Instruction for use: Coplavix

Dosage form: film-coated tablets

Active substance: Acidum acetylsalicylicum+Clopidogrelum

ATX

B01AC30 Inhibitors of platelet aggregation in combination

Pharmacological groups

Antiaggregants in combinations

The nosological classification (ICD-10)

I20.0 Unstable angina: heberden disease; Angina pectoris; The attack of angina pectoris; recurrent angina; Spontaneous angina; Stable angina pectoris; Angina rest; Angina progressing; Angina mixed; Angina spontaneous; stable angina; Chronic stable angina; Angina Syndrome X

I21 Acute myocardial infarction: Myocardial infarction in the acute phase; Acute Myocardial Infarction; Myocardial infarction with pathologic Q wave and without; Myocardial infarction complicated by cardiogenic shock; Infarction left ventricular; Transmural myocardial infarction; Myocardial infarction netransmuralny (subendocardial); Netransmuralny myocardial infarction; Subendocardial myocardial infarction; The acute phase of myocardial infarction; Acute myocardial infarction;Sub-acute phase of myocardial infarction; Subacute phase of myocardial infarction; Thrombosis of the coronary arteries (the arteries); Threatened myocardial infarction; Myocardial infarction without Q wave

I24.9 Acute ischemic heart disease, unspecified: Coronary heart disease; Coronary insufficiency; Acute coronary insufficiency; Acute coronary syndrome

I25.2 Transferred last myocardial infarction: Cardiac syndrome; Myocardial infarction; post-MI; Rehabilitation after myocardial infarction; Reocclusion of the operated vessel; Angina postinfarctnaya; Status after myocardial infarction; Status after myocardial infarction; myocardial infarction

I48 Atrial fibrillation and flutter: Permanent atrial tachyarrhythmias; Relief frequent ventricular rate during atrial flutter or blink; atrial fibrillation; Paroxysm of atrial fibrillation and flutter; Paroxysm of atrial fibrillation; Paroxysmal atrial fibrillation; Atrial premature beats; Tahiaritmicheskoy atrial fibrillation; Tahisistolicheskoy atrial fibrillation; auricular flutter; Life-threatening ventricular fibrillation; Atrial fibrillation; Chronic atrial fibrillation; supraventricular arrhythmia; Paroxysmal atrial fibrillation and flutter; Paroxysmal fibrilloflutter; Atrial premature beats

I49.8 Other specified cardiac arrhythmias: atrial fibrillation; Arrhythmia Paroxysmal atrial; Atrial arrhythmia tachysystolic; sinus arrhythmia; Asynergia ventricular; Asynergia left ventricle; Corrigan's pulse; atrial fibrillation; atrial tachyarrhythmia; The migration of supraventricular pacemaker; Orthostatic changes in pulse; Disclaimer sinoatrial node; The paradoxical pulse; Paroxysm of atrial fibrillation; Paroxysmal atrial fibrillation; Paroxysmal dysrhythmia; Paroxysmal atrial-ventricular rhythm; Romano-Ward syndrome; trigemini; bigeminy

I64 Unspecified Stroke as a bleeding or heart attack: Primary stroke; Stroke; Stroke in the course of; microstroke; stroke; The completed stroke

I74 Embolism and arterial thrombosis: Thrombosis of effort (stress); Arterial thrombosis; Arteriothrombosis; Subacute and chronic arterial thrombosis; Subacute thrombosis of peripheral arteries; Postoperative thrombosis; Vascular thrombosis; Vascular embolism; Thrombosis of aortocoronary shunt; Arterial thrombosis; Thrombosis of arteries; Coronary artery thrombosis; Coronary thrombosis; Thrombosis of blood vessels; Thrombosis with ischemic stroke; Thrombosis with general surgical operations; Thrombosis in Oncology Operations; Vascular thrombosis; Thrombus formation in the postoperative period; Thrombotic complications; Thromboembolic diseases; Thromboembolic syndrome; Thromboembolic complication in the postoperative period; Thromboembolism of arteries; Partial vascular thrombosis; Embolism; Embolism of arteries

