Plagril A modified-release capsules 75mg+75mg, 30pcs

Composition

Each modified-release capsule contains: Active ingredients: Clopidogrel hydrosulfate (form-I) 97.857 mg (based on clopidogrel 75 mg) [as part of a film-coated tablet,312 mg*] Acetylsalicylic acid 75 mg [as part of an enteric-coated tablet,122 mg**]* – Each film-coated tablet contains: Active ingredient: Clopidogrel hydrosulfate (form-I) 97.857 mg (based on clopidogrel 75 mg)Auxiliary substances: Microcrystalline cellulose 140,643 mg Mannitol 45 mgCroscarmellose sodium 12 mg Hydrogenated castor oil 4.5 mgfilm shell: Opadrai rosea [hypromellose 6 cP 62.50% Titanium dioxide (E 171) 30.60%Macrogol 400 6.25%Iron oxide dye red (E 172) 0.65%] 12 mg** – Each enteric coated tablet of acetylsalicylic acid contains: Active ingredient: Acetylsalicylic acid 75 mg Excipients: Lactose monohydrate 25.9 mg Pregelatinized starch 7.5 mg Citric acid anhydrous 0.1 mg Colloidal silicon dioxide 0.5 mg Stearic acid 1 Mgcompetitive substances (film coating): Hypromellose 6 cps 2.2 mg Propylene Glycol 0.22 mg, Talc 0.22 mg, Titanium dioxide 0.11 mg; Excipients (enteric coating): Methacrylic acid and ethyl acrylate copolymer [1: 1] (methacrylic acid copolymer (type C)) 7.5 mgMacrogol 4000 0.6 mgtalk 1.15 mgcomposition of gelatin solid capsule No. 0: Gelatin 82.31%Water 14.50%Sodium Lauryl Sulfate 0.08% Methyl Parahydroxybenzoate 0.80%Propyl parahydroxybenzoate 0.20% Composition of black ink for writing on the capsule lid and body: Ethanol 30-34% Isopropanol 3-6% Butanol 3-5%Shellac 20-24% Propylene Glycol 0.5-2.0% Iron Oxide Dye Black (E 172) 20-24%Purified water q. s.

