Plagril, pills 75 mg 30 pcs.

Composition

Each film-coated tablet contains:Active ingredient:clopidogrel hydrosulfate (form-I) 97.875 mg, equivalent to 75 mg of clopidogrel. Auxiliary substances:Microcrystalline cellulose (Avicel PH 112) 211.125 mg, mannitol 58.0 mg, croscarmellose sodium 12.0 mg, colloidal silicon dioxide 2.0 mg, magnesium stearate 4.0 mg; film coated:opadray pink 03 V 54202 (hypromellose 62.50%, titanium dioxide 30.60%, macrogol 400 6.25%, iron oxide dye red 0.65%) 13.475 mg

. Pharmacological action

Pharmacodynamicaclopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y12 platelet receptor and subsequent ADP-mediated activation of the GPIIb/IIIa complex, leading to suppression of platelet aggregation. Due to irreversible binding, platelets remain immune to ADP stimulation for the rest of their life (approximately 7-10 days), and the restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal. Platelet aggregation caused by agonists other than ADP is also inhibited by blocking enhanced platelet activation by released ADP. Since the formation of the active metabolite occurs with the help of isoenzymes of the P 450 system, some of which may differ in polymorphism or may be inhibited by other drugs, not all patients can adequately inhibit platelet aggregation. When taking clopidogrel daily at a dose of 75 mg from the first day of administration, there is a significant suppression of ADP-induced platelet aggregation, which gradually increases over 3-7 days and then reaches a constant level (when an equilibrium state is reached). At steady state, platelet aggregation is suppressed by an average of 40-60%. After discontinuation of clopidogrel, platelet aggregation and bleeding time gradually return to baseline, on average, within 5 days. Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular damage, in particular, in lesions of the cerebral, coronary or peripheral arteries. The ACTIVE-A clinical trial 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 acetylsalicylic acid (compared to taking acetylsalicylic acid alone) reduced the combined incidence of stroke, myocardial infarction, systemic thromboembolism outside the central nervous system (CNS), or vascular death, to a greater extent by reducing the risk of risk of stroke. The effectiveness of taking clopidogrel in combination with acetylsalicylic acid was detected early and persisted for up to 5 years. The reduction in the risk of major vascular complications in the group of patients taking clopidogrel in combination with acetylsalicylic acid was mainly due to a greater reduction in the frequency of strokes. The risk of stroke of any severity was reduced when taking clopidogrel in combination with acetylsalicylic acid, and there was a tendency to reduce the incidence of myocardial infarction in the group treated with clopidogrel in combination with acetylsalicylic acid, but there were no differences in the frequency of non-CNS thromboembolism or vascular death. In addition, taking clopidogrel in combination with acetylsalicylic acid reduced the total number of days of hospitalization for cardiovascular reasons. Pharmacokinetics of absorption clopidogrel is rapidly absorbed with a single and repeated oral dose of 75 mg per day. Average values of the maximum concentration (Cmax) of unchanged clopidogrel in blood plasma (approximately 2.2-2.5 ng/ml after oral administration of a single dose of 75 mg) are reached approximately 45 minutes after taking the drug. According to the urinary excretion of clopidogrel metabolites, its absorption is approximately 50%. In vitro distribution clopidogrel and its main circulating inactive metabolite reversibly bind to plasma proteins (by 98% and 94%, respectively), and this bond is unsaturated to a concentration of 100 mg/ml. Metabolism Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, clopidogrel