Z100 * CLASS XXII Surgical practice: Abdominal surgery; adenomectomy; Amputation; Coronary angioplasty; Angioplasty of the carotid arteries; Antiseptic skin treatment for wounds; Antiseptic Hand; Appendectomy; atherectomy; Balloon coronary angioplasty; Vaginal hysterectomy; The coronary bypass; Interventions in the vagina and cervix; Interventions on the bladder; Intervention in the mouth; Restoration and reconstructive surgery; Hand hygiene of medical personnel; Gynecologic surgery; Gynecological intervention; Gynecological surgery; Hypovolemic shock during operations; Disinfection of purulent wounds; Disinfection of wounds edges; Diagnostic intervention; Diagnostic procedures; Cervical Diathermocoagulation; Long-surgery; Replacing the fistula catheters; Infection in orthopedic surgery; Artificial heart valve; cystectomy; Short-term outpatient surgery; Short-term operation; Short surgical procedures; Krikotireotomiya; Blood loss during surgery; Bleeding during surgery and in the postoperative period; Kuldotsentez; laser photocoagulation; laser coagulation; retinal laser coagulation; Laparoscopy; Laparoscopy in Gynecology; CSF fistula; Small gynecological operations; Small surgical procedures; Mastectomy and subsequent plastic; mediastinotomy; Microsurgical operations on the ear; Mukogingivalnye operation; suturing; Minor surgery; neurosurgical operation; Immobilization of the eyeball in ophthalmic surgery; testectomy; pancreatectomy; Perikardektomiya; The period of rehabilitation after surgery; The period of convalescence after surgery; Percutaneous transluminal coronary angioplasty; Pleural thoracentesis; Pneumonia postoperative and posttraumatic; Preparation for surgical procedures; Preparation for surgery; Preparation of the surgeon's hands before surgery; Preparation of the colon for surgical procedures; Postoperative aspiration pneumonia in neurosurgical and thoracic surgery; Postoperative nausea; Postoperative bleeding; postoperative granuloma; postoperative shock; The early postoperative period; myocardial revascularization; Radiectomy; gastric Resection; bowel resection; uterine Resection; liver Resection; enterectomy; Resection of part of the stomach; Reocclusion of the operated vessel; Bonding tissues during surgical procedures; Removal of sutures; Condition after eye surgery; Condition after surgery; Condition after surgery in the nasal cavity; Condition after gastrectomy; Status after resection of the small intestine; Condition after tonsillectomy; Condition after removal of the duodenum; Condition after phlebectomy; Vascular surgery; Splenectomy; Sterilization of surgical instruments; Sterilization of surgical instruments; sternotomy; Dental surgery; Dental intervention in periodontal tissues; strumectomy; Tonsillectomy; Thoracic surgery; Thoracic surgery; total gastrectomy; Transdermal intravascular coronary angioplasty; Transurethral resection; Turbinektomiya; Removal of a tooth; cataract surgery; Removal of cysts; tonsillectomy; Removal of fibroids; Removing the mobile primary teeth; Removing polyps; Removing broken tooth; Removal of the uterus body; Removal of sutures; Fistula likvoroprovodyaschih ways; Frontoetmoidogaymorotomiya; Surgical infection; Surgical treatment of chronic limb ulcers; Surgery; The surgery in the anal area; The surgery on the colon; Surgical practice; The surgical procedure; Surgical interventions; Surgery on the gastrointestinal tract; Surgical procedures on the urinary tract; Surgical procedures on the urinary system; Surgical intervention of the genitourinary system; Surgical procedures on the heart; Surgical manipulation; surgery; Surgery on the veins; Surgical intervention; Vascular surgery; Surgical treatment of thrombosis; Surgery; cholecystectomy; Partial gastric resection; hysterectomy; Percutaneous transluminal coronary angioplasty; Percutaneous transluminal angioplasty; Coronary artery bypass; tooth Extirpation; Extirpation of milk teeth; pulpectomy; pulsative cardiopulmonary bypass; tooth Extraction; teeth Extraction; cataract extraction; Electrocoagulation; endourological intervention; episiotomy; Etmoidotomiya; Complications after tooth extraction

Composition

Active substances: Clopidogrel hydrogen sulfate in Form II 97.875 mg

(In terms of clopidogrel - 75 mg)

Acetylsalicylic acid 100 mg

Excipients

Nucleus: mannitol - 68.925 mg; Macrogol 6000 - 34 mg; MCC - 144.764 mg; Giprolose low-substituted - 19.567 mg; Castor oil hydrogenated - 3.3 mg; Stearic acid - 1.161 mg; Silicon dioxide colloidal - 0.631 mg; Corn starch - 11,111 mg

Film sheath: Opadry® pink (lactose monohydrate, hypromellose, titanium dioxide (E171), triacetin, iron dye red oxide (E172) - 20 mg, carnauba wax - traces

Description of dosage form

The tablets covered with a film cover: oval biconvex light pink color, with engraving "C75" on one side and "A100" on the other side.