Pharmacological action

Pharmacodynamics  Clopidogrel Clopidogrel (more precisely, its active metabolite) irreversibly binds to platelet ADP receptors and selectively inhibits the binding of ADP to platelet ADP receptors and the subsequent activation of the GPIIb/IIIa complex by ADP, thereby suppressing ADP-induced platelet aggregation. Clopidogrel also inhibits platelet aggregation caused by other agonists by blocking the increase in platelet activity with released adenosine diphosphate. Due to the irreversible binding of clopidogrel to platelet ADP receptors, platelets remain immune to ADP stimulation for the rest of their life, and the restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal. With daily use of clopidogrel at a dose of 75 mg from the first day of use, 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 over an average of 5 days. Acetylsalicylic Acid (ASA)ASA suppresses platelet aggregation due to irreversible inhibition of cyclooxygenase-1 (COX-1), which reduces the formation of thromboxane A2, which is an inducer of platelet aggregation and vasoconstriction. This effect persists throughout the life of platelets. ASA does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, while clopidogrel enhances the effect of acetylsalicylic acid on collagen-induced platelet aggregation. Both active substances are 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. Pharmacokineticsabsorption of clopidogrel With a single and course oral use of 75 mg per day, clopidogrel is rapidly absorbed in the intestine. Average maximum concentrations of unchanged clopidogrel in blood plasma (about 2.2-2.5 ng / ml after oral use of a single dose of 75 mg)are reached approximately 45 minutes after a single dose. According to the renal excretion of clopidogrel metabolites, its absorption is approximately 50%. Acetylsalicylic Acid After absorption, ASA undergoes hydrolysis to form salicylic acid, the maximum concentrations of which in blood plasma are reached one hour after oral use of ASA. Due to rapid hydrolysis, ASA is practically undetectable in blood plasma 1.5-3 hours after oral use. Distribution of Clopidogrelin vitro clopidogrel and its main inactive metabolite circulating in the blood reversibly bind to plasma proteins (by 98% and 94%, respectively) and this bond is unsaturated in vitro up to a concentration of 100 mg/l. Acetylsalicylic acid ASA is weakly bound to plasma proteins and has a small volume of distribution (10 liters). Its metabolite, salicylic acid, binds well to plasma proteins, but its binding to plasma proteins depends on its concentration in blood plasma(non-linear relationship). At low concentrations ( Salicylic acid is well distributed in tissues and body fluids, including the central nervous system, breast milk, and fetal tissues. Metabolism Clopidogrel Clopidogrel is rapidly metabolized in the liver. In vitro and in vivo, clopidogrel is metabolized by two metabolic pathways: the first pathway is carried out by esterases, which leads to hydrolysis to form an inactive metabolite of a carboxylic acid derivative (85% of the metabolites circulating in the systemic circulation); the second pathway is carried out by several cytochrome P450 isoenzymes. In this case, clopidogrel is initially metabolized to 2-oxo-clopidogrel, which is 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 pathway is metabolized by the isoenzymes CYP2C19, CYP1A2, CYP3A4, and CYP2B6. The active thiol metabolite of clopidogrel, which has been isolated in vitro studies, binds rapidly and irreversibly to platelet receptors, inhibiting platelet aggregation. After taking a loading dose of clopidogrel 300 mg, the maximum concentration (Cmax) of the active metabolite is 2 times higher than that after taking a maintenance dose of clopidogrel 75 mg for 4 days, while its Cmax is reached approximately 30-60 minutes after taking clopidogrel. Acetylsalicylic acid ASA, when taken in combination with clopidogrel, is rapidly hydrolyzed in blood plasma to salicylic acid with a half-life of 0.3-0.4 hours for ASA doses of 75-100 mg. Salicylic acid is mainly conjugated in the liver to form salicyluric acid, phenolic glucuronide and acyl glucuronide, as well as a large number of minor metabolites. Elimination of Clopidogrel Within 120 hours of human ingestion of 14C-labeled clopidogrel, approximately 50% of the radioactivity is excreted by the kidneys and approximately 46% of the radioactivity is excreted through the intestines. After a single oral dose of 75 mg, the half-life of clopidogrel is approximately 6 hours. After a single and continuous use of clopidogrel, the elimination half-life of the main inactive metabolite circulating in the blood is 8 hours. Acetylsalicylic Acid The plasma half-life of salicylic acid is about 2 hours. The metabolism of salicylate is saturated, and total 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 g), the plasma half-life may increase to 20 hours. At high doses of ASA, the elimination of salicylic acid corresponds to a zero-order kinetics (i. e., the rate of elimination depends on the concentration in blood plasma) with a half-life of 6 hours or more. Renal excretion of the unchanged Active ingredient depends on the pH of the urine. If the pH is higher than 6.5, the renal clearance of free salicylate increases from <5% to >80%. After taking therapeutic doses, approximately 10% of the dose taken is found in the urine as salicylic acid,75% of the dose taken as salicyluric acid,10% of the dose taken as phenolic glucuronides, and 5% of the dose taken as acyl glucuronides. Pharmacogenetics: Several polymorphic isoenzymes of the cytochrome P450 system are involved in the activation of clopidogrel. The CYP2C19 isoenzyme is involved in the formation of both the active metabolite and the intermediate metabolite of 2-oxoclopidogrel. The pharmacokinetics and antiplatelet effects of the active metabolite of clopidogrel studied by platelet aggregation in vivo differ depending on the genotype of the CYP2C19 isoenzyme. The CYP2C19*1 allele is responsible for normal functioning metabolism, while the CYP2C19*2 and CYP2C19*3 alleles are responsible for reduced metabolism. These alleles are responsible for a decrease in metabolism in approximately 85% of the Caucasian race and 99% of the Mongoloid race. Other alleles responsible for reduced metabolism are represented by CYP2C19 isoenzymes*4, *5, *6, *7 and *8, but they are rare in the general population.Pharmacogenetic testing makes it possible to determine the genotype with variability in the activity of the CYP2C19 isoenzyme. Genetic variants of other enzymes of the P 450 system with an effect on the formation of active metabolites of clopidogrel are also possible. Individual patient groups are elderly patients. No differences in platelet aggregation and bleeding time were found in elderly volunteers (over 75 years of age) when compared with young volunteers. No dose adjustment is required for elderly patients. Children and teenagers. No data available. Impaired renal function. After repeated use of clopidogrel at a dose of 75 mg / day in patients with severe renal impairment (creatinine clearance from 5 to 15 ml / min), the inhibition of ADP-induced platelet aggregation was lower (25%) compared to that in healthy volunteers, but the prolongation of bleeding time was similar to that in healthy volunteers receiving clopidogrel at a dose of 75 mg/day. Impaired liver function. After taking clopidogrel daily for 10 days at a daily dose of 75 mg in patients with severe hepatic impairment (Class A and B less than 9 points on the Child-Pugh scale), the inhibition of ADP-induced platelet aggregation is similar to that in healthy volunteers. The average bleeding time was comparable in both groups. Ethnicity. The prevalence of alleles of the CYP2C19 isoenzyme genes responsible for intermediate and reduced metabolism is different among representatives of different ethnic groups. There are limited literature data on their prevalence among representatives of the Mongolian race to assess the clinical significance of the influence of the genotypes of the CYP2C19 isoenzyme on clinical outcomes. The specific pharmacokinetics and metabolism of both active substances of the drug Plagril® A exclude clinically significant pharmacokinetic interactions.