is metabolized in two ways: the first pathway, carried out by esterases, leads to hydrolysis of clopidogrel to form an inactive carboxylic acid derivative(85% of the circulating metabolites), and the second pathway is carried out by cytochrome P 450 isoenzymes. Initially, clopidogrel is metabolized to 2-oxo-clopidogrel, an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of the active metabolite of clopidogrel, the thiol derivative of clopidogrel. In vitro, this active metabolite is formed mainly by the isoenzyme CYP2C19, but it also involves several other isoenzymes, including CYP1A2, CYP2B6, and CYP3A4. The active thiol metabolite of clopidogrel, which has been isolated in vitro studies, binds rapidly and irreversibly to platelet receptors, thus blocking their aggregation. The maximum concentration (Cmax) of the active metabolite of clopidogrel, after a single dose of 300 mg, is 2 times higher than that after 4 days of taking a maintenance dose of clopidogrel 75 mg. Cmax is reached within approximately 30-60 minutes. Excretion Within 120 hours of human ingestion of 14C-labeled clopidogrel, approximately 50% of the radioactivity is excreted through the kidneys in the urine and approximately 46% of the radioactivity is excreted through the intestines with feces. After a single oral dose of 75 mg, the half – life (T1/2) of clopidogrel is approximately 6 hours. After a single dose and repeated doses of clopidogrel, the T1/2 of its main inactive metabolite circulating in the blood is 8 hours. PharmacogeneticS With the help of the CYP2C19 isoenzyme, both the active metabolite and the intermediate metabolite,2-oxo-clopidogrel, are formed. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel in the study of platelet aggregation ex vivo vary depending on the genotype of the CYP2C19 isoenzyme. The allele of the CYP2C19*1 gene corresponds to a fully functional metabolism, whereas the alleles of the CYP2C19 genes correspond to a fully functional metabolism. *2 and CYP2C19*3 are non-functional. Alleles of the CYP2C19 genes*2 and CYP2C19 * 3 are the cause of decreased metabolism in most representatives of the Caucasian (85%) and Mongoloid race (99%). Other alleles associated with an absence or decrease in metabolism are less common and include, but are not limited to, alleles of the CYP2C19 genes*4, *5, *6, *7 and *8. Patients with low activity of the CYP2C19 isoenzyme should have the two above-mentioned alleles of the gene with loss of function. The published frequencies of phenotypes of individuals with low activity of the CYP2C19 isoenzyme are 2% in Caucasians,4% in Negroes, and 14% in Chinese. There are special tests to determine the patient’s genotype of the CYP2C19 isoenzyme. According to a cross-sectional study (40 volunteers), which included individuals with very high, high, intermediate and low activity of the CYP2C19 isoenzyme, no significant differences were found in the exposure of the active metabolite and in the average values of inhibition of platelet aggregation (IAT) induced by ADP in volunteers with very high, high and intermediate activity of the CYP2C19 isoenzyme. In volunteers with low activity of the CYP2C19 isoenzyme, exposure to the active metabolite decreased by 63-71%, compared with individuals with high activity of the CYP2C19 isoenzyme. When using the 300 mg loading dose / 75 mg maintenance dose regimen (300 mg/75 mg) in volunteers with low activity of the CYP2C19 isoenzyme, the antiplatelet effect decreased with average IAT values of 24% (after 24 hours) and 37% (on day 5 of treatment), compared with IAT values of 39% (after 24 hours) and 58% (on day 5 of treatment) in volunteers with high activity of the CYP2C19 isoenzyme and 37% (after 24 hours) and 60% (after 24 hours). (on day 5 of treatment) in volunteers with intermediate activity of the CYP2C19 isoenzyme. When volunteers with