efavirents belong To the medicaments suppressing activity of CYP2C19.

Inhibitors of a Proton Pomp (IPP). Omeprazolum in a dose of 80 mg of 1 times a day, at simultaneous use with klopidogrely or within 12 hours between intake of these drugs, reduced concentration of an active metabolite in blood by 45% (load dose) and 40% (maintenance dose). This decrease was followed by reduction suppression of aggregation of thrombocytes for 39% (load dose) and 21% (maintenance dose). It is expected that interaction of esomeprazole with klopidogrely similar.

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as a result of observation and clinical tests obtained contradictory data on clinical consequences of these pharmacokinetic (FC) and pharmakodinamichesky (FD) interactions in terms of development of the main cardiovascular events. As a measure of restraint, it is not necessary along with klopidogrely to apply omeprazolum or esomeprazole.

Less significant decrease in concentration of a metabolite in blood was observed by

at use of a pantoprazol or lansoprazol.

At simultaneous use of a pantoprazol in a dose of 80 mg of 1 times a day the plasma concentration of an active metabolite decreased by 20% (load dose) and for 14% (maintenance dose). This decrease was followed by reduction of an average value suppression of aggregation of thrombocytes for 15% and 11% respectively. The received results indicate a possibility of simultaneous use klopidogrelya and a pantoprazola.

do not have

proofs that other medicines reducing producing acid in a stomach such as N ₂ - blockers (except for Cimetidinum which is CYP2C19 inhibitor) or antacids, affect antithrombocytic activity klopidogrelya.

Combination with other medicines. Clinically significant pharmakodinamichesky interaction was not observed if klopidogrel applied along with atenolol, nifedipine or with both drugs. Besides, the pharmakodinamichesky activity klopidogrelya remained almost not changed at simultaneous use of phenobarbital, Cimetidinum or estrogen.

Pharmacokinetics of digoxin and theophylline does not change at simultaneous use klopidogrelya. Antacids do not influence extent of absorption klopidogrelya.

Carboxyl metabolites klopidogrelya can suppress activity of P4502C9 cytochrome. Potentially it can lead to increase in level in blood plasma of such medicaments as Phenytoinum and tolbutamide, and NPVP which are metabolized by P4502C9. Phenytoinum and tolbutamide can be applied safely along with klopidogrely.

Medicines which are CYP2C8 enzyme substrates. It was shown what klopidogrel increases exposure of a repaglinid at healthy volunteers. The researches in vitro showed that this increase in exposure of a repaglinid is caused by CYP2C8 enzyme inhibition a glyukuronidny metabolite klopidogrelya. Considering risk of increase in concentration in blood plasma, simultaneous use klopidogrelya and medicines which are removed from an organism mainly by means of the metabolism mediated by CYP2C8 enzyme (such as repaglinid, paklitakset), demands care (see the section "Features of Use").

except for information on interaction with specific medicines given above, researches concerning interaction klopidogrelya with medicines which are usually appointed the patient aterotrombozy were not carried out. However at patients who used at the same time other medicaments including diuretics, beta-blockers, inhibitors of angiotensin-converting enzyme, antagonists of calcium, means which reduce cholesterol level, coronary vazodilatator, anti-diabetic means (including insulin), antiepileptic means, gormonozamestitelny therapy and antagonists of GPIIb/IIIa, clinically significant side reactions are not revealed.

Feature of use.

Bleeding and hematologic disorders. because of risk of developing bleeding and hematologic side effects it is necessary to carry out immediately developed blood test and/or other corresponding tests if during use of medicament symptoms which testify to possible bleeding are observed (see the section "side reactions"). as well as other antithrombocytic means, klopidogrel patients should apply carefully with the increased risk of bleeding as a result of an injury, surgical intervention or other morbid conditions and also in case of use by patients ask, heparin, inhibitors of a glycoprotein iib/iiia or non-steroidal anti-inflammatory drugs, including inhibitors tsog-2. it is necessary to watch closely manifestations at sick symptoms of bleeding, including concealed hemorrhage, especially in the first weeks of treatment and/or after the invasive procedures on heart and surgical interventions. simultaneous use klopidogrelya with oral anticoagulants is not recommended as it can enhance intensity of bleedings (see the section "interaction with other medicines and other types of interactions").