Indications

Combined drug Plagril® A is indicated for use in patients who are already receiving both clopidogrel and acetylsalicylic acid (see section “Dosage and use”). Prevention of atherothrombotic complications 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;- with ST-segment elevation (acute myocardial infarction) during drug treatment and the possibility of thrombolysis. Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation (atrial fibrillation)In adult 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.

Use during pregnancy and lactation

Pregnancy As a precautionary measure, the drug Plagril® A should not be used during the first two trimesters of pregnancy, unless the clinical condition of the woman requires treatment with clopidogrel in combination with ASA. Due to the presence of ASA, the drug is contraindicated in the third trimester of pregnancy. Animal studies have shown no direct or indirect adverse effects of clopidogrel on pregnancy, fetal development, delivery, or postnatal development. However, sufficient volume and controlled clinical studies have not been conducted in pregnant women. ASA was found to have a teratogenic effect, although in clinical studies it was found that doses of ASA up to 100 mg per day, which are used only in obstetrics and require specialized monitoring, proved to be safe. Breast-feeding period Breast-feeding in the case of treatment with Plagril® A should be discontinued, as acetylsalicylic acid has been found to pass into breast milk, and studies in rats have shown that clopidogrel and/or its metabolites are also excreted in the milk of lactating rats. Whether or not clopidogrel penetrates into breast milk is unknown.

Contraindications

Hypersensitivity to any of the active or auxiliary substances of the drug. – Severe liver failure (more than 9 points on the Child-Pugh scale). – Severe renal insufficiency (creatinine clearance less than 30 ml / min) due to the content of acetylsalicylic acid in the preparation. – Acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage. – Bronchial asthma induced by taking salicylates and other nonsteroidal anti-inflammatory drugs (NSAIDs); a combination of bronchial asthma, rhinitis and recurrent nasal and paranasal sinus polyposis due to the content of acetylsalicylic acid in the drug. – Mastocytosis, in which the use of ASA can cause severe hypersensitivity reactions, including the development of shock, with hyperemia of the skin, decreased blood pressure, tachycardia and vomiting (due to the content of acetylsalicylic acid in the preparation). – Rare hereditary conditions: galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome due to the lactose content of the drug. – Pregnancy and lactation (see the section “Use during pregnancy and lactation”). – Children under 18 years of age (safety and efficacy have not been established). With caution:With moderate hepatic insufficiency (7-9 points on the Child-Pugh scale), in which a predisposition to bleeding is possible (limited clinical experience). – With mild to moderate renal insufficiency (creatinine clearance 60-30 ml / min) (limited clinical experience). – For injuries, surgical procedures, including invasive cardiological procedures or surgical procedures (see the section “Special instructions”). – In diseases where there is a predisposition to the development of bleeding, especially gastrointestinal (with peptic ulcer of the stomach and duodenum or gastrointestinal bleeding in the anamnesis, with symptoms of disorders of the upper gastrointestinal tract) or intraocular. – In case of a recent transient cerebrovascular accident or ischemic stroke (see the section “Special instructions”). – With the simultaneous use of NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors (see the section “Interaction with other drugs”). – With simultaneous use of warfarin, heparin, glycoprotein IIb/IIIa inhibitors, selective serotonin reuptake inhibitors (SSRIs) and thrombolytic drugs (see the sections “Interaction with other drugs” and “Special instructions”). – With a history of bronchial asthma and allergies (increased risk of allergic reactions to ASA). – 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 the activity of the CYP2C19 isoenzyme (in such patients, when using clopidogrel at the recommended doses, a smaller amount of its active metabolite is formed and they have a less pronounced antiplatelet effect of the drug, in addition, in the case of acute coronary syndrome or percutaneous coronary intervention, they may have a higher frequency of cardiovascular complications after myocardial infarction compared to patients with normal activity of the CYP2C19 isoenzyme). – In patients with glucose-6-phosphate dehydrogenase deficiency (due to the risk of hemolysis) (see sections “Side effects”, “Special instructions”). – With simultaneous use of methotrexate at a dose of less than 20 mg per week (see the section “Interaction with other medications”). – If there is a history of allergic reactions to thienopyridines (for example, to ticlopidine, prazugrel), the possibility of cross-allergy.