low activity of the CYP2C19 isoenzyme received a 600 mg loading dose / 150 mg maintenance dose regimen (600 mg/150 mg), exposure to the active metabolite was higher than when taking the 300 mg/75 mg treatment regimen. In addition, IAT was 32% (after 24 hours) and 61% (on day 5 of treatment), which was higher than in individuals with low activity of the CYP2C19 isoenzyme treated with a 300 mg/75 mg regimen, and was similar to that in groups of patients with a higher intensity of CYP2C19 metabolism treated with a 300 mg/75 mg regimen. However, in studies based on clinical outcomes, the dosage regimen of clopidogrel for patients in this group (patients with low activity of the CYP2C19 isoenzyme) has not yet been established. Similarly to the results of this study, a meta-analysis of six studies, which included data from 335 volunteers treated with clopidogrel and who were in a state of reaching equilibrium concentration, showed that compared with volunteers with high activity of the CYP2C19 isoenzyme, in volunteers with intermediate activity of the CYP2C19 isoenzyme, exposure to the active metabolite decreased by 28%, and in volunteers with low activity of the CYP2C19 isoenzyme – by 72%, while IAT was reduced with differences in IAT amounting to 5.9% and 21.4%, respectively. The effect of the CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been evaluated in prospective, randomized, or controlled trials.However, there are currently several retrospective analyses available. Genotyping results are available in the following clinical trials: CURE, CHARISMA, CLARITY-TIMI 28, TRITON-TIMI 38, and ACTIVE-A, as well as in several published cohort studies. In the TRITON-TIMI 38 study and 3 cohort studies (Collet, Sibbing, Giusti), patients in the combination group with intermediate or low activity of the CYP2C19 isoenzyme had a higher incidence of cardiovascular complications (death, myocardial infarction, and stroke) or stent thrombosis, compared with patients with high activity of the CYP2C19 isoenzyme. In the CHARISMA study and one cohort study (Simon), an increase in the incidence of cardiovascular complications was observed only in patients with low activity of the CYP2C19 isoenzyme (when compared with patients with high activity of the CYP2C19 isoenzyme). The CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk) did not show an increase in the frequency of cardiovascular complications depending on the intensity of CYP2C19 metabolism. The pharmacokinetics of the active metabolite of clopidogrel in these groups have not been studied. Elderly patients and elderly volunteers (older than 75 years) when compared with young volunteers, there were no differences in platelet aggregation and bleeding time. No dose adjustment is required in the elderly. Child data is missing. Patients with impaired renal function After repeated administration of clopidogrel 75 mg / day in patients with severe renal impairment (creatinine clearance from 5 ml / min to 15 ml / min), the inhibition of ADP-induced platelet aggregation was lower (by 25%) compared to that in healthy volunteers, but the prolongation of bleeding time was similar to that in healthy volunteers receiving clopidogrel 75 mg / day. Patients with impaired liver function After ten days of taking clopidogrel daily at a daily dose of 75 mg in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean bleeding time was also comparable in both groups. Racial affinity The distribution of alleles of the CYP2C19 isoenzyme genes, which cause intermediate and low activity of this isoenzyme, differs among representatives of different racial groups. There are limited literature data on their prevalence in representatives of the Mongoloid race, which does not allow us to assess the significance of genotyping of the CYP2C19 isoenzyme for the development of ischemic complications.

