Acetylsalicylic acid + Clopidogrel (Acetylsalicylic acid + Clopidogrel)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Dosage form: & nbspfilm coated tablets
Composition:

1 tablet, film-coated, contains:

active ingredients: acetylsalicylic acid - 100 mg, clopidogrel hydrogensulfate - 97.9 mg in terms of clopidogrel - 75 mg

auxiliary substances (core): cellulose microcrystalline - 146.1 mg, mannitol - 76.0 mg, giprolose (low-substituted hydroxypropylcellulose) - 20.0 mg, macrogol 6000 (polyethylene glycol 6000) - 35.0 mg, sodium stearyl fumarate - 3.0 mg, silicon dioxide colloid aerosil) 2.0 mg

auxiliary substances (shell): hypromellose - 7,19964 mg; polysorbate-80 (tween-80) - 3.29983 mg; talc - 2.99985 mg; titanium dioxide E 171 - 1.49993 mg; dye of carmoazine (azorubin) - 0.00075 mg.

Description:

The tablets covered with a film cover of light pink color, round, biconcave. On the cross section, the core of the tablet is white or almost white in color.

Pharmacotherapeutic group:Antiaggregant agent
ATX: & nbsp
  • Inhibitors of platelet aggregation (excluding heparin) in combinations
    • Pharmacodynamics:

    Clopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. Its active metabolite irreversibly binds to platelet ADP receptors (adenosine diphosphate receptors) and selectively inhibits the binding of ADP to ADP receptors of platelets and subsequent activation of the complex GPIIb/IIIa under the action of ADP, due to which ADP-induced aggregation of platelets is suppressed. Clopidogrel also inhibits platelet aggregation caused by other agonists, due to the fact that it blocks the activation of platelets by the released ADP. In connection with the irreversibility of the binding of clopidogrel with ADP-receptors of platelets, platelets remain immune to stimulation of ADP during the rest of their life (approximately 7 - 10 days), and the restoration of the normal function of platelets occurs at a rate corresponding to the rate of platelet renewal.

    Since the formation of an active metabolite occurs with cytochrome P450 isoenzymes, some of which may be polymorphic or may be inhibited by other drugs, not all patients may have sufficient inhibition of platelet aggregation.

    With a daily intake of clopidogrel at a dose of 75 mg, a significant inhibition of ADP-induced platelet aggregation is noted from the first day of administration, which gradually increases for 3-7 days and then reaches a constant level (when the equilibrium state is reached).In the equilibrium state, platelet aggregation is suppressed on average by 40-60%. After stopping the use of clopidogrel, platelet aggregation and bleeding time gradually return to the baseline level on average for 5 days.

    Acetylsalicylic acid (ASA) has a different mechanism than clopidogrel and its complementary mechanism of antiplatelet action. ACA suppresses platelet aggregation by irreversible inhibition of prostaglandin cyclooxygenase-1 and, as a consequence, decreases the formation of thromboxane A2, which is an inducer of platelet aggregation and vasoconstriction. This effect persists throughout the life span of platelets.

    ASA does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, while clopidogrel enhances the effect of ASA on collagen-induced platelet aggregation.

    Both active substances in monotherapy and with simultaneous application are able to prevent the development of atherothrombosis in any localization atherosclerotic vascular lesions, in particular for lesions of the cerebral, coronary or peripheral arteries.

    Clinical study ACTIVE-A showed that in patients with atrial fibrillation who had at least one risk factor for vascular complications, but were unable to take indirect anticoagulants, clopidogrel in combination with ASA (compared with the use of only one ASA) reduced the incidence of combined stroke, myocardial infarction, systemic thromboembolism outside the central nervous system (CNS), or death from vascular causes, largely by reducing the risk of stroke.

    The advantage of taking clopidogrel in combination with ASA compared with the administration of ASA in combination with placebo was detected early and persisted throughout the study period (up to 5 years). Reduction of the risk of major vascular complications in the group of patients taking clopidogrel in combination with ASA, was mainly due to a large decrease in the incidence of strokes.

    The risk of stroke of any severity with the use of clopidogrel in combination with ASA decreased, and there was a tendency to decrease the incidence of myocardial infarction in the group of patients taking clopidogrel in combination with ASA, but there was no difference in the frequency of thromboembolism outside the central nervous system or death from vascular causes.In addition, the use of clopidogrel in combination with ASA reduced the total number of days of hospitalization for cardiovascular disease.

    Pharmacokinetics:

    Suction

    Clopidogrel

    With a single and course administration in a dose of 75 mg per day clopidogrel quickly absorbed in the intestine.

    The mean maximum concentration of unchanged clopidogrel in the blood plasma (approximately 2.2-2.5 ng / ml after ingestion of a single dose of 75 mg) is reached approximately 45 minutes after its single administration. According to excretion of metabolites of clopidogrel with kidneys, its absorption is approximately 50%.

    ASA

    After absorption, ASA undergoes hydrolysis with the formation of salicylic acid, the maximum concentration of which in the blood plasma is reached 1 hour after the administration of ASA. Thanks to rapid hydrolysis through 1,5-3 hours after ingestion Acetylsalicylic acid + Clopidogrel ASA in blood plasma is practically not determined.

    Distribution

    Clopidogrel

    In vitro Clopidogrel and its main circulating non-active metabolite in the blood reversibly bind to blood plasma proteins (by 98% and 94%, respectively) and this bond in vitro is unsaturated up to a concentration of 100 mg / l.