Pharmachologic effect

Mode of action - antiaggregational.

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 and selectively inhibits the binding of ADP to platelet ADP receptors and 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 activation of platelets by the released ADP. Due to the irreversibility of clopidogrel binding to platelet ADP receptors, platelets remain immune to ADP stimulation for the remainder of their life span (about 7-10 days), and the restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal.

Due to the fact that the formation of the active metabolite occurs with the isoenzymes of the cytochrome P450 system, some of which may be polymorphic or 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) Acetylsalicylic acid (ASA) has a different mechanism than clopidogrel and its complementary mechanism of antiplatelet action. ASA suppresses platelet aggregation due to irreversible inhibition of COX-1, due to this reduction in the formation of thromboxane A2, which is an inducer of platelet aggregation and vasoconstriction. This effect persists for the entire life span of platelets.

ASA does not change 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 in monotherapy and with simultaneous application are able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, particularly in the lesions of the cerebral, coronary or peripheral arteries.

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

The advantage of taking clopidogrel in combination with ASA in comparison 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 greater 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 Reasons. 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 of oral administration at a dose of 75 mg / day, clopidogrel is rapidly absorbed into the intestine.

The mean Cmax of unchanged clopidogrel in 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 clopidogrel metabolites by the kidneys, its absorption is approximately 50%.

ASA. After absorption, ASA undergoes hydrolysis with the formation of salicylic acid, Cmax of which in the blood plasma is reached in 1 h after administration of ASA. Due to rapid hydrolysis, after 1.5-3 hours after ingestion of the preparation, Coplanix® ASA in the blood plasma is practically not determined.

Distribution

Clopidogrel. In vitro clopidogrel and its basic circulating inactive inactive metabolite bind reversibly to plasma proteins (by 98 and 94%, respectively), and this in vitro bond is unsaturated up to a concentration of 100 mg / l.

ASA

ASA weakly binds to plasma proteins and has a small Vd (10 L). Its metabolite, salicylic acid, binds well to blood plasma proteins, but its association with plasma proteins depends on its concentration in the blood plasma (nonlinear bonding). At low concentrations (<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 is intensively 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 derivative of carboxylic acid (accounting for 85% of circulating metabolites in the systemic bloodstream); The second way is metabolism with the help of several isoenzymes of the cytochrome P450 system. At the same time, clopidogrel is first 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. The active metabolite is formed predominantly with the help of CYP2C19 with the participation of some other isoenzymes, including CYP1A2, CYP2B6 and CYP3A4. The active thiol clapidogrel metabolite, which was isolated in in vitro studies, quickly and irreversibly binds to platelet receptors, inhibiting platelet aggregation.

After taking a loading dose of clopidogrel, 300 mg of active metabolite Cmax is 2 times greater than that after receiving a maintenance dose of clopidogrel 75 mg for 4 days, while its Cmax is approximately 30-60 minutes after taking clopidogrel.

ASA when taken in combination with clopidogrel quickly undergoes hydrolysis in blood plasma to salicylic acid with T1 / 2, 0.3-0.4 h for doses of ASC 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 of 14C-labeled clopidogrel, about 50% of the radioactivity is released by the kidneys and about 46% through the intestine. After a single oral dose of 75 mg of T1 / 2 clopidogrel is approximately 6 hours. After a single and course administration of clopidogrel, T1 / 2 of the main circulating inactive inactive metabolite is 8 hours.

ASA. When taking the drug, Coplavix® salicylic acid has T1 / 2 from the blood plasma, approximately 2 hours. Salicylate metabolism 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 g), plasma T1 / 2 may increase 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 plasma concentration) with T1 / 2 , Which is 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 salicyluric 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

With the help of the CYP2C19 isoenzyme, both an active metabolite and an 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 (in vitro, the study of platelet aggregation in blood taken from a patient taking clopidogrel inwards, ie after the metabolism of clopidogrel in the body) varies depending on the genotype of the isoenzyme CYP2C19.