Indications

Secondary prevention of atherothrombotic complications in adult patients with myocardial infarction (from a few days to 35 days ago), ischemic stroke (from 7 days to 6 months ago) or diagnosed occlusive peripheral artery disease. In adult patients with acute coronary syndrome:- without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), including patients who underwent stenting during percutaneous coronary intervention (in combination with acetylsalicylic acid);- with ST segment elevation (acute myocardial infarction) during drug treatment and the possibility of thrombolysis (in combination with acetylsalicylic acid). Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation (atrial fibrillation). In patients with atrial fibrillation (atrial fibrillation), who have at least one risk factor for vascular complications, cannot take indirect anticoagulants and have a low risk of bleeding (in combination with acetylsalicylic acid).

Use during pregnancy and lactation

Pregnancy

Animal studies have shown no direct or indirect adverse effects on pregnancy, fetal development, delivery, or postnatal development. Since it is not always possible to predict a reaction in humans based on animal studies, and due to the lack of data from controlled clinical studies on the use of clopidogrel in pregnant women, it is not recommended to take clopidogrel during pregnancy as a precautionary measure, except in cases where, in the opinion of the doctor, its use is urgently necessary.

Breast-feeding period

Studies in rats have shown that clopidogrel and / or its metabolites are excreted in breast milk. Whether clopidogrel penetrates human breast milk is unknown. Since many medications can be excreted in breast milk and have an adverse effect on the infant, the attending physician, based on the importance of taking the drug Plagril® for the mother, should recommend that she either stop taking the drug, or take the drug, but refuse to breastfeed.

Contraindications

• Hypersensitivity to clopidogrel or any of the excipients of the drug

• Severe liver failure.

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

• Rare hereditary problems of galactose intolerance, lactase deficiency, and glucose-galactose malabsorption.

• Pregnancy and lactation period (see the section “Pregnancy and lactation period”).

• Children under 18 years of age (safety and efficacy have not been established).

With caution:With moderate hepatic insufficiency, in which a predisposition to bleeding is possible (limited clinical experience). In patients with renal insufficiency (limited clinical experience). For diseases that have a predisposition to the development of bleeding (in particular gastrointestinal or intraocular), and especially with the simultaneous use of medications that can cause damage to the gastrointestinal mucosa (such as acetylsalicylic acid [ASA] and nonsteroidal anti-inflammatory drugs [NSAIDs]). In patients who have an increased risk of bleeding: due to injury, surgery or other pathological conditions, as well as in patients receiving treatment with ASA, heparin, warfarin, glycoprotein IIb/IIIa inhibitors, NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, as well as other drugs associated with the risk of bleeding, selective serotonin reuptake inhibitors (SSRIs) (see the sections “Interaction with other medicinal products”, “Special instructions”). When used concomitantly with drugs that are substrates of the CYP2C8 isoenzyme (repaglinide, paclitaxel) (see the section “Interaction with other drugs”). In patients with low activity of the CYP2C19 isoenzyme (see section “Pharmacokinetics”, subsection “Pharmacogenetics”, sections “Dosage and administration”, “Special instructions”). If there is a history of allergic and hematological reactions to other thienopyridines (such as ticlopidine, prasugrel) (the possibility of cross-allergic and hematological reactions, see the section “Special instructions”). In case of a recent transient cerebral circulatory disorder or ischemic stroke (in combination with ASA, see the section “Special instructions”.