in case of planned surgical intervention which temporarily does not demand use of antithrombocytic means treatment klopidogrely should be stopped in 7 days prior to operation. Patients have to report to the doctor (including to the stomatologist) about what they accept klopidogrel, before purpose of any operation by him or before use of new medicine. Klopidogrel prolongs bleeding duration therefore it should be applied carefully to patients with the increased risk of bleeding (especially gastrointestinal and intraocular).

Patients should warn that during treatment klopidogrely (separately or in a combination with ASK) bleeding can stop later, than usually and that they have to report to the doctor about each case unusual (in the place or duration) bleedings.

Trombotichesky Werlhof's Disease (TWD). Cases of the trombotichesky Werlhof's disease (TWD) after use klopidogrelya, sometimes even after its short-term use were very seldom observed. The TPP is shown by thrombocytopenia and mikroangiopatichesky hemolytic anemia with neurologic manifestations, renal dysfunction or fever. The TPP is potentially dangerous state which can lead to a lethal outcome and therefore needs immediate treatment including carrying out a plasma exchange.

Acquired hemophilia. It was reported about cases of development of the acquired hemophilia after use klopidogrelya. In cases of the confirmed isolated increase APTT (the activated partial tromboplastinovy time) that is followed or is not followed by bleeding, the question of diagnosing of the acquired hemophilia has to be considered. Patients with the confirmed diagnosis of the acquired hemophilia have to be under observation of the doctor and receive treatment, use klopidogrelya has to be stopped.

Recently had ischemic stroke. Because of insufficiency of data it is not recommended to appoint klopidogrel in the first 7 days after an acute ischemic stroke.

P450 2C19 Cytochrome (CYP2C19). Pharmacogenetics: at patients with genetically reduced CYP2C19 function the smaller concentration of an active metabolite klopidogrelya in plasma and less significant antithrombocytic effect is observed. Now there are tests allowing to reveal CYP2C19 genotype at the patient.

As klopidogrel turns into the active metabolite partially under the influence of CYP2C19, use of the medicaments reducing activity of this enzyme, most likely, will lead to reduction of concentration of an active metabolite klopidogrelya in blood plasma. However the clinical value of this interaction is not found out. Therefore as a precautionary measure it is necessary to avoid simultaneous use of strong and moderate CYP2C19 inhibitors (see the section "Interaction with Other Medicines and Other Types of Interactions"; the list of CYP2C19 inhibitors is provided in the section "Pharmacokinetics").

Cross-responsiveness between thienopyridines. Patsiyentov it is necessary to check for existence in the anamnesis of hypersensitivity to other thienopyridines (such as tiklopidin, prasugrel) because there are data on a cross allergy between thienopyridines (see the section "Side reactions"). Use of thienopyridines can lead to emergence from lungs before heavy allergic reactions, such as rash, Quincke's edema, or hematologic reactions, such as thrombocytopenia and neutropenia. Patients who in the past had allergic reactions and/or hematologic reactions to one thienopyridine in the anamnesis can have the increased risk of development of the same or other reaction to other thienopyridine. Monitoring on cross-responsiveness is recommended.

Renal failure. Therapeutic experience of use klopidogrelya to patients with a renal failure is limited therefore such patients should appoint medicament with care (see the section "Route of Administration and Doses").

Abnormal liver function. Experience of use of medicament to patients with diseases of a moderately severe liver and risk of developing of hemorrhagic diathesis is limited therefore such patients klopidogrel should appoint with care (see the section "Route of Administration and Doses").

Excipients. Klopidogrel-Pharmex contains lactose. Patients with such rare hereditary diseases as intolerance of a galactose, deficiency of Lappa lactase or disturbance of malabsorption of glucose galactose should not take this drug.

castor oil hydrogenated which can cause indigestion and diarrhea contains

Klopidogrel-Pharmex.