    ASA

    ASA weakly binds to proteins in the blood plasma and has a small volume of distribution (10 liters). Her metabolite - salicylic acid - binds well to blood plasma proteins, but its relationship to blood plasma proteins depends on its concentration in the blood plasma (nonlinear connection). At low (<100 μg / ml), about 90% of salicylic acid binds to plasma albumin. Salicylic acid is well distributed in tissues and body fluids, including the central nervous system, breast milk and fetal tissues.

    Metabolism

    Clopidogrel

    Clopidogrel is extensively metabolized in the liver. In vitro and in vivo Clopidogrel is metabolized along two metabolic pathways: the first way: metabolism is carried out with the help of enzymes (esterases), which leads to hydrolysis with the formation of an inactive metabolite, a carboxylic acid derivative (85% of circulating metabolites in the systemic bloodstream), the second way: metabolism with several isoenzymes of the cytochrome P450 system. At the same time, in the beginning clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite.Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of an active metabolite of clopidogrel-thiol clopidogrel derivative. In vitro this pathway of metabolism occurs by means of isoenzymes CYP2C19, CYP1A2, CYP3A4 and CYP2B6. The active thiol metabolite of clopidogrel, which was isolated in studies in vitro, quickly and irreversibly binds to platelet receptors, inhibiting the aggregation of platelets.

    After taking a loading dose of clopidogrel, 300 mg the maximum concentration (CmOh) of the active metabolite is 2 times greater than that after taking a maintenance dose of clopidogrel 75 mg for 4 days, while its CmOh is reached approximately in 30 - 60 minutes after reception clopidogrel.

    ASA

    ASA when taken in combination with clopidogrel quickly undergoes hydrolysis in blood plasma to salicylic acid with a half-life period of 0.3 to 0.4 hours for doses of ASA 75-100 mg. Salicylic acid, is mainly subjected to conjugation in the liver with the formation of salicyluric acid, phenolic glucuronide and acyl glucuronide, as well as a large number of secondary metabolites.

    Excretion

    Clopidogrel

    Within 120 hours after ingestion by a human 14C-labeled clopidogrel at about 50% of the radioactivity is excreted by the kidneys and approximately 46% of radioactivity - through the intestine. After a single oral dose of 75 mg half-life of clopidogrel is approximately 6 hours. After a single and course administration of clopidogrel, the half-life of the inactive metabolite circulating in the blood is 8 hours.

    ASA

    When taking the drug Acetylsalicylic acid + Clopidogrelsalicylic acid has a half-life of approximately 2 hours from the blood plasma. The metabolism of salicylate is saturable and the overall clearance decreases at higher serum concentrations due to the limited ability of the liver to form salicyluric acid and phenolic glucuronide. After taking toxic doses of ASA (10-20 d), the plasma half-life can be increased to 20 hours. At high doses of ASA, the elimination of salicylic acid corresponds to kinetics of zero order (ie, the elimination rate depends on the concentration in the blood plasma) with a half-life of 6 hours or more.

    Renal excretion of unchanged active substance depends on the pH of the urine.With a pH increase of more than 6.5, the renal clearance of free salicylate increases from <5% to> 80%. After taking therapeutic doses in urine, approximately 10% of the dose in the form of salicylic acid is detected, 75% of the dose taken in the form of salicylicuric acid, 10% of the dose taken is in the form of phenolic glucuronides and 5% of the accepted dose in the form of acyl glucuronides.

    Pharmacogenetics

    Using isoenzyme CYP2C19 formed as an active metabolite, and an intermediate metabolite - 2-oxo-clopidogrel. Pharmacokinetics and antiplatelet effect of the active metabolite clopidogrel in the study of platelet aggregation ex vivo (in vitro study of platelet aggregation in the blood taken from the patient taking clopidogrel inside, that is, after the metabolism of clopidogrel in the body) vary depending on the genotype of the isoenzyme CYP2C19. Allele of the isoenzyme gene CYP2C19*1 corresponds to fully functional metabolism, whereas alleles of isoenzyme genes CYP2C19*2 and CYP2C19*3 are non-functional. Alleles of isoenzyme genes CYP2C19*2 and CYP2C19*3 are the cause of a decrease in metabolism in the majority of representatives of the Caucasoid (85%) and Mongoloid races (99%).Other alleles that are associated with a lack or decrease in metabolism are less common and include but are not limited to alleles of isoenzyme genes CYP2C19*4, * 5, * 6, * 7 and * 8. A patient with a low isoenzyme activity CYP2C19 will have the two alleles of the above gene with loss of function. Published frequencies of occurrence in general populations of people with a phenotype with a low isoenzyme activity CYP2C19 are: for Caucasians 2%, for Negroids 4% and for Chinese 14%. To determine the patient's isoenzyme genotype CYP2C19 there are corresponding tests.

    According to a cross-sectional study (40 healthy volunteers) and according to a meta-analysis of six studies (335 volunteers taking clopidogrel), which included healthy volunteers with very high, high, intermediate and low isoenzyme activity CYP2C19, no significant differences in the exposure of the active metabolite, and in the mean values ​​of platelet aggregation inhibition (IDA) (induced by ADP) in healthy volunteers with very high, high and intermediate isoenzyme activity CYP2C19 it was not revealed. In healthy volunteers with low isoenzyme activity CYP2C19 Exposure of the active metabolite decreased compared to healthy volunteers with high isoenzyme activity CYP2C19.

    When volunteers with low isoenzyme activity CYP2C19 have taken clopidogrel according to the scheme: 600 mg loading dose / 150 mg maintenance dose (600 mg / 150 mg), the exposure of the active metabolite was higher than when taking clopidogrel under the scheme: 300 mg / 75 mg. In addition, the IAT was similar to that in groups of patients with a higher metabolic rate by isoenzyme CYP2C19, who took clopidogrel according to the scheme: 300 mg / 75 mg. However, in studies with clinical outcomes, the dosing regimen of clopidogrel for patients in this group (patients with low isoenzyme activity CYP2C19) not yet installed. This is due to the fact that the clinical trials conducted to date have not had a sufficient sample size to detect differences in the clinical outcome in patients with low isoenzyme activity CYP2C19.