Side effects

Data from clinical studiesthe safety of clopidogrel has been studied in more than 44,000 patients, including more than 12,000 patients treated for a year or more. Overall, the tolerability of clopidogrel 75 mg/day in the CAPRIE study was consistent with that of ASA 325 mg/day, regardless of age, gender, or race. The following are clinically significant adverse events observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE-A. Bleeding and hemorrhagescomparison of clopidogrel and ASA monotherapy in the CAPRIE clinical trial, the overall incidence of all bleeding in patients taking clopidogrel and in patients taking ASA was 9.3%. The incidence of severe bleeding with clopidogrel and ASA was comparable: 1.4% and 1.6%, respectively. Overall, the incidence of gastrointestinal bleeding in patients treated with clopidogrel and in patients treated with ASA was 2.0% and 2.7%, respectively, including the incidence of gastrointestinal bleeding requiring hospitalization was 0.7% and 1.1%, respectively. The overall incidence of non-local bleeding with clopidogrel compared to ASA was higher (7.3% vs.6.5%, respectively). However, the incidence of severe bleeding with clopidogrel and ASA was comparable (0.6% or 0.4%, respectively). The following bleeding events were most frequently reported: purpura / bruising, nosebleeds. Less frequently, hematomas, hematuria, and ocular hemorrhages (mainly conjunctival) were reported. The incidence of intracranial hemorrhage with clopidogrel and ASA was comparable (0.4% or 0.5%, respectively). Comparison of combination therapy with clopidogrel + ASA and placebo + ASA in the CURE clinical trial, patients taking clopidogrel + ASA compared with patients taking placebo + ASA, there was an increase in the incidence of major bleeding (3.7% vs.2.7%) and minor bleeding (5.1% vs.2.4%). The main sources of major bleeding were the gastrointestinal tract and arterial puncture sites.The incidence of life-threatening bleeding in patients taking clopidogrel + ASA, compared with patients taking placebo + ASA, did not significantly differ (2.2% and 1.8%, respectively), the incidence of fatal bleeding was the same (0.2% with both types of therapy). The incidence of non-life-threatening major bleeding was significantly higher in patients taking clopidogrel + ASA compared to patients taking placebo + ASA (1.6% and 1%, respectively), but the incidence of intracranial hemorrhage was the same (0.1% for both types of therapy). The incidence of major bleeding in the clopidogrel + ASA group was dose-dependent (<100 mg: 2.6%; 100-200 mg: 3.5%; >200 mg: 4.9%), as was the incidence of major bleeding in the placebo + ASA group (<100 mg: 2.6%; 100-200 mg: 3.5%; ><100 mg: 2.0%; 100-200 mg: 2.3%; >200 mg: 4.0%). In patients who stopped antiplatelet therapy more than 5 days before coronary artery bypass grafting, there was no increase in cases of major bleeding within 7 days after the intervention (4.4% in the clopidogrel + ASA group and 5.3% in the placebo + ASA group). In patients who continued antiplatelet therapy for the last five days before coronary artery bypass grafting, the incidence of these events after the intervention was 9.6% (clopidogrel + ASA) and 6.3% (placebo + ASA). In the CLARITY clinical trial, the incidence of major bleeding (defined as intracranial bleeding or bleeding with a decrease in hemoglobin> 5 g/dl) in both groups (clopidogrel + ASA and placebo + ASA) was comparable in both treatment groups (1.3% vs.1.1% in the clopidogrel + ASA and placebo + ASA groups, respectively). It was the same in subgroups of patients divided by baseline characteristics and by types of fibrinolytic therapy or heparin therapy. The incidence of fatal bleeding (0.8% vs.0.6%) and intracranial hemorrhage (0.5% vs.0.7%) with clopidogrel + ASA and placebo + ASA, respectively, was low and comparable in both treatment groups. In the COMMIT clinical trial, the overall incidence of non-cerebral major bleeding or cerebral hemorrhage was low and similar (0.6% in the clopidogrel + ASA group and 0.5% in the placebo + ASA group). In the ACTIVE-A clinical trial, the incidence of major bleeding in the clopidogrel + ASA group was higher than in the placebo + ASA group (6.7% vs.4.3%, respectively). Major hemorrhages were mostly extracranial in both groups (5.3% vs.3.5%), mainly from the gastrointestinal tract (3.5% vs.1.8%). There were more intracranial hemorrhages in the clopidogrel + ASA group than in the placebo + ASA group (1.4% vs.0.8%, respectively). There were no statistically significant differences between these treatment groups in the incidence of fatal bleeding (1.1% vs.0.7%) and hemorrhagic stroke (0.8% vs.0.6%). Circulatory disorders CAPRIE severe neutropenia (Two of the 9599 patients treated with clopidogrel showed a complete absence of neutrophils in the peripheral blood, which was not observed in any of the 9586 patients treated with ASA. Although the risk of developing myelotoxic effects when taking clopidogrel is quite low, if the patient taking clopidogrel has a fever or other signs of infection, the patient should be examined for possible neutropenia. In one case, the development of aplastic anemia was observed during treatment with clopidogrel. Frequency of severe thrombocytopenia (The CURE and CLARITY studies observed a comparable number of patients with thrombocytopenia or neutropenia in both treatment groups. Other clinically significant adverse reactions observed in the CAPRIE, CURE, CLARITY COMMIT and ACTIVE clinical trials-The frequency of adverse reactions observed during the above clinical trials is presented in accordance with the WHO classification:

• very often (≥ 10%); often (≥ 1% and < 10%);
• infrequently (≥ 0.1% and <1%); rarely (≥ 0.01% and <Is 0.1%);
• very rare (<0,01%);
• the frequency is unknown – to determine the frequency of occurrence of side effects according to the available data it is not possible.