Side effects

The safety of clopidogrel in clinical trials was evaluated in more than 44,000 patients, including more than 12,000 patients who took it for a year or more, and 30,000 patients who took clopidogrel and acetylsalicylic acid simultaneously; in the CURE clinical trial, the safety of clopidogrel in combination with acetylsalicylic acid was evaluated in more than 6,200 patients who took them for 1 year or more. The following are clinically significant adverse effects (NE) observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE A, and in post-marketing use of the combination of clopidogrel + acetylsalicylic acid, clopidogrel alone, and acetylsalicylic acid alone. The frequency of side effects was determined according to the WHO classification: very common >10%; often > > 1% and >><10%; infrequently >0.1% and <10%; infrequently ><1%; rarely >0.01% and <1%; rarely ><0.1%; very rarely Hemorrhagic adverse events (purpura/bruising; nosebleeds; hematuria; hemorrhages in skin tissue, bones and muscles; hematomas; hemorrhages in the joint cavity [hemarthrosis], conjunctiva, internal media and retina of the eye; bleeding from the respiratory tract, hemoptysis; bleeding from an operating wound; intracranial hemorrhages (hemorrhagic strokes); bleeding from the gastrointestinal tract, retroperitoneal hemorrhages, etc. )

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

• Common: major bleeds [life-threatening bleeds requiring 4 or more blood transfusions; other major bleeds requiring 2-3 blood transfusions; non-life-threatening major bleeds (according to the COMMIT study, the incidence of major non-cerebral bleeds and intracranial hemorrhages was “infrequent”)]; minor bleeding (according to the ACTIVE-A study, the incidence of minor bleeding was “very common”), bleeding at the site of vascular puncture; bruising; hematomas. The frequency of major bleeding events when using the combination of clopidogrel + acetylsalicylic acid depended on the dose of acetylsalicylic acid (<100 mg 2.6%; 100-200 mg 3.5%, >200 mg 4.9%), as well as their frequency when using ASA alone (<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 treatment more than 5 days before coronary artery bypass grafting, there was no increase in cases of major bleeding within 7 days after this intervention (4.4% with clopidogrel + acetylsalicylic acid versus 5.3% with acetylsalicylic acid alone). In patients who remained on antiplatelet therapy for the last five days before coronary artery bypass grafting, the incidence of these bleeds after the intervention was 9.6% (clopidogrel + acetylsalicylic acid) and 6.3% (acetylsalicylic acid alone).

• Infrequently: fatal bleeding; life-threatening bleeding [bleeding with a decrease in blood hemoglobin by more than 5 g / dl (according to the CLARITY clinical study, the frequency of their development was “often”)1; bleeding requiring surgical intervention; intracranial hemorrhages (hemorrhagic strokes) (according to the CLARITY clinical study, the frequency of their development was “frequent”); bleeding requiring the introduction of inotropic drugs]; severe bleeding (purpura, nosebleeds were most common; hematuria and intraocular hemorrhages, mainly conjunctival, were less common).

• Rare: intraocular hemorrhages with significant visual impairment, retroperitoneal hemorrhages. Frequency unknown (post-marketing experience): serious cases of bleeding, mainly hemorrhages in the skin, bones, muscles and joint cavity (hemarthrosis), in the eye tissues (conjunctival, internal media and retina), bleeding from the respiratory tract, hemoptysis, nosebleeds, hematuria, bleeding from an operating wound; intracranial hemorrhages, including fatal cases, especially in elderly patients; other cases of fatal bleeding (in particular, bleeding from a surgical wound). gastrointestinal tract and retroperitoneal hemorrhages).

Disorders of the blood and lymphatic system:

• Infrequently: a decrease in the number of platelets in the peripheral blood, severe thrombocytopenia with the number of platelets in the peripheral blood <80 x 109/l, but > 30 x 109/l; leukopenia; a decrease in the number of neutrophils in the peripheral blood, eosinophilia, prolongation of bleeding time.

• Rare: neutropenia, including severe neutropenia ( Although the risk of myelotoxic effects with clopidogrel is quite low, it should be considered when a patient taking clopidogrel develops fever and other infectious manifestations.