The allele of the CYP2C19 * 1 isoenzyme gene corresponds to fully functional metabolism, whereas the CYP2C19 * 2 and CYP2C19 * 3 isoenzyme genes are non-functional. Alleles of the CYP2C19 * 2 and CYP2C19 * 3 isoenzymes genes cause a decrease in metabolism in the majority of representatives of the Caucasoid (85%) and Mongoloid races (99%). Other alleles associated with lack or decrease in metabolism are less common and include, but are not limited to, the alleles of the CYP2C19 * 4, * 5, * 6, * 7, and * 8 isoenzymes. A patient with a low activity of the CYP2C19 isoenzyme will have the two alleles of the above gene with loss of function. Published frequency of occurrence in general populations of people with a phenotype with a low activity of the isoenzyme CYP2C19 is: in Caucasoid - 2%, Negroid - 4% and Chinese - 14%. To determine the patient's existing CYP2C19 isoenzyme genotype there are corresponding tests.

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

When volunteers with low activity of the CYP2C19 isoenzyme took clopidogrel according to the scheme: 600 mg - loading dose / 150 mg - maintenance dose (600/150 mg), the exposure of the active metabolite was higher than when taking clopidogrel according to the scheme: 300/75 mg. In addition, IAT was similar to that in patients receiving clopidogrel with a higher metabolic rate with the CYP2C19 isoenzyme, taking clopidogrel under the 300/75 mg schedule. However, in studies with clinical outcomes, the dosage regimen of clopidogrel for patients in this group (patients with low activity of the isoenzyme CYP2C19) has not yet been established. 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 a low activity of the CYP2C19 isoenzyme.

Individual patient groups

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

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

Children and teenagers. No data available.

Patients with impaired renal function. After repeated use of clopidogrel at a dose of 75 mg / day in patients with severe renal dysfunction (Cl creatinine - from 5 to 15 ml / min), inhibition of ADP-induced platelet aggregation was lower (25%) than in healthy volunteers, however The lengthening of bleeding time was similar to that of healthy volunteers taking clopidogrel at a dose of 75 mg / day.

Patients with impaired liver function. After daily administration of clopidogrel at a daily dose of 75 mg for patients with severe liver function abnormalities (greater than 9 on the Child-Pugh scale) for 10 days, the inhibition of ADP-induced platelet aggregation was similar to that of healthy volunteers. The mean bleeding time was also comparable in both groups.

Ethnicity. The prevalence of alleles of the CYP2C19 isoenzyme genes responsible for intermediate and decreased metabolism differs among representatives of different ethnic groups. There are limited literature data on their prevalence among representatives of the Mongoloid race, which does not allow to assess the clinical significance of the influence of the CYP2C19 isoenzyme genotypes on clinical outcomes. Based on the pharmacokinetics and metabolic peculiarities of both active substances of the Coplawix ® preparation, clinically significant pharmacokinetic interactions are not expected between them.

Indications for Coplavix

This combination drug is indicated for use in patients who are already receiving clopidogrel and ASA simultaneously (see "Dosage and Administration").

Prevention of atherothrombotic complications:

Adult patients with acute coronary syndrome:

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

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

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

Adult patients with atrial fibrillation (atrial fibrillation) who have at least 1 risk factor for vascular complications, cannot 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 insufficiency (more than 9 on the Child-Pugh scale);

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

Acute bleeding, eg bleeding from peptic ulcers or intracranial hemorrhage;

The bronchial asthma, induced by the intake of salicylates and other 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 shock, with skin flushing, lowering of blood pressure, tachycardia and vomiting (due to the content of the ASA preparation);

Rare hereditary conditions: galactose intolerance; Lactose intolerance due to lactase deficiency; Syndrome of malabsorption of glucose-galactose (due to the content of lactose in the formulation);

pregnancy;

The period of breastfeeding (see "Application in pregnancy and lactation");