Nervous system disorders

• Infrequently: headache, dizziness, paresthesia.
• Rare: vertigo.
• Gastrointestinal disorders
• are common: dyspepsia, abdominal pain, diarrhea.
• Infrequently: nausea, gastritis, bloating, constipation, vomiting, stomach ulcer, duodenal ulcer.

Skin and subcutaneous tissue disorders

• Infrequently: rash, itching.
• Disorders of the blood and lymphatic system
• Infrequently: increased bleeding time, decreased platelet count in peripheral blood; leukopenia, decreased neutrophil count in peripheral blood, eosinophilia.

Post-marketing experience with the use of preparata. lechenie the blood and lymphatic system

• Frequency unknown: serious cases of bleeding, mainly subcutaneous, musculoskeletal, eye bleeding (conjunctival, in the tissue and the retina of the eye), bleeding from the airway (hemoptysis, pulmonary hemorrhage), nasal bleeding, hematuria, and bleeding from surgical wounds and cases of bleeding with fatal outcome (especially intracranial hemorrhage, gastrointestinal bleeding and retroperitoneal hemorrhage), agranulocytosis, granulocytopenia, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired haemophilia A.

Cardiac disorders

• Frequency unknown: Kounis syndrome (vasospastic allergic angina / allergic myocardial infarction) due to a hypersensitivity reaction to clopidogrel.

Immune system disorders

• Frequency unknown: anaphylactoid reactions, serum sickness; cross-allergic and hematological reactions with other thienopyridines (such as ticlopidine, prasugrel) [see section “Special instructions”].

Mental disorders

• Frequency unknown: confusion, hallucinations.

Nervous system disorders

• Frequency unknown: taste perception disorders.
• Vascular disorders
• Frequency unknown: vasculitis, low blood pressure.

Liver and biliary tract

• disorders Frequency unknown: hepatitis (non-infectious), acute liver failure.

Violations of the skin and subcutaneous tissues

• Frequency unknown: maculate-papular erythematous or exfoliative rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, and Stevens-Johnson syndrome, toxic epidermal necrolysis), acute generalized eczematous pustules, the drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations (DRESS syndrome), eczema, oral lichen planus.

Musculoskeletal and connective tissue

• disorders Frequency unknown: arthralgia (joint pain), arthritis, myalgia.
• Renal and urinary tract
• disorders Frequency unknown: glomerulonephritis.

Genital and breast disorders

• Frequency unknown: gynecomastia.

General disorders and disorders at the injection

• site Frequency unknown: fever.

Laboratory and instrumental data

• The frequency is unknown: deviation from the norm of laboratory parameters of the functional state of the liver, an increase in the concentration of creatinine in the blood.

Interaction

Concomitant use with clopidogrel of drugs that are associated with a risk of bleeding should be carried out with caution (with warfarin, with IIb/IIIa receptor blockers, with acetylsalicylic acid, with heparin, with thrombolytics, NSAIDs, with SSRIs).