Special instructions on destruction of the remains and waste. Unused medicament or waste need to be destroyed according to local requirements.

Use during pregnancy or feeding by a breast.

As do not have

clinical data on use klopidogrelya during pregnancy, it is undesirable to appoint klopidogrel to pregnant women.

Animal experiments did not reveal the direct or mediated negative impact on the pregnancy course, development of an embryo/fruit, childbirth and post-natal development.

Does not know to

whether it is excreted klopidogrel in breast milk at women. Researches on animals showed that medicament is excreted in breast milk. Therefore during the Klopidogrel-Pharmex medicament treatment the feeding by a breast should be stopped.

Ability to influence speed of response at control of motor transport or other mechanisms.

Klopidogrel does not influence or has insignificant influence on speed of response at control of motor transport or work with other mechanisms.

Route of administration and doses.

Adults and patients of advanced age. klopidogrel to accept 75 mg of 1 times a day, irrespective of meal.

treatment klopidogrely to begin with

For patients with a sharp coronary syndrome without raising of a segment of ST (unstable stenocardia or a myocardial infarction without Q tooth on the ECG) with a single load dose 300 mg, and then to continue by a dose 75 mg of 1 times a day (with acetylsalicylic acid (ASK) in a dose of 75-325 mg a day). As use of higher doses of ASK increases risk of bleeding, it is recommended not to exceed a dose of acetylsalicylic acid of 100 mg. The optimum duration of treatment is formally not established. There are data testifying in advantage use of medicament up to 12 months, and the maximum effect was observed in 3 months of treatment.

with an acute myocardial infarction with raising of a segment of ST klopidogrel to appoint

Sick on 75 mg of 1 times a day, since a single load dose of 300 mg in a combination with ASK, using thrombolytic medicaments or without them. To begin treatment of patients from 75 years without load dose klopidogrelya. Combination therapy should be begun as soon as possible after emergence of symptoms and to continue, at least, 4 weeks. The advantage of use of a combination klopidogrelya with ASK in this disease was not studied more than four weeks.

to Patients with fibrillation of auricles klopidogrel to apply 75 mg in a single daily dose. Together with klopidogrely it is necessary to begin and continue use of ASK (in a dose of 75-100 mg a day).

in case of the admission of reception of a dose:

• if since the moment when it was necessary to accept the next dose, there passed less than 12 hours: the patient has to accept immediately passed dose, and already to accept the following dose in usual time;
• if there passed more than 12 hours, the patient has to accept the following next dose in usual time and not double a dose for the purpose of compensation of the passed dose.

Children and teenagers. Safety and efficiency of use of medicament are not established to children and teenagers.

Renal failure. Therapeutic experience of use of medicament to patients with a renal failure is limited (see the section "Features of Use").

Liver failure. Therapeutic experience of use of medicament to patients with diseases of a moderately severe liver and possibility of hemorrhagic diathesis is limited (see the section "Features of Use").

Children.

Safety and efficiency of use of medicament are not established to children by

therefore it should not be applied to patients up to 18 years.

Overdose.

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At overdose klopidogrely extension of a bleeding time with further complications can be observed. in case of developing of bleeding the symptomatic treatment is recommended.

Antidote of pharmacological activity klopidogrelya is unknown to

. In need of immediate correction of the prolonged bleeding time klopidogrelya it can be terminated by transfusion of platelet concentrate.

Side reactions.

Side reactions are distributed by

on a system "body class", the frequency of their emergence is determined as follows: often (ot1/100 to 1/1000 to 1/10000 to

Bleeding is the most widespread side reaction, it most often arises in the first month of treatment.

from blood and lymphatic system.

Infrequently. Thrombocytopenia, leukopenia, eosinophilia.

it is rare. A neutropenia, including a heavy neutropenia.

It is very rare, frequency neizvestna*. The Trombotichesky Werlhof's Disease (TWD) (see the section "Features of Use"), aplastic anemia, a pancytopenia, an agranulocytosis, heavy thrombocytopenia, the acquired hemophilia And, a granulocytopenia, anemia.

from heart.