• Very rare: aplastic anemia, severe thrombocytopenia with the number of platelets in the peripheral blood Frequency unknown (post-marketing experience): thrombocytopenia, hemolytic anemia in patients with glucose-6 – phosphate dehydrogenase deficiency, agranulocytosis; aplastic anemia/pancytopenia, bicytopenia, bone marrow hematopoiesis disorders, neutropenia, leukopenia, granulocytopenia, anemia, acquired hemophilia A, thrombotic thrombocytopenic purpura (TTP).

Central and peripheral nervous system disorders:

• Infrequently: headache, dizziness and paresthesia.

• Rare: vertigo.

• Frequency unknown (post-marketing experience): changes in taste sensations.

 Disorders of the digestive system

• are common: gastrointestinal bleeding, dyspepsia, abdominal pain, diarrhea.

• Infrequently: nausea, gastritis, flatulence, constipation, vomiting, stomach ulcer and duodenal ulcer.

• Frequency unknown (post-marketing experience): colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, esophagitis, ulceration/perforation of the esophagus, erosive gastritis, erosive duodenitis, ulcer or ulcerative perforation of the stomach and / or duodenum, upper gastrointestinal symptoms such as gastralgia, ulcers of the small intestine (jejunum and ileum) and large intestine (colon and rectum, intestinal perforation (these reactions may or may not be accompanied by bleeding and may occur with any dose of acetylsalicylic acid, as well as in patients who have cautionary symptoms and a history of serious gastrointestinal complications, or who do not have them); acute pancreatitis due to a hypersensitivity reaction to acetylsalicylic acid.

Liver and biliary tract disorders 

• Frequency unknown (post-marketing experience): hepatitis (non-infectious nature), acute liver failure, increased activity of “liver” enzymes, liver damage, mainly hepatocellular, chronic hepatitis.

Skin and subcutaneous tissue disorders

• Infrequently: skin rash, pruritus.

• Frequency unknown (post-marketing experience): macular-papular, erythematous or exfoliative skin rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), acute generalized exanthematous pustulosis, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations (DRESS-syndrome), eczema, flat lichen, a fixed skin rash (single or multiple skin changes, usually in the form of round or oval erythematous plaques that appear in the same place during the next drug intake).

Immune system disorders

• Frequency unknown (post-marketing experience): anaphylactoid reactions, serum sickness, hypersensitivity cross-reactions with other thienopyridines (such as ticlopidine, prasugrel), anaphylactic shock, increased food allergy symptoms.

 Psychiatric disorders

• Frequency unknown (post-marketing experience): confusion, hallucinations.

Vascular disorders

• Frequency unknown (post-marketing experience): vasculitis, including Schonlein-Heinoch purpura, low blood pressure 2.

Cardiac disorders

• Frequency unknown (post-marketing experience): Kounis syndrome (allergic coronary syndrome), caused by a hypersensitivity reaction to acetylsalicylic acid.

Respiratory, thoracic and mediastinal

• disorders Frequency unknown (post-marketing experience): bronchospasm, interstitial pneumonitis, eosinophilic pneumonia, non-cardiogenic pulmonary edema during chronic drug use associated with a hypersensitivity reaction.

Musculoskeletal and connective tissue

• disorders Frequency unknown (post-marketing experience): arthralgia, arthritis, and myalgia.

Kidney and urinary tract disorders 

• Frequency unknown (post-marketing experience): glomerulopathy, including glomerulonephritis, renal insufficiency, acute renal failure (especially in patients with pre-existing renal insufficiency, decompensated chronic heart failure, nephritic syndrome, or in patients taking concomitant diuretics).

Genital and breast disorders

• Frequency unknown (post-marketing experience): gynecomastia.

General disorders

• Frequency unknown (post-marketing experience): fever.

Laboratory and instrumental data

• Frequency unknown (post-marketing experience): deviation from the norm of biochemical parameters of the functional state of the liver, an increase in the concentration of creatinine in the blood.

Metabolic and nutritional

• disorders Frequency unknown (post-marketing experience): hypoglycemia, gout.

Hearing disorders and labyrinth disorders

• Frequency unknown (post-marketing experience): hearing loss, tinnitus.

Interaction

Thrombolytic agents

The safety of co-use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytics, and heparin was analyzed in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the case of combined use of thrombolytic drugs and heparin with ASA. Due to the lack of clinical data on the combined use of the drug Plagril® A and thrombolytic drugs, caution should be exercised when prescribing them simultaneously (see the section “Special instructions”). Glycoprotein IIb/IIIa Inhibitors

There may be a pharmacodynamic interaction between glycoprotein IIb/IIIa inhibitors and the drug Plagril® A, which requires caution when using them simultaneously in patients with an increased risk of bleeding (due to injuries and surgical interventions or other pathological conditions) (see the section “Special Instructions”).