How to take, course of administration and dosage

Clopidogrel should be taken orally, regardless of food intake. Secondary prevention of atherothrombotic complications in adult patients with myocardial infarction (with a prescription of several days to 35 days), ischemic stroke (with a prescription of 7 days to 6 months) or diagnosed occlusive peripheral artery disease, the drug should be taken 75 mg once a day.  Secondary prevention of atherothrombotic complications in adult patients with non-ST-segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing percutaneous coronary intervention stenting (in combination with acetylsalicylic acid)Treatment with clopidogrel should begin with a single loading dose of 300 mg, and then continue with a maintenance dose of 75 mg once a day (in combination with ASA at doses of 75-325 mg per day). Since the use of higher doses of ASA is associated with an increased risk of bleeding, the recommended dose of ASA for this indication should not exceed 100 mg. The optimal duration of treatment is not officially defined. Data from clinical studies support taking the drug for up to 12 months, and the maximum beneficial effect was observed by the third month of treatment.Secondary prevention of atherothrombotic complications in adult patients with acute ST-segment elevation coronary syndrome (acute myocardial infarction) during drug treatment and the possibility of thrombolysis (in combination with acetylsalicylic acid)Clopidogrel should be taken once a day at a dose of 75 mg with an initial single loading dose of clopidogrel 300 mg in combination with ASA in combination with thrombolytics or without combination with thrombolytics. In patients over 75 years of age, treatment with clopidogrel should begin without taking its loading dose. Combination therapy should be initiated as early as possible after the onset of symptoms and continued for at least four weeks. The effectiveness of using a combination of clopidogrel and ASA for this indication for more than 4 weeks has not been studied. Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation (atrial fibrillation) in patients with atrial fibrillation (atrial fibrillation) who have at least one risk factor for vascular complications, cannot take indirect anticoagulants and have a low risk of bleeding (in combination with acetylsalicylic acid)Clopidogrel should be taken once a day at a dose of 75 mg. In combination with clopidogrel, you should start and then continue taking ASA (75-100 mg / day). Skipping the next dose – If less than 12 hours have passed since skipping the next dose, then you should immediately take the missed dose of the drug, and then take the next dose at the usual time. – If more than 12 hours have passed since the next dose was missed, then the patient should take the next dose at the usual time (do not take a double dose). Special patient groups Patients with genetically determined reduced activity of the CYP2C19 isoenzyme Low activity of the CYP2C19 isoenzyme is associated with a decrease in the antiplatelet effect of clopidogrel. A higher dose regimen (600 mg as a loading dose, followed by 150 mg once daily) in patients with low CYP2C19 activity increases the antiplatelet effect of clopidogrel (see section “Pharmacokinetics”). However, currently in clinical studies that take into account clinical outcomes, the optimal dosage regimen of clopidogrel has not been established for patients with its reduced metabolism due to the genetically determined low activity of the CYP2C19 isoenzyme. Elderly subjects and elderly volunteers (over 75 years of age), when compared with young volunteers, there were no differences in platelet aggregation and bleeding time. No dose adjustment is required for the elderly. Dethiotexperience of using the drug in children. Patients with impaired renal function After repeated administration of clopidogrel 75 mg / day in patients with severe renal impairment (creatinine clearance from 5 to 15 ml / min), the inhibition of ADP-induced platelet aggregation (25%) was lower compared to that in healthy volunteers, however, the prolongation of bleeding time was similar to that in healthy volunteers receiving clopidogrel 75 mg / day. In addition, all patients had good drug tolerance. Patients with impaired liver function After taking clopidogrel daily for 10 days at a daily dose of 75 mg in patients with severe liver damage, the inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean bleeding time was also comparable in both groups. Patients of different ethnicitythe prevalence of alleles of the CYP2C19 isoenzyme genes responsible for the intermediate and reduced metabolism of clopidogrel to its active metabolite differs among representatives of different ethnic groups (see the section “Pharmacogenetics”). There are only limited data available for the Mongoloid race to assess the effect of the CYP2C19 isoenzyme genotype on clinical outcome events. Female and male patients In a small study comparing the pharmacodynamic properties of clopidogrel in men and women, women showed less inhibition of ADP-induced platelet aggregation, but there were no differences in prolongation of bleeding time. In a large controlled trial of CAPRIE (clopidogrel versus acetylsalicylic acid in patients at risk of developing ischemic complications), the incidence of clinical outcomes, other side effects, and abnormal clinical and laboratory parameters was similar in both men and women.

Overdose

Overdose of clopidogrel can lead to an increase in bleeding time with subsequent complications in the form of bleeding. If bleeding occurs, appropriate treatment measures are required.

The antidote of clopidogrel has not been established. If a rapid correction of prolonged bleeding time is required, platelet transfusion is recommended.