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

With caution: moderate hepatic insufficiency (7-9 points on the Child-Pugh scale), in which predisposition to bleeding is possible (limited clinical experience of use); Renal failure of mild to moderate severity (Cl creatinine 60-30 ml / min) (limited clinical experience); Trauma, surgery, including invasive cardiac procedures or surgical procedures (see "Special instructions"); Diseases in which there is a predisposition to the development of bleeding, especially intraocular or gastrointestinal (gastric ulcer and duodenal ulcer or gastrointestinal hemorrhage in history, symptoms of violations of the upper GI tract); Recent transient ischemic stroke or ischemic stroke (see "Special instructions"); Simultaneous application of NSAIDs, including selective inhibitors of COX-2 (see "Interaction"); Simultaneous use of warfarin, heparin, glycoprotein IIb / IIIa inhibitors, selective serotonin reuptake inhibitors (SSRIs), and thrombolytic agents (see "Interaction" and "Special instructions"); Bronchial asthma and an allergy in the anamnesis (increased risk of allergic reactions to ASA); Gout, hyperuricemia (ASA, including low doses, increases the concentration of uric acid in the blood); Simultaneous reception of alcohol (ethanol) (because of the presence of ASA in the formulation, see "Interaction" and "Special instructions"). Patients with a genetically determined decrease in the activity of the isoenzyme CYP2D9 (see "Pharmacokinetics", subsection Pharmacogenetics, "Method of administration and dose", "Special instructions"); Patients with deficiency of glucose-6-phosphate dehydrogenase (due to the risk of hemolysis) (see "Side effects", "Special instructions"); Simultaneous use of methotrexate in a dose of more than 20 mg / week (see "Interaction"); The presence of indications in the anamnesis for allergic and hematological reactions to other thienopyridines (such as ticlopidine, prasugrel) (the possibility of cross-allergic and hematological reactions, see "Special instructions"); Simultaneous use of drugs associated with the risk of bleeding and drugs that are substrates of the isoenzyme CYP2C8 (such as repaglinide, paclitaxel) - because of the identified drug interaction.

Pregnancy and breast-feeding

As a precaution, Coplavix® should not be taken during the first two trimesters of pregnancy, unless 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. Animal studies did not reveal either direct or indirect adverse effects on clopidogrel during pregnancy, embryonic development, childbirth and postnatal development.

However, sufficient in terms of volume and controlled studies in pregnant women was not conducted. ASC has been shown to have a teratogenic effect, although it has been established in clinical studies that doses of ASA up to 100 mg / day, restricted in obstetrics and requiring specialized monitoring, have shown themselves to be safe.

Breastfeeding should be discontinued in the case of treatment with Coplavix®; Found 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. Whether clopidogrel is released into human breast milk is unknown.

Side effects

The safety of clopidogrel in clinical studies has been studied in more than 44,000 patients, incl. More than 12,000 patients taking it for a year or more, and 30,000 patients taking clopidogrel and ASA concomitantly; In a clinical study of CURE, the safety of clopidogrel in combination with ASA was evaluated in more than 6,200 patients who took them for 1 year or more.

The clinically relevant adverse effects observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE A, and in the post-marketing application of a combination of clopidogrel + ASA, clopidogrel in monotherapy and ASA in monotherapy, are listed below.

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 frequency of NE arising from available data.

Conventional notation. 1NE, which were observed with the use of a combination of clopidogrel and ASA. 2NE, which were observed with the use of clopidogrel. 3NE, which were observed with the use of ASA.

Hemorrhagic adverse events (purpura / bruising, nasal bleeding, hematuria, hemorrhages in skin tissues, bones and muscles, hematomas, hemorrhages in the joint cavity (hemarthrosis), conjunctiva, in the internal environment 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 they occurred during the 1st month of treatment : Often - large bleeding1 (life-threatening bleeding, requiring transfusion of 4 or more blood units, other large bleeding requiring 2-3 blood transfusions, no life-threatening large bleeding (according to the COMMIT study, the incidence of major non-cerebral bleeding and intracranial hemorrhage was " Infrequently ") 1; Small bleeding (according to the ACTIVE-A study, the incidence of small bleeding was "very frequent"), 1 bleeding at the site of vascular puncture1,2; Bruising; Hematomas. The frequency of major bleeding with the use of a combination of 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 the use of a single ASA (<100 mg - 2%, 100-200 mg - 2.3%,> 200 mg - 4%). Patients who discontinued treatment more than 5 days prior to coronary artery bypass grafting did not experience an increase in cases of major bleeding within 7 days after this intervention (4.4% - with clopidogrel + ASA versus 5.3% - with single ASA). In patients who remained antiplatelet therapy for the last five days before coronary artery bypass grafting, the incidence of these bleeding after intervention was 9.6% (clopidogrel + ASA) and 6.3% (one ASA); Infrequently - bleeding with a lethal outcome1; Life-threatening bleeding (hemorrhage with a decrease in blood hemoglobin of more than 5 g / dL (according to the CLARITY clinical trial, the frequency of their development was "frequent"); 1 bleeding requiring surgery; 1 intracranial hemorrhage (hemorrhagic strokes) (according to the clinical study CLARITY frequency of their development was "often") 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 (postmarketing experience) - serious cases of bleeding2, mainly hemorrhage in the skin tissue2, bones, muscles and joint cavity (hemarthrosis) 2, in the eye tissue (conjunctival, in the internal environment and the retina) 2, bleeding from the respiratory tract2 , Hemoptysis2, nasal bleeding2, hematuria2, bleeding from operating wound2; Intracranial hemorrhage, 3 including fatal cases, 3 especially in elderly patients; Other cases of bleeding with a fatal outcome (in particular bleeding from the gastrointestinal tract and retroperitoneal hemorrhage) 2.