Heparin According to a clinical study conducted in healthy volunteers, clopidogrel did not require a change in the dose of heparin and did not change its anticoagulant effect. Concomitant use of heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation. There may be a pharmacodynamic interaction between the drug Plagril® A and heparin, which may increase the risk of bleeding and requires caution when using them together (see the section “Special instructions”).

Indirect anticoagulants

Concomitant use of clopidogrel and oral anticoagulants may increase the intensity of bleeding, and therefore the use of this combination is not recommended. Clopidogrel 75 mg does not affect the pharmacokinetics of warfarin and does not change the value of the International Normalized Ratio (INR) in patients taking warfarin for a long time. However, co-use of warfarin with clopidogrel may increase the risk of bleeding due to the independent effect of these drugs on hemostasis.

Nonsteroidal anti-inflammatory drugs (NSAIDs) 

In a clinical study conducted in healthy volunteers, the combined use of clopidogrel and naproxen increased hidden blood loss through the gastrointestinal tract. Therefore, the use of NSAIDs, including COX-2 inhibitors, in combination with the drug Plagril® A is not recommended (see the section “Special instructions”).

Experimental data suggest that ibuprofen (when taken once at a dose of 400 mg between 8 hours before and 30 minutes after direct use of ASA at a dose of 81 mg in the form of immediate release) can inhibit the effect of low doses of ASA on platelet aggregation. However, when taken on an irregular basis, ibuprofen does not have any clinically significant effects on the antiplatelet effect of ASA.

Selective serotonin reuptake inhibitors (SSRIs) 

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

Other combination therapy with clopidogrel

Strong to moderate inhibitors of the CYP2 C 9 isoenzyme

Since clopidogrel is metabolized to its active metabolite in part by the CYP2C19 isoenzyme, 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 precautionary measure, concomitant use of clopidogrel and strong or moderate inhibitors of the CYP2C9 isoenzyme should be avoided.

Strong and moderate inhibitors of the CYP2C9 isoenzyme are omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, variconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol. Concomitant use with clopidogrel of proton pump inhibitors that are strong or moderate inhibitors of the CYP2C19 isoenzyme (for example, omeprazole, esomeprazole) is not recommended. If the patient still needs to use proton pump inhibitors simultaneously with taking the drug Plagril® A, then a proton pump inhibitor with a slight effect on the activity of the CYP2C19 isoenzyme, such as pantoprazole or lansoprazole, should be used.

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

• when using clopidogrel together with atenolol, nifedipine or both of these drugs

• taken at the same time, clinically significant pharmacodynamic interactions were observed;

• concurrent use of phenobarbital, cimetidine and estrogen had no significant effect on the pharmacodynamics of clopidogrel;

• the pharmacokinetic parameters of digoxin or theophylline was not altered in their joint application with clopidogrel;

• antacid drugs did not reduce the absorption of clopidogrel;

• phenytoin and tolbutamide can be safely administered concomitantly with clopidogrel (CAPRIE study), despite the fact that the data obtained in studies with human liver microsomes, indicate that carboxyl metabolite of clopidogrel may inhibit the activity of isozyme CYP2C9, which can lead to increased concentration in blood plasma of certain drugs, e. g. phenytoin, tolbutamide, and some NSAIDs, which are metabolized through CYP2C9 isoenzyme.

Other combination therapies:The reported therapy with ASA indicates the interaction of ASA with the following medications:

• Uricosuric drugs (drugs that promote the elimination of uric acid: benzbromarone, probenecid, sulfinpyrazone) 

• ASA may inhibit their uricosuric effect due to competition with uric acid at the excretion level.

• Methotrexate Methotrexate taken at doses greater than 20 mg / week should be used with caution in combination with the drug Plagril® A, as ASA in the composition of the drug can reduce the renal clearance of methotrexate, which in turn can increase its myelotoxic effect (see the section “With caution”).

• Metamizole, when used concomitantly with ASA, may 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 is recommended when concomitantly using salicylates and acetazolamide due to the increased risk of developing metabolic acidosis.

• Angiotensin-converting enzyme (ACE) inhibitors, acetazolamide, anticonvulsants (phenytoin and valproic acid), beta-blockers, diuretics and hypoglycemic drugs for internal use may interact with ASA used in high (anti-inflammatory) doses.

• Ethanol When used concomitantly with ASA, the risk of bleeding increases with chronic use of large amounts of ethanol (alcohol) (see the section “Special instructions”).