It is very rare, frequency neizvestna*. Kounis-sindrom (vasospastic allergic stenocardia / an allergic myocardial infarction) as a result of hypersensitivity reaction to klopidogrelyu*.

from the immune system.

It is very rare, frequency neizvestna*. A serum disease, anaphylactoid reactions, cross hypersensitivity between thienopyridines (such, as tiklopidin, prasugrel) (see the section "Features of Use") *.

Mental disturbances.

It is very rare, frequency neizvestna*. Hallucinations, confusion of consciousness.

from nervous system.

Infrequently. Intracranial bleedings (in certain cases — with a lethal outcome), a headache, paresthesia, dizziness.

It is very rare, frequency neizvestna*. Change of flavoring perception.

from organs of sight.

Infrequently. Hemorrhage to the area of an eye (conjunctival, ocular, retinal).

from organs of hearing and a labyrinth.

it is rare. Vertigo.

from vessels.

it is frequent. Hematoma.

It is very rare, frequency neizvestna*. Heavy hemorrhage, bleeding from an operational wound, a vasculitis, arterial hypotension.

from the respiratory system, bodies of a thorax and mediastinum.

it is frequent. Nasal bleeding.

It is very rare, frequency neizvestna*. Bleedings of a respiratory way (pneumorrhagia, pulmonary bleedings), bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.

from digestive tract.

it is frequent. Gastrointestinal bleeding, diarrhea, abdominal pain, dyspepsia.

Infrequently. Ulcer of stomach and duodenum, gastritis, vomiting, nausea, constipation, meteorism.

it is rare. Retroperitoneal hemorrhage.

It is very rare, frequency neizvestna*. Gastrointestinal and retroperitoneal bleedings with a lethal outcome, pancreatitis, colitis (in particular ulcer or lymphocytic), stomatitis.

from a gepatobiliarny system.

It is very rare, frequency neizvestna*. Acute liver failure, hepatitis, abnormal results of indicators of function of a liver.

from skin and hypodermic cellulose.

it is frequent. Hypodermic hemorrhage.

Infrequently. Rash, itching, intracutaneous hemorrhages (purpura).

It is very rare, frequency neizvestna*. Bullous dermatitis (toxic epidermal necrolysis, Stephens-Johnson's syndrome, multiformny erythema), sharp generalized exanthematous pustulez, a Quincke's disease, erythematic rash, a small tortoiseshell, a medicamentous syndrome of hypersensitivity, medicamentous rash with an eosinophilia and system manifestations (DRESS syndrome), erythematic or exfoliative rashes, eczema, flat deprive.

Disorder from a reproductive system and mammary glands.

it is rare. A gynecomastia

from the musculoskeletal system and connective tissue.

It is very rare, frequency neizvestna*. Musculoskeletal hemorrhages (hemarthrosis), arthritis, arthralgia, myalgia.

from kidneys and urinary tract.

Infrequently. Hamaturia.

It is very rare, frequency neizvestna*. A glomerulonephritis, increase in level of creatinine in blood.

General disturbances.

it is frequent. Bleeding in the place of an injection.

It is very rare, frequency neizvestna*. Fever.

Change in results of laboratory indicators.

Infrequently. Lengthening of a bleeding time, decrease in quantity of neutrophils and thrombocytes.

Message about the suspected side reactions.

Message about the suspected side reactions after medicine approval by allowing bodies is the important procedure. It allows to carry out continuous monitoring of a ratio "advantage/risk" of use of this medicine. Health workers are asked to report about all suspected side reactions.

* — information with a frequency "frequency is unknown to

".

Expiration date.

2 years.

Storage conditions.

to Store

in original packing at a temperature not over 25 ºс. to store out of children's reach.

Packing.

On 10 tablets in the blister; on 1 or 3 blisters in a cardboard pack.

Category of release.

According to the prescription.

Producer.

Ltd company "pharmex groups".

Location of the producer and its address of the place of implementation of activity.

Ukraine, 08301, Kiev Region, city of Boryspil, Shevchenko's street, house 100.