On the part of the blood and lymphatic system: infrequently - a decrease in the number of platelets in the peripheral blood, 1 severe thrombocytopenia with a platelet count in the peripheral blood <80 · 109 / l, but> 30 · 109 / l1; Leukopenia; A decrease in the number of neutrophils in peripheral blood, 1 eosinophilia, 1 an extension of bleeding time; Rarely - neutropenia1, including severe neutropenia (<0.451 · 109 / L) 1. Although the risk of myelotoxic effects when using clopidogrel is low enough, its potential should be considered when a patient taking clopidogrel develops fever and other infectious manifestations; Very rarely - aplastic anemia1, severe thrombocytopenia with a platelet count in peripheral blood <30 · 109 / l1; Frequency unknown (postmarketing experience) - thrombocytopenia3, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency3, agranulocytosis2,3; Aplastic anemia 2,3 / pancytopenia 2,3, bicitopenia, 3 bone marrow hematopoiesis, 3 neutropenia, 3 leukopenia, 3 granulocytopenia, 3 anemia, 1 acquired hemophilia A2, thrombotic thrombocytopenic purpura (TTP) 2.

From the central and peripheral nervous system: infrequently - headache1, dizziness1 and paresthesia1; Rarely - vertigo1; Frequency is unknown (postmarketing experience) - changes in taste sensations2.

From the digestive system: often - gastrointestinal bleeding1, dyspepsia1, abdominal pain1, diarrhea1; Infrequently - nausea, gastritis, meteorism, constipation, vomiting, gastric ulcer and duodenal ulcer; Frequency is unknown (post-marketing experience) - colitis 2,3 (including ulcerative or lymphocytic colitis) 2, pancreatitis 2, stomatitis 2, esophagitis 3, ulceration / perforation of esophagus 3, erosive gastritis3, erosive duodenitis3, ulcer or peptic ulcer of stomach and / or duodenum3, Upper gastrointestinal tract, such as gastralgia3 (see "Special instructions"), ulcers of the small intestine (lean and ileum) 3 and large intestine (colon and rectum) 3, perforation of the intestine3 (these reactions may or may not be accompanied by bleeding and may Arise with the use of 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 a hypersensitivity reaction to acetylsalicylic acid.

From the liver and bile ducts: the frequency is unknown (postmarketing experience) - hepatitis (non-infectious nature) 2, acute liver failure2, increased activity of "liver" enzymes3, liver damage, mainly hepatocellular3, chronic hepatitis3.

From the skin and subcutaneous tissues: infrequently - skin rash1, itd1; Frequency is unknown (post-marketing experience) - maculopapular, erythematous or exfoliative skin rash2, urticaria2, itching2, angioedema, 2 bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) 2, acute generalized exanthematous pustulosis, 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 drug intake ) 3.

From the side of the immune system: the frequency is unknown (postmarketing experience): anaphylactoid reactions2, serum sickness2, cross-reactive hypersensitivity reactions with other thienopyridines (such as ticlopidine, prasugrel) 2 (see "Special instructions"), anaphylactic shock3, increased symptoms of food allergy3.

Disorders of the psyche: frequency unknown (postmarketing experience) - confusion 2, hallucinations2.

On the vascular side: the frequency is unknown (post-marketing experience) - vasculitis2,3, including purple Shenlaine-Genoha3, decreased AD2.

From the heart: the frequency is unknown (postmarketing experience) - the syndrome of Kounis (allergic coronary syndrome), caused by the reaction of hypersensitivity to ASK3.

On the part of the respiratory system, chest and mediastinum: the frequency is unknown (post-marketing experience) - bronchospasm2, interstitial pneumonitis2, eosinophilic pneumonia2, noncardiogenic pulmonary edema in chronic drug administration associated with hypersensitivity reaction3.