    Individual patient groups

    The pharmacokinetics of the active metabolite of clopidogrel in certain groups of patients has not been studied.

    Elderly people

    In elderly volunteers(over 75 years), when compared with young volunteers, there was no difference in platelet aggregation and bleeding time. Do not require dose adjustment for the elderly.

    Children and teens

    No data available.

    Patients with impaired renal function

    After repeated receptions of clopidogrel 75 mg / day in patients with severe renal impairment (creatinine clearance of 5 to 15 ml / min) inhibition of ADP-induced platelet aggregation was lower (25%) compared with those in healthy volunteers but the elongation bleeding time was similar to that of healthy volunteers taking clopidogrel in a dose of 75 mg per day.

    Patients with impaired hepatic function

    Following daily for 10 days Hour clopidogrel in a daily dose of 75 mg patients with severe hepatic impairment (more than 9 points on the Child-Pugh) inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean bleeding time was also comparable in both groups.

    Ethnicity

    Prevalence of alleles of isoenzyme genes CYP2C19, responsible for intermediate and reduced metabolism, is different in representatives of different ethnic groups. There is limited literature on their prevalence among members of the Mongoloid race for assessment of the clinical significance of the effect of genotypes of the isoenzyme CYP2C19 on clinical outcomes.

    Based on the pharmacokinetics and metabolic peculiarities of both active substances of the preparation Acetylsalicylic acid + Clopidogrel between them is not expected clinically significant pharmacokinetic interactions.

    Indications:

    This combined preparation is indicated for use in patients who are already receiving concomitantly clopidogrel and acetylsalicylic acid (see section "Method of administration and dose").

    Prevention of atherothrombotic complications

    - In adults with acute coronary syndrome:

    - without segment elevation ST (unstable angina or myocardial infarction without a tooth Q), including patients who underwent stenting with percutaneous coronary intervention;

    - with segment lift ST (acute myocardial infarction) with drug treatment and the possibility of carrying out thrombolysis.

    Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation (atrial fibrillation)

    - In adults with atrial fibrillation (atrial fibrillation), which have at least one risk factor for vascular complications, they can not take indirect anticoagulants and have a low risk of bleeding.

    Contraindications:

    - Hypersensitivity to any of the active or auxiliary substances of the drug.

    - Severe hepatic failure (more than 9 on the Child-Pugh scale).

    - Severe renal failure (creatinine clearance less than 30 ml / min) - due to the content of the drug ASA).

    - Acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage.

    - Bronchial asthma induced by the intake of salicylates and other non-steroidal anti-inflammatory drugs (NSAIDs); syndrome of bronchial asthma, rhinitis and recurrent polyposis of the nose and paranasal sinuses, hypersensitivity to NSAIDs (due to the content of the ASA preparation).

    - Mastocytosis, in which the use of ASA can cause severe hypersensitivity reactions,including the development of shock with flushing of the skin, a decrease in blood pressure, tachycardia and vomiting (due to the content of the drug ASA).

    - Pregnancy and the period of breastfeeding (see section "Application during pregnancy and during breast-feeding").

    - Children under 18 years of age (safety and efficacy not established).

    Carefully:

    - With moderate hepatic impairment (7-9 points on the Child-Pugh scale), in which a predisposition to bleeding is possible (limited clinical experience of use).

    - With renal insufficiency of mild and moderate severity (creatinine clearance 60 - 30 ml / min) (limited clinical experience of use).

    - For injuries, surgical interventions, including invasive cardiac procedures or surgical interventions (see section "Special instructions").

    - In diseases in which there is a predisposition to the development of bleeding, especially intraocular or gastrointestinal (with gastric ulcer and duodenal ulcer or gastrointestinal hemorrhage in anamnesis, with symptoms of violations from the upper divisionsgastrointestinal tract).

    - With a recent transient impairment of cerebral circulation or ischemic stroke (see section "Special instructions").

    - At simultaneous application of NSAIDs, including selective inhibitors of cyclooxygenase 2 (COX-2) (see the section "Interaction with other drugs").

    - With the simultaneous use of warfarin, heparin, glycoprotein inhibitors IIb/IIIa, selective serotonin reuptake inhibitors (SSRIs) and thrombolytic agents (see "Interaction with other drugs" and "Special instructions").

    - At a bronchial asthma and an allergy in the anamnesis (the raised or increased risk of development of allergic reactions on ASK).

    - With gout, hyperuricemia (ASA, including, in low doses, increases the concentration of uric acid in the blood).

    - In patients with a genetically determined decrease in isoenzyme activity CYP2C19 (see section "Pharmacokinetics", subsection "Pharmacogenetics", sections "Method of administration and dose", "Special instructions").

    - In patients with a deficiency of glucose-6-phosphate dehydrogenase (due to the risk of hemolysis) (see the sections "Side effect", "Special instructions").

    - With simultaneous use of methotrexate in a dose of more than 20 mg per week (see the section "Interaction with other drugs").

    At the instructions in the anamnesis on allergic and hematological reactions to other thienopyridine (such as ticlopidine, prasugrel) (the possibility of cross-allergic and hematological reactions, see the section "Special instructions").

    Pregnancy and lactation:

    Pregnancy

    As a precautionary measure, the drug Acetylsalicylic acid + Clopidogrel should not be taken during the first two trimesters of pregnancy, except when the woman's clinical condition requires treatment with clopidogrel in combination with ASA. Due to the presence of ASA in the drug, it is contraindicated in the third trimester of pregnancy.