Special instructions

During treatment with clopidogrel, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients should be carefully monitored for signs of bleeding, including latent bleeding. Due to the risk of bleeding and undesirable effects from the blood (see the section “Side effects”), if clinical symptoms appear during treatment that are suspicious of the occurrence of bleeding, a general clinical blood test should be urgently performed, activated partial thromboplastin time (APTT), platelet count, platelet functional activity indicators should be determined, and other necessary studies should be carried out. Clopidogrel, as well as other antiplatelet agents, should be used with caution in patients who have an increased risk of bleeding associated with injuries, surgery or other pathological conditions, as well as in patients taking ASA, NSAIDs, including COX-2 inhibitors, heparin or glycoprotein IIb/IIIa inhibitors. Concomitant use of clopidogrel with warfarin may increase the risk of bleeding (see section “Interactions with other medications”), so caution should be exercised when using clopidogrel and warfarin together. If the patient is going to undergo elective surgery and there is no need for an antiplatelet effect, then clopidogrel should be discontinued 5-7 days before the operation. Clopidogrel prolongs the bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (especially gastrointestinal and intraocular). Medications that can cause damage to the gastrointestinal mucosa (such as ASA, NSAIDs) Caution should be exercised in patients taking clopidogrel. Patients should be warned that it may take longer to stop bleeding when taking clopidogrel (alone or in combination with ASA), and that if they experience unusual (by location or duration) bleeding, they should inform their doctor about this. Patients should inform their doctor (including their dentist) about taking clopidogrel before any upcoming surgery and before starting any new medication. Very rarely, after the use of clopidogrel (sometimes even for a short time), cases of TTP have been observed, 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 that requires immediate treatment, including plasmapheresis. The combination of ASA and clopidogrel has been shown to increase the risk of major bleeding in patients with a recent transient cerebrovascular accident or stroke who are at high risk for recurrent ischemic events. Therefore, such combination therapy should be carried out with caution and only if there is clinical evidence of benefits from its use. Cases of acquired hemophilia have been reported with clopidogrel. If there is a confirmed isolated increase in APTT, accompanied or not accompanied by the development of bleeding, the possibility of developing acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated by specialists for this condition and stop taking clopidogrel. In patients with low activity of the CYP2C19 isoenzyme, when using clopidogrel at the recommended doses, less of the active metabolite of clopidogrel is formed and its antiplatelet effect is less pronounced, and therefore, when taking the usually recommended doses of clopidogrel in acute coronary syndrome or percutaneous coronary intervention, a higher incidence of cardiovascular complications is possible than in patients with normal activity of the CYP2C19 isoenzyme. Tests are available to determine the CYP2C19 genotype. These tests can be used to help you choose a therapeutic strategy. The use of higher doses of clopidogrel in patients with low CYP2C19 activity is being considered (see section “Pharmacokinetics”, subsection “Pharmacogenetics”, sections “With caution”, “Method of administration and doses”). Patients should have a history of previous allergic and / or hematological reactions to other thienopyridines (such as ticlopidine, prasugrel), as cross-allergic and/or hematological reactions between thienopyridines have been reported (seesection “Side effects”). Thienopyridines can cause moderate to severe allergic reactions (such as rash, angioedema) or hematological reactions (such as thrombocytopenia and neutropenia). Patients who have previously experienced allergic and / or hematological reactions to one of the thienopyridine drugs may have an increased risk of developing similar reactions to another thienopyridine drug. Monitoring of cross-allergic and/or hematological reactions is recommended. During treatment, it is necessary to monitor the functional state of the liver. With severe liver damage, you should be aware of the risk of developing hemorrhagic diathesis. Taking clopidogrel is not recommended for acute stroke with a duration of less than 7 days (since there are no data on its use in this condition). The drug Plagril® does not significantly affect the ability required to drive a car or engage in other potentially dangerous activities.

Storage conditions

In the original packaging, at a temperature not exceeding 25 °C. Keep out of reach of children!

Shelf life

1 year

Active ingredient

Clopidogrel

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Prevention of thrombosis, Prevention of heart attacks and strokes

Weight

Weight: 24 gr.