From the musculoskeletal and connective tissue: the frequency is unknown (post-marketing experience) - arthralgia2, arthritis2, myalgia2.

From the side of the kidneys and urinary tract: frequency is unknown (postmarketing experience) - glomerulopathy, including glomerulonephritis, 2 acute renal dysfunction (especially in patients with pre-existing renal failure, CHF decompensation, nephritic syndrome, or in patients taking diuretics simultaneously) 3, renal Insufficiency3.

General disorders: frequency unknown (postmarketing experience) - fever2.

From the genitals and the breast: the frequency is unknown (postmarketing experience) - gynecomastia2.

Laboratory and instrumental data: the frequency is 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.

From the side of metabolism and nutrition: the frequency is unknown (post-marketing experience) - hypoglycemia3, gout.

From the side of the hearing organ and labyrinthine disorders: the frequency is unknown (post-marketing experience) - hearing loss3, tinnitus3.

General disorders and disorders at the site of administration: swelling, reported when taking ASA in high (anti-inflammatory) doses.

Interaction

Drugs associated with risk of bleeding

There is an increased risk of bleeding due to the potential additive effect. Simultaneous use of 23 drugs associated with the risk of bleeding should be done with caution.

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 drugs and heparin with ASA. Due to the lack of clinical data on the joint use of Coplavix® and thrombolytic drugs, when combined, care should be taken (see "Special instructions").

Inhibitors of glycoprotein IIb / IIIa

Between the inhibitors of glycoprotein IIb / IIIa and the preparation of Coplavix®, pharmacodynamic interaction is possible, which requires caution when they are used together.

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 Coplawiks ® and heparin pharmacodynamic interaction is possible, which may increase the risk of bleeding, and therefore the joint use of these drugs requires caution (see "Special instructions").

Indirect anticoagulants

Simultaneous administration of Coplavix® and oral anticoagulants (warfarin) 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 value of INR in patients taking long-acting warfarin. However, simultaneous administration of warfarin with clopidogrel may increase the risk of bleeding due to the independent effect of these drugs on hemostasis.

NSAID

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, incl. Inhibitors of COX-2, in combination with the preparation of Coplavix® is not recommended (see "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 at a dose of 81 mg in the immediate-release dosage form) 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.

SSRIs

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

Another combination therapy with clopidogrel

Strong and moderate inhibitors of the isoenzyme CYP2C9. 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 can 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 inhibitors of the CYP2C9 isoenzyme should be avoided. Strong and moderate inhibitors of the CYP2C9 isoenzyme are omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol. The simultaneous use of proton pump inhibitors with clopidogrel, which are strong or moderate inhibitors of the CYP2C19 isoenzyme (eg omeprazole, esomeprazole), is not recommended. If a patient still needs the use of proton pump inhibitors while taking Coplawix®, a proton pump inhibitor with little effect on the activity of the CYP2C19 isoenzyme, such as pantoprazole or lansoprazole, should be used.

Drugs that are substrates of the isoenzyme CYP2C8. Clopidogrel increased the systemic exposure of repaglinide in healthy volunteers. In vitro studies have shown that an increase in the systemic exposure of repaglinin is a consequence of the inhibition of the isoenzyme CYP2C8 by the glucuronide metabolite clopidogrel. Caution should be exercised while using clopidogrel and medications that are primarily excreted from the body by metabolism using the CYP2C8 isoenzyme (eg, repaglinide, paclitaxel).

A number of clinical studies with clopidogrel and other concomitant drugs were used to study the possible pharmacodynamic and pharmacokinetic interactions that showed:

- that when using clopidogrel together with atenolol, nifedipine or both these drugs taken simultaneously, clinically significant pharmacodynamic interaction was not observed;

- simultaneous use of phenobarbital, cimetidine and estrogens did not significantly affect the pharmacodynamics of clopidogrel;

- pharmacokinetic indices of digoxin and theophylline did not change when they were used together with clopidogrel;

- Antacid drugs did not reduce the absorption of clopidogrel;

- Phenytoin and tolbutamide can safely be used concomitantly with clopidogrel (CAPRIE study), although the data obtained from studies with human liver microsomes indicate that the carboxylic metabolite of clopidogrel can inhibit the activity of the CYP2C9 isoenzyme, which can lead to increased concentrations In the blood plasma of some drugs, for example, phenytoin, tolbutamide and certain NSAIDs that are metabolized by the CYP2C9 isoenzyme.