    Studies in animals showed no direct or indirect adverse effects in pregnancy, fetal development, childbirth, and postnatal development in clopidogrel. However, sufficient in volume and controlled studies in pregnant women were not conducted. At ASA, the presence of teratogenic effect was established, although it was established in clinical studies,that doses of ASA to 100 mg / day, limitedly used in obstetrics and requiring specialized monitoring, proved to be safe.

    Breastfeeding period

    Breastfeeding in case of drug treatment Acetylsalicylic acid + Clopidogrel should be discontinued, since it has been established that ASA is excreted in breast milk, and studies in rats have shown that clopidogrel and / or its metabolites are also excreted into the milk of lactating rats. Is it allocated or not? clopidogrel in the human breast milk is unknown.

    Dosing and Administration:

    Mode of application

    A drug Acetylsalicylic acid + Clopidogrel should be taken 1 time a day, regardless of food intake.

    Doses

    Adults and elderly patients with normal activity isoenzyme CYP2C19

    Acute coronary syndrome (ACS)

    Treatment begins as soon as possible after the onset of symptoms. Reception of the drug Acetylsalicylic acid + Clopidogrel begin after receiving a single loading dose of clopidogrel in combination with ASA as separate drugs, namely clopidogrel in a dose of 300 mg and ASA in doses of 75 - 325 mg per day, and with acute myocardial infarction with segment elevation ST - in combination with thrombolytics or without them.Since the use of higher doses of ASA is associated with an increased risk of bleeding, the recommended dosage for ASA should not exceed 100 mg. With acute myocardial infarction with segment elevation ST the patients older than 75 years of treatment with clopidogrel should begin without taking its loading dose.

    In patients with ACS without segment elevation ST (unstable angina or myocardial infarction without a tooth Q) the maximum favorable effect is observed by the 3rd month of treatment. The optimal duration of treatment is not officially defined. Clinical trials support the use of the drug for up to 12 months.

    In patients with acute myocardial infarction with segment elevation ST Treatment should be continued for at least 4 weeks.

    Atrial fibrillation

    A drug Acetylsalicylic acid + Clopidogrel should be taken once a day, after the start of treatment with clopidogrel 75 mg and ASA 100 mg in the form of individual drugs.

    Patients with genetically determined reduced isoenzyme activity CYP2C19

    Low isoenzyme activity CYP2C19 is associated with a decrease in the antiplatelet effect of clopidogrel.The mode of application of higher doses of clopidogrel (600 mg - loading dose, then 150 mg once a day daily) in patients with low isoenzyme activity CYP2C19 increases antiplatelet effect of clopidogrel (see section "Pharmacokinetics"). However, at the moment, clinical trials that take into account clinical outcomes have not established an optimal dosing regimen for clopidogrel for patients with reduced metabolism due to genetically determined low isoenzyme activity CYP2C19.

    Special patient groups

    Children

    Safety and effectiveness in children have not been established to date.

    Elderly patients

    In elderly patients, correction of the dosing regimen is not required.

    Patients with hepatic insufficiency

    The therapeutic experience of using the drug is limited to use in patients with mild liver disease, which may have a tendency to develop hemorrhagic diathesis. Therefore, when the drug is used Acetylsalicylic acid + Clopidogrel caution should be exercised in such patients.

    Patients with renal insufficiency

    There is limited therapeutic experience with the drug in patients with mild to moderate renal failure. Therefore, when the drug is used Acetylsalicylic acid + Clopidogrel caution should be exercised in such patients.

    Side effects:

    The incidence of adverse events was determined according to the WHO classification: very often ≥ 10%; often ≥ 1% and <10%; infrequently ≥0,1 % and <1%; rarely ≥ 0.01% and <0.1%; very rarely <0.01%; the frequency is unknown - it is not possible to determine the incidence of undesirable effects (NE) from the available data.

    Legend:

    1NE, which were observed when using a combination of clopidogrel and ASA;

    2NE, which were observed with the use of clopidogrel;

    3HE, which were observed with the use of ASA.

    Hemorrhagic adverse events (purpura / bruising, nasal bleeding, hematuria, hemorrhages in skin tissues, bone and muscle, hematomas, hemorrhages in the joint cavity [hemarthrosis], conjunctiva, internal environments and the retina of the eye, bleeding from the respiratory tract, hemoptysis bleeding from the operating wound, intracranial hemorrhage (hemorrhagic strokes), bleeding from the gastrointestinal tract,retroperitoneal hemorrhage, etc.)

    Bleeding and hemorrhages were the most frequently observed adverse events in clinical trials and in the post-marketing use of the drug, mainly during the first month of treatment.

    - Often: large bleeding1 [Life-threatening bleeding, requiring transfusion of 4 or more units of blood; other large bleeding, requiring transfusion of 2-3 units of blood; not life-threatening large bleeding]; minor bleeding1, bleeding at the site of vascular puncture1,2; bruising2; hematoma2.

    The frequency of major bleeding when applying the combination clopidogrel + ASA depended on the dose of ASA (<100 mg - 2.6%, 100 - 200 mg - 3.5%,> 200 mg - 4.9%), as well as their frequency with one ASA (<100 mg - 2.0%, 100 - 200 mg - 2.3%,> 200 mg - 4.0%).

    In patients who discontinued treatment more than 5 days before aortocoronary shunting, there was no increase in cases of large bleeding within 7 days after this intervention (4.4% - with clopidogrel + ASA versus 5.3% - with one ASA). In patients who remained on antiplatelet therapy for the last five days before aortocoronary bypass surgery,the incidence of these bleeding after intervention was 9.6% (clopidogrel + ASA) and 6.3% (one ASA).