Other interactions with clopidogrel and ASA: ACE inhibitors, diuretics, beta-blockers, slow calcium channel blockers, hypolipidemic drugs, vasodilators, hypoglycemic drugs (including insulin), antiepileptic drugs, hormone replacement therapy and GPIIb/IIIa glycoprotein receptor blockers In clinical studies on the use of clopidogrel in combination with ASA in maintenance doses

How to take, course of use and dosage

The drug Plagril® And it should be taken 1 time a day, regardless of food intake. Dosage Adults and elderly patients with normal activity of the CYP2C19 isoenzyme. Acute coronary syndrome (ACS)Treatment is started as early as possible after the onset of symptoms. Taking the drug Plagril ® A begins after taking a single loading dose of clopidogrel in combination with ASA in the form of separate drugs, namely clopidogrel at a dose of 300 mg and ASA at doses of 75-325 mg per day, and in acute ST – segment elevation myocardial infarction-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 dose of ASA for this indication should not exceed 100 mg. In acute ST-segment elevation myocardial infarction in patients over 75 years of age, treatment with clopidogrel should begin without taking its loading dose. In patients with ACS without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), the maximum beneficial effect is observed by 3 months of treatment. The optimal duration of treatment is not officially defined. Data from clinical studies support taking the drug for up to 12 months. In patients with acute ST-segment elevation myocardial infarction, treatment should be continued for at least 4 weeks. Atrial Fibrillationplagril® A should be taken once a day after starting treatment with clopidogrel 75 mg and ASA 100 mg as separate medications. 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 regimen of higher doses of clopidogrel (600 mg as a loading dose, then 150 mg once daily) in patients with low activity of the CYP2C19 isoenzyme increases the antiplatelet effect of clopidogrel (see section “Pharmacokinetics”). However, currently, clinical studies that take into account clinical outcomes have not established the optimal dosage regimen of clopidogrel for patients with its reduced metabolism due to the genetically determined low activity of the CYP2C19 isoenzyme.

Overdose

Symptoms and treatment of Clopidogrel overdosingclopidogrel overdose can lead to increased bleeding time with subsequent complications in the form of bleeding. If bleeding occurs, appropriate treatment is required. The antidote of clopidogrel has not been established. If a rapid correction of prolonged bleeding time is required, platelet transfusion is recommended. Symptoms and treatment of Acetylsalicylic acid overdose Moderate overdose: dizziness, ringing in the ears, headaches, confusion, and gastrointestinal symptoms (nausea, vomiting, and stomach pain). When symptoms of severe intoxication are detected, severe violations of the acid-base state occur. Initially occurring 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 in the blood, metabolic acidosis develops. In addition, the following symptoms appear: hyperthermia and heavy sweating, leading to dehydration, motor restlessness, convulsions, hallucinations and the development of hypoglycemia. Nervous system depression can lead to coma, collapse, and respiratory arrest. The lethal dose of acetylsalicylic acid is 25-30 g. A plasma salicylate concentration of more than 300 mg / l (1.67 mmol/L) confirms the presence of intoxication. Acute and chronic ASA overdose may result in non-cardiogenic pulmonary edema (see section “Side effects”). If symptoms of severe overdose are detected, hospitalization is required. With moderate intoxication, you can try to artificially induce vomiting, in case of failure, gastric lavage is recommended. After that, it should be taken orally (if the patient can swallow) or otherwise injected into the stomach through a probe with activated charcoal (adsorbent) and a saline laxative. For the purpose of forced alkalinization of urine to accelerate the excretion of salicylates, intravenous drip use of 250 mmol of sodium bicarbonate is indicated for 3 hours under the control of urine pH and acid-base state. The preferred treatment for severe overdose is hemodialysis or peritoneal dialysis. If necessary, symptomatic treatment of other manifestations of intoxication is carried out.