Another combination therapy with ASA

The interaction of ASA with the following drugs was reported:

- uricosuric drugs (preparations that promote the excretion of uric acid, benzbromarone, probenecid, sulfinpyrazone) - care must be taken since ASA can suppress their uricosuric effect due to competition with uric acid at the elimination level;

- Methotrexate, taken in doses of more than 20 mg / week, should be used with caution when combined with a preparation of Coplavix® (due to the presence of ASA in the formulation), because ASA can reduce the renal clearance of methotrexate, which in turn can increase its myelotoxic effect (see With caution);

- 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 a low dose of ASA for cardioprotective action;

-acetazolamide - caution should be exercised when using salicylates and acetazolamide simultaneously, because of the increased risk of developing metabolic acidosis;

- vaccine against varicella - it is recommended that patients do not take salicylates for 6 months after vaccination against chicken pox because During the disease with chicken pox, there were cases of development of Ray's syndrome after the intake of salicylates (see "Special instructions");

- levothyroxine - salicylates, especially at doses of more than 2.0 g / day, can inhibit the binding of thyroid hormones to carrier proteins and therefore lead to an initial transient increase in the concentrations of free thyroid hormones, followed by a decrease in their concentrations. Monitor thyroid hormone concentrations (see "Specific guidance");

- valproic acid - simultaneous application of valproic acid and salicylates may lead to a decrease in the binding of valproic acid to blood proteins and inhibition of valproic acid metabolism, leading to an increase in the total serum concentration of valproic acid and the serum concentration of its free fraction;

- tenofovir - simultaneous use of tenofovir, dizoproxil fumarate and NSAIDs may increase the risk of developing kidney failure;

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

- ethanol - with the simultaneous use of ASA, the risk of bleeding increases with chronic use of large amounts of alcohol (ethanol). In addition, ethanol may increase the risk of gastrointestinal damage when applying ASA. Therefore, patients taking ASA should drink alcohol (ethanol) with caution (see "Special instructions").

Other interactions with clopidogrel and ASA

- ACE inhibitors, diuretics, beta-adrenoblockers, CCB, lipid-lowering drugs, coronary vasodilators, hypoglycemic drugs (including insulin), antiepileptic drugs, hormone replacement therapy and glycoprotein receptors blockers GPIIb / IIIa - in clinical studies on the use of clopidogrel in Combinations with ASC in maintenance doses (<325 mg), conducted with the participation of more than 30,000 patients, there were no clinically significant adverse interactions with these drugs.

Dosing and Administration

Inside, 1 time per day, regardless of food intake.

Adults and elderly patients with normal activity of the isoenzyme CYP2C19

Acute coronary syndrome (ACS). Treatment begins as soon as possible after the onset of symptoms. Reception of the drug Coplavix ® is started after taking a single loading dose of clopidogrel in combination with ASA in the form of separate drugs, namely clopidogrel - 300 mg and ASA - at doses of 75-325 mg / day, and with acute myocardial infarction with ST segment elevation - 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 ASC should not exceed 100 mg. In acute myocardial infarction with ST segment elevation in patients older than 75 years, treatment with clopidogrel should begin without taking its loading dose. In patients with ACS without ST segment elevation (unstable angina or myocardial infarction without Q wave), the maximum beneficial effect is observed by the 3rd month of treatment. The optimal duration of treatment is not officially defined. Clinical trials support drug administration up to 12 months. In patients with acute myocardial infarction with elevation of the ST segment, treatment should be continued for at least 4 weeks.

Atrial fibrillation. Coplavix ® should be taken once a day, after the start of treatment with clopidogrel at a dose of 75 mg and ASA at a dose of 100 mg in the form of individual drugs.

Patients with genetically determined reduced activity of the isoenzyme CYP2C19

The low activity of the isoenzyme 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 isozyme activity CYP2C19 increases the antiplatelet effect of clopidogrel (see "Pharmacokinetics"). However, at the present time 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 caused low activity of the CYP2C19 isoenzyme.

Special patient groups

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

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

Patients with hepatic insufficiency. The therapeutic experience of the drug is limited to use in patients with mild liver disease, which may have a tendency to develop hemorrhagic diathesis. Therefore, when using Coplavix® in such patients, care should be taken.

Patients with renal insufficiency. There is limited therapeutic experience with the drug in patients with mild to moderate renal failure. Therefore, when using Coplavix® in such patients, care should be taken.

Overdose

Clopidogrel

Symptoms: an overdose of clopidogrel