    - Infrequently: bleeding with lethal outcome1; life-threatening hemorrhage [bleeding with a decrease in hemoglobin of more than 5 g / dL1; bleeding requiring surgery1; intracranial hemorrhage (hemorrhagic stroke)1; bleeding, requiring the introduction of inotropic drugs]1; severe bleeding (most often purpura, nasal bleeding, less common hematuria and intraocular hemorrhages, mainly conjunctival2).

    - Rarely: intraocular hemorrhages with significant visual impairment1, retroperitoneal hemorrhage1.

    - Frequency is unknown (post-marketing experience): serious cases of bleeding2, mainly, hemorrhage in the skin tissue2, in the bones, muscles and joint cavity (hemarthrosis)2, in the eye tissues (conjunctival, in the internal environment and the retina of the eye)2, bleeding from the respiratory tract2, hemoptysis2, nosebleeds2, hematuria2, bleeding from an operating wound2, intracranial hemorrhage3, including fatal cases3, especially in elderly patients; other cases of bleeding with a fatal outcome (in particular, bleeding from the gastrointestinal tract and retroperitoneal hemorrhage)2.

    Violations of the blood and lymphatic system

    - Infrequently: decrease in the number of platelets in peripheral blood1, severe thrombocytopenia with a platelet count in the peripheral blood ≤ 80x109/ l, but > 30x109/ l1; leukopenia1; decrease in the number of neutrophils in peripheral blood1, eosinophilia1, prolongation of bleeding time1.

    - Rarely: neutropenia1, including severe neutropenia (< 0,45x109/ l)1. Although the risk of myelotoxic effects when using clopidogrel is low enough, its potential should be considered when the patient receiving clopidogrel, develops fever and other infectious manifestations.

    - Rarely: aplastic anemia1, severe thrombocytopenia with the number of platelets in the peripheral blood ≤ 30x109 / l1.

    - Frequency is unknown (post-marketing experience): thrombocytopenia3, hemolytic anemia in patients with insufficiency of glucose-6-phosphate dehydrogenase3, agranulocytosis2,3; aplastic anemia2,3/ pancytopenia2,3, bitsitopenia3, disorders of bone marrow hematopoiesis3, neutropenia3, leukopenia3, granulocytopenia3, anemia1, acquired hemophilia A2, thrombotic thrombocytopenic purpura (TTP)2.

    Disorders from the central and peripheral nervous system

    - Infrequently: headache1, dizziness1 and paresthesia1.

    - Rarely: vertigo1.

    - Frequency is unknown (post-marketing experience): changes in taste2.

    Disorders from the digestive system

    - Often: gastrointestinal bleeding1, dyspepsia1, abdominal pain1, diarrhea1.

    - Infrequently: nausea1, gastritis1, flatulence1, constipation1, vomiting1, a stomach ulcer1 and duodenal ulcer1.

    - Frequency unknown (post-marketing experience): colitis2,3, (including ulcerative or lymphocytic colitis)2, pancreatitis2, stomatitis2, esophagitis3, ulceration / perforation of the esophagus3, erosive gastritis3, erosive duodenitis3, an ulcer or peptic ulcer perforation of the stomach and / or duodenum3, symptoms of the upper gastrointestinal tract, such as gastralgia3 (see section "Special instructions"), ulcers of the small intestine (lean and ileum)3 and large intestine (colon and rectum)3, intestinal perforation3 (these reactions may or may not be accompanied by bleeding and can occur with any dose of ASA, as well as in patients who have warning signs and anamnesis of serious gastrointestinal complications and those who do not); acute pancreatitis, which is a manifestation of the hypersensitivity reaction to acetylsalicylic acid3.

    Disturbances from the liver and bile ducts

    - Frequency unknown (post-marketing experience): hepatitis (non-infectious nature)2, acute hepatic impairment2, increased activity of "hepatic" enzymes3, deviations from the norm of indicators of the functional state of the liver2, liver damage, mainly hepatocellular3, chronic hepatitis3.

    Disturbances from the skin and subcutaneous tissues

    - Infrequently: skin rash1, itchy skin1.

    - Frequency unknown (post-marketing experience): maculopapular, erythematous or exfoliative skin rash2, urticaria2, itching2, angioedema2, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis)2, acute generalized exanthematous pustulosis2, drug hypersensitivity syndrome, drug Rash with eosinophilia and systemic manifestations (DRESS-syndrome)2, eczema2, flat lichen2, a fixed skin rash (single or multiple skin changes, usually in the form of erythematous plaques of round or oval shape, appearing in the same place with the next intake of the drug)3.

    Immune system disorders

    - Frequency unknown (post-marketing experience):

    anaphylactoid reactions2, serum sickness2, cross-reactive hypersensitivity reactions with other thienopyridines (such as ticlopidine, prasugrel)2 (see section "Special instructions"), anaphylactic shock3, increased symptoms of food allergy3.

    Disorders of the psyche

    - Frequency unknown (post-marketing experience):

    confusion2, hallucinations2.

    Vascular disorders

    - Frequency unknown (post-marketing experience): vasculitis2,3, including the purple Shenlaine-Genocha3, lowering blood pressure2.

    Heart Disease

    - Frequency unknown (post-marketing experience): Kunis syndrome (allergic coronary syndrome) due to the hypersensitivity reaction to acetylsalicylic acid3.

    Disturbances from the respiratory system, chest organs and the mediastinum

    - Frequency is unknown (post-marketing experience):

    Bronchospasm2, interstitial pneumonitis2, eosinophilic pneumonia2, non-cardiogenic pulmonary edema in chronic drug administration associated with a hypersensitivity reaction3.