Special instructions

Bleeding and blood disorders Due to the risk of bleeding and blood disorders (see the section “Side effects”), if clinical symptoms appear during treatment that are suspected of bleeding, a general clinical blood test should be performed urgently, activated partial thromboplastin time (APTT), platelet count, platelet functional activity indicators should be determined, and other necessary studies should be performed. Due to the presence of two antiplatelet agents in the composition of Plagril® A, it should be used with caution in patients at increased risk of bleeding due to injuries, surgery or other pathological conditions, as well as in patients receiving NSAIDs (including COX-2 inhibitors), heparin, glycoprotein IIb/IIIa inhibitors, SSRIs and thrombolytics. Patients should be carefully monitored for signs of bleeding, including latent bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery. Concomitant use of Plagril ® A with indirect anticoagulants is not recommended, as this may increase the intensity of bleeding (see section “Interaction with other medications”), therefore, except in special rare clinical situations (such as the presence of a floating blood clot in the left ventricle, stenting in patients with atrial fibrillation or other indications for the appointment of indirect anticoagulants), the combined use of Plagril® A and warfarin is not recommended. If the patient is going to have a planned surgical intervention and there is no need to achieve an antithrombotic effect, then 7 days before the operation, Plagril®is recommended. A should be canceled. Plugril® A increases the 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 advised that it may take longer than usual to stop bleeding when taking Plagril® A, and that if they develop any unusual location and duration of bleeding, they should inform their doctor about this. Patients should inform the doctor (including the dentist) about the treatment with the drug before any upcoming surgical intervention and before starting to take any new medication. Plagril ® A. Thrombotic thrombocytopenic purpura Very rarely after the use of clopidogrel, cases of thrombotic thrombocytopenic purpura (TTP) have been reported, 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. Acquired hemophilias Cases of acquired hemophilia have been reported with clopidogrel. If there is a confirmed isolated increase in activated partial thromboplastin time (APTT), accompanied or not accompanied by bleeding, the development of acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated by a specialist for this condition and stop taking clopidogrel. Cross-allergic and/or hematological reactions between thienopyridines Patients should have a history of previous allergic and/or hematological reactions to other thienopyridines (such as ticlopidine, prazugrel), as cross-allergic and / or hematological reactions between thienopyridines have been reported (see section “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. Recent ischemic stroke It has been shown that in patients with a recent ischemic transient cerebrovascular accident or stroke who have an increased risk of developing an ischemic complication, the combination of acetylsalicylic acid and clopidogrel increases the possibility of major bleeding. Therefore, the use of the drug Plagril® A in such patients should be carried out with caution and only in the case of proven clinical benefit from its use. Effect on the gastrointestinal tract of Plagril® A should be used with caution in patients with a history of gastric and duodenal ulcers or gastrointestinal bleeding, or in patients with even minor symptoms from the upper gastrointestinal tract, which may be manifestations of ulcerative lesions of the stomach that can lead to gastric bleeding. Upper gastrointestinal symptoms such as gastralgia, heartburn, nausea, vomiting, and gastrointestinal bleeding may occur at any time during treatment with Plagril® A. Despite the fact that during treatment with the drug Plagril® While minor side effects from the gastrointestinal tract, such as dyspeptic disorders, are common, the doctor should always exclude ulceration of the gastrointestinal mucosa and bleeding in these cases, even if there is no history of pathology from the gastrointestinal tract. Functional activity of the CYP2C19 isoenzyme%^%In patients with low metabolic activity of the CYP2C19 isoenzyme, when using clopidogrel at the recommended doses, less of the active metabolite of clopidogrel is formed, and its effect on platelet function decreases. Therefore, such patients with acute coronary syndrome or undergoing percutaneous coronary intervention and taking clopidogrel may have a higher frequency of cardiovascular events than patients with normal activity of the CYP2C19 isoenzyme. – There may be a relationship between acetylsalicylic acid and the occurrence of life-threatening Ray’s syndrome (encephalopathy and acute fatty liver with rapid development of liver failure), usually observed in the prodromal period of infections in children. – Due to the presence of acetylsalicylic acid in the preparation, the drug Plagril® A should be prescribed to patients with glucose-6-phosphate dehydrogenase deficiency under close medical supervision (due to the risk of developing hemolysis) (seesections “With caution”, “Side effect”). – The drug contains hydrogenated castor oil, which can cause stomach upset or diarrhea. – Due to the presence of ASA in the composition of the drug, patients should be warned about the increased risk of bleeding when taking the drug Plagril® A with chronic use of large amounts of alcohol. – The drug Plagril® It is not recommended for patients with rare hereditary problems of galactose tolerance, lactase deficiency, or glucose-galactose malabsorption syndrome. Plugril® A does not significantly affect the ability to drive vehicles and engage in other potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions. However, if the patient experiences adverse side effects from the nervous system and psyche, it is possible to reduce the concentration of attention and the speed of psychomotor reactions, which may prevent such activities. In such cases, the question of the possibility of performing potentially dangerous activities should be decided by the doctor.

Form of production

Modified-release capsules

Storage conditions

At a temperature not exceeding 25 C. Keep out of reach of children!

Shelf life

1 year

Active ingredient

: Acetylsalicylic acid, Clopidogrel

Conditions of release from pharmacies

By prescription

Dosage form

long-acting capsules

Purpose

For adults as directed by your doctor

Indications

Prevention of heart attacks and strokes, Prevention of thrombosis