    Disturbances from musculoskeletal and connective tissue

    - Frequency is unknown (post-marketing experience): arthralgia2, arthritis2, myalgia2.

    Disorders from the kidneys and urinary tract

    - Frequency is unknown (post-marketing experience):

    Glomerulopathy, including glomerulonephritis2, kidney failure3, acute renal dysfunction (especially in patients with pre-existing renal failure, decompensation of chronic heart failure, nephritic syndrome, or patients simultaneously taking diuretics)3, kidney failure3.

    Violations of the genitals and mammary gland

    - Frequency unknown (post-marketing experience):

    gynecomastia2.

    General disorders

    - Frequency unknown (post-marketing experience):

    fever2.

    Laboratory and instrumental data

    - Frequency unknown (post-marketing experience):

    deviation from the norm of biochemical indicators of the functional state of the liver2, an increase in the concentration of creatinine in the blood2.

    Disorders from the metabolism and nutrition

    - Frequency unknown (post-marketing experience):

    hypoglycemia3, gout3.

    Hearing disorders and labyrinthine disorders

    - Frequency unknown (post-marketing experience): hearing loss3, noise in ears3.

    Overdose:

    Symptoms and treatment of clopidogrel overdose

    An overdose of clopidogrel may lead to an increase in bleeding time with subsequent complications in the form of bleeding. When bleeding occurs, appropriate treatment is required. The antidote of clopidogrel is not established. If you need fast correction of prolonged bleeding time, then a transfusion of platelet mass is recommended.

    Symptoms and treatment of ASA overdose

    Moderate overdose: dizziness, ringing in the ears, headaches, confusion and symptoms from the gastrointestinal tract (nausea,vomiting and pain in the stomach).

    When there are signs of severe intoxication, severe acid-base disturbances occur. Initially, the resulting hyperventilation leads to the development of respiratory alkalosis. Then, respiratory acidosis develops, as a consequence of the inhibitory effect of respiratory alkalosis on the respiratory center. Also, due to the presence of salicylates, metabolic acidosis develops in the blood. In addition, the following symptoms appear: hyperthermia and abundant sweating, leading to dehydration, motor anxiety, convulsions, hallucinations and the development of hypoglycemia. Oppression of the nervous system can lead to the development of coma, collapse and stopping breathing. The lethal dose of acetylsalicylic acid is 25 - 30 g. The plasma concentration of salicylate exceeds 300 mg / l (1.67 mmol / l) confirms the presence of intoxication. Overdose of salicylates, especially in young children, can lead to severe hypoglycemia and potentially fatal poisoning.

    In acute and chronic overdose of ASA, noncardiogenic pulmonary edema may develop (see section "Side effect").

    When identifying the symptoms of severe overdose, hospitalization is required. With moderate intoxication, you can try to induce vomiting artificially, in case of failure, gastric lavage is indicated. After this, take in (if the patient can swallow) or, otherwise, enter the stomach through a probe Activated carbon (adsorbent) and salt laxative. For the purpose of forced alkalinization of urine, an intravenous dropping of 250 mmol of sodium bicarbonate is shown for 3 hours under the control of the pH of the urine and the acid-base state to accelerate the removal of salicylates.

    The preferred treatment for severe overdose is hemodialysis or peritoneal dialysis. If necessary, symptomatic treatment of other manifestations of intoxication is used.

    Interaction:

    Thrombolytics

    The safety of the combined use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic agents and heparin was analyzed in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the joint use of thrombolytic agents andheparin with ASA. In connection with the lack of clinical data on the joint use of the drug Acetylsalicylic acid + Clopidogrel and thrombolytic agents should be used with caution when using them together (see section "Special instructions").

    Inhibitors of glycoprotein IIb/IIIa

    Between inhibitors of glycoprotein IIb/IIIbut also with a drug Acetylsalicylic acid + Clopidogrel possibly pharmacodynamic interaction, which requires caution in their joint use in patients who have an increased risk of bleeding (with trauma and surgical interventions or other pathological conditions) (see section "Special instructions").

    Heparin

    According to a clinical study conducted with the participation of healthy volunteers, when taking clopidogrel did not require a change in the dose of heparin and did not change its anticoagulant effect. The simultaneous use of heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation. Between the drug Acetylsalicylic acid + Clopidogrel and heparin pharmacodynamic interaction is possible, which may increase the risk of bleeding, and therefore their joint use requires caution (see section "Special instructions").

    Indirect anticoagulants

    Simultaneous use of clopidogrel and oral anticoagulants may increase the intensity of bleeding, and therefore the use of this combination is not recommended. Clopidogrel at a dose of 75 mg does not affect the pharmacokinetics of warfarin and does not change the values ​​of the International Normalized Ratio (INR) in patients taking long-term warfarin. However, simultaneous administration of warfarin with clopidogrel may increase the risk of bleeding due to the independent effect of these drugs on hemostasis.

    NSAIDs

    In a clinical study conducted with the participation of healthy volunteers, the combined use of clopidogrel and naproxen increased latent blood loss through the gastrointestinal tract. Therefore, the use of NSAIDs, including cyclooxygenase-2 inhibitors (COX-2), in combination with the drug Acetylsalicylic acid + Clopidogrel not recommended (see section "Special instructions").

    Experimental evidence suggests that ibuprofen (with a single dose of 400 mg between 8 h and 30 min after the immediate administration of ASA in a dose of 81 mg in the form of immediate release) can inhibit the effect of low doses of ASA on platelet aggregation.However, with irregular intake of ibuprofen, no clinically significant effects of it on the antiaggregant effect of ASA are expected.

    Selective serotonin reuptake inhibitors (SSRIs)

    Since SSRIs disrupt platelet activation and increase the risk of bleeding, simultaneous use of SSRI with clopidogrel should be carried out with caution.

    Another combination therapy with clopidogrel

    Strong or moderate isoenzyme inhibitors CYP2C9

    As clopidogrel metabolized to its active metabolite in part by isoenzyme CYP2C19, it is expected that the use of drugs that inhibit the activity of this isoenzyme may lead to a decrease in the concentration of the active metabolite of clopidogrel. The clinical significance of this interaction is unknown. As a precaution, simultaneous use of clopidogrel and strong or moderate isoenzyme inhibitors should be avoided CYP2C9. Strong and moderate isoenzyme inhibitors CYP2C9 are the omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol.

    The simultaneous use with clopidogrel of proton pump inhibitors, which are strong or moderate inhibitors of the isoenzyme CYP2C19 (eg, omeprazole, esomeprazole) is not recommended. If the patient still needs the use of proton pump inhibitors at the same time as taking the drug Acetylsalicylic acid + Clopidogrel, then a proton pump inhibitor should be used with little effect on isoenzyme activity CYP2C19, such as pantoprazole or lansoprazole.

    A number of clinical studies with clopidogrel and other concomitant medications have been conducted to study possible pharmacodynamic and pharmacokinetic interactions that have shown that:

    - when clopidogrel was used in conjunction with atenolol, nifedipine, or both, concomitantly, there was no clinically significant pharmacodynamic interaction;

    - simultaneous use of phenobarbital, cimetidine and estrogens had no significant effect on the pharmacodynamics of clopidogrel;

    - pharmacokinetic indices of digoxin and theophylline did not change when combined with clopidogrel;

    - antacid drugs did not reduce the absorption of clopidogrel;

    - phenytoin and tolbutamide can safely be used concurrently with clopidogrel (study CAPRIE), despite the fact that the data obtained from studies with human liver microsomes indicate that the carboxylic metabolite clopidogrel can inhibit the activity of the isoenzyme CYP2C9, which can lead to an increase in the plasma concentrations of certain drugs, for example, phenytoin, tolbutamide and certain NSAIDs that are metabolized by isoenzyme CYP2C9.

    Another combination therapy with ASA

    The interaction of ASA with the following drugs has been reported:

    - uricosuric drugs (medicines, contributing to the excretion of uric acid) (benzbromarone, probenecid, sulfinpyrazone): ASA can suppress their uricosuric effect due to competition with uric acid at the elimination level;

    - Methotrexate: methotrexate, taken in doses over 20 mg / week, should be used with caution when combined with the drug Acetylsalicylic acid + Clopidogrel (due to the presence of ASA in the formulation Acetylsalicylic acid + Clopidogrel), since ASA can reduce renal clearance of methotrexate, which in turn can increase its myelotoxic effect (see section "With caution");

    - metamizole: metamizole with simultaneous application with ASA can reduce the effect of ASA on platelet aggregation. Therefore, this combination should be used with caution in patients taking low doses of ASA for cardioprotective action;

    - acetazolamide: caution should be exercised when simultaneous application of salicylates and acetazolamide, because of the increased risk of developing metabolic acidosis;

    - inhibitors of angiotensin-converting enzyme (ACE), anticonvulsants (phenytoin and valproic acid), β-adrenoblockers, diuretics and oral hypoglycemic agents: possible interaction of these drugs with ASA, used in high (anti-inflammatory) doses;

    - ethanol: when used simultaneously with ASA, the risk of developing bleeding is increased with chronic use of large amounts of alcohol (ethanol) (see section "Special instructions").

    Other interactions with clopidogrel and ASA

    ACE inhibitors, diuretics, β-adrenoblockers, slow calcium channel blockers, lipid-lowering drugs, vasodilators, hypoglycemic drugs (including insulin), antiepileptic drugs, hormone replacement therapy and glycoprotein receptor blockers GPIIb/IIIa - Clinical studies on the use of clopidogrel in combination with ASA in maintenance doses ≤ 325 mg, conducted with the participation of more than 30,000 patients, showed no clinically significant adverse interactions.

    Special instructions:

    Bleeding and hematologic disorders

    In connection with the risk of bleeding and hematological adverse effects (see the section "Side effect"), if clinical symptoms appearing during treatment, suspicious for bleeding, it is urgent to do a clinical blood test, determine APTT (activated partial thromboplastin time), the amount platelets in the peripheral blood, indicators of the functional activity of platelets and conduct other necessary studies.

    In connection with the presence of the drug Acetylsalicylic acid + Clopidogrel two antiplatelet agents should be used with caution in patients at high risk of bleeding caused by trauma, surgery or other pathological conditions, as well as in patients on NSAID (including COX-2 inhibitors), heparin, a glycoprotein inhibitors IIb/IIIa, SSRIs and thrombolytic drugs. It is necessary to conduct a thorough monitoring of patients in order to exclude signs of bleeding, including the hidden, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgery. Simultaneous use of the drug Acetylsalicylic acid + Clopidogrel with indirect anticoagulants it is not recommended since it may increase the intensity of bleeding (see. section "Interaction with other medicinal products").

    If the patient is under planned surgical intervention, and there is no need for permanent anti-aggregative therapy, then 5 to 7 days before surgery clopidogrel should be canceled. A drug Acetylsalicylic acid + Clopidogrel increases bleeding time and should be used with caution in patients with diseases and conditions predisposing to the development of bleeding (especially bleeding from the gastrointestinal tract and intraocular hemorrhages).

    Patients should be warned that when taking the drug Acetylsalicylic acid + Clopidogrel to stop bleeding, they may need more time than usual, and that if they have any unusual (localized or prolonged) bleeding, they should inform their doctor about it.

    Before any future surgical intervention and before proceeding to receive any new drug, patients should inform the doctor (including the dentist) about the drug treatment Acetylsalicylic acid + Clopidogrel.

    Recently suffered ischemic stroke

    It was shown that in patients with recent ischemic transient cerebral infarction or stroke having an increased risk of developing ischemic complications,the combination of ASA and clopidogrel increases the possibility of developing large bleeding. Therefore, the drug Acetylsalicylic acid + Clopidogrel These patients should be administered with caution and only in the case of proven clinical benefit from its use.

    Thrombotic thrombocytopenic purpura

    Very rarely, after the use of clopidogrel (sometimes even a short one), cases of thrombotic development thrombocytopenic purpura (TTP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever. TTP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

    Acquired hemophilia

    The cases of development of acquired hemophilia with the use of clopidogrel were reported. With a confirmed isolated increase in activated partial thromboplastin time, accompanied or not accompanied by the development of bleeding, should consider the possibility of developing acquired hemophilia.Patients with a confirmed diagnosis of acquired hemophilia should be observed and to be treated by specialists in this field. disease and stop taking clopidogrel.

    Cross-allergic and / or hematologic reactions between thienopyridines

    Patients should collect anamnesis for any previously allergic and / or hematologic reactions to other thienopyridine (such as ticlopidine, prasugrel), since it has been reported that there are cross-allergic and / or hematological reactions between thienopyridines (see "Side effect" section).

    Thienopyridines can cause mild to severe allergic reactions (such as skin rash, angioedema) or hematologic reactions (such as thrombocytopenia and neutropenia). Patients who have previously experienced allergic and / or hematologic reactions to one of the drugs of the thienopyridine group may have an increased risk of developing similar reactions to another drug of the thienopyridine group. It is recommended to monitor cross-allergic and / or hematological reactions.

    Functional activity of the isoenzyme CYP2C19

    In patients with low metabolic activity of the isoenzyme CYP2C19 when clopidogrel is used in recommended doses, less active metabolite of clopidogrel is formed and its effect on platelet function is reduced. Therefore, such patients with acute coronary syndrome or patients undergoing percutaneous coronary intervention and taking clopidogrel, may have a greater incidence of cardiovascular events than patients with normal isoenzyme activity CYP2C19.

    There are tests to determine the genotype CYP2C19, these tests can be used to help choose a therapeutic strategy.

    The use of higher doses of clopidogrel in patients with low isozyme activity CYP2C19 (see the section "Pharmacokinetics", subsection "Pharmacogenetics", sections "With caution", "Method of administration and dose"), but the efficacy and safety of the use of increased doses of clopidogrel in patients with low isoenzyme activity CYP2C19 have not been established to date.

    Effect on the gastrointestinal tract

    A drug Acetylsalicylic acid + Clopidogrel should be used with caution in patients with gastric ulcer and duodenal ulcer orgastrointestinal hemorrhages in the anamnesis or in patients with even minor symptoms from the upper gastrointestinal tract, which may be manifestations of ulcerative lesions of the stomach, which can lead to gastric bleeding.

    When treating the drug Acetylsalicylic acid + Clopidogrel at any time, there may be symptoms from the upper part of the digestive tract, such as gastralgia, heartburn, nausea, vomiting and gastrointestinal bleeding. Despite the fact that when treating the drug Acetylsalicylic acid + Clopidogrel minor side effects from the gastrointestinal tract, such as dyspeptic disorders, are often found, the treating doctor always in these cases should exclude ulceration of the gastrointestinal mucosa and bleeding, even if there is no history of gastrointestinal pathology.

    Patients should be informed of the symptoms of unwanted reactions from the digestive tract.

    Other

    Perhaps the relationship between ASA and the emergence of life-threatening Ray syndrome (encephalopathy and acute fatty liver disease with rapid development of liver failure),usually observed in the prodromal period of infections in children.

    In connection with the presence of the drug ASA drug Acetylsalicylic acid + Clopidogrel should be prescribed to patients with deficiency of glucose-6-phosphate dehydrogenase under careful medical supervision (due to the risk of hemolysis) (see sections "With caution", "Side effect").

    In connection with the presence of ASA during the drug Acetylsalicylic acid + Clopidogrel patients should be warned about an increased risk of bleeding when chronic use of large amounts of alcohol (ethanol).

    Effect on the ability to drive transp. cf. and fur:

    Usually Acetylsalicylic acid + Clopidogrel does not significantly affect the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. However, if the patient experiences adverse side reactions from the nervous system and the psyche (see the "Side effect" section), it is possible to reduce the concentration of attention and the speed of psychomotor reactions, which may hinder the employment of such activities.In such cases, the question of the possibility of engaging in potentially hazardous activities should be decided by the attending physician.

    Form release / dosage:

    Tablets, film-coated, 100 mg + 75 mg.

    Packaging:

    For 10 or 14 tablets in a planar cell package.

    For 30 tablets in a polymer can with a lid or in a polymer bottle with a lid.

    By 3, 6, 9 contour cell packs of 10 tablets, 1, 2, 4, 6 contour packs of 14 tablets, a can or bottle together with instructions for use in a cardboard bundle.

    Storage conditions:

    In a dry, the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after the expiry date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-004093
    Date of registration:23.01.2017
    Expiration Date:23.01.2022
    The owner of the registration certificate:NORTH STAR, CJSC NORTH STAR, CJSC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp06.02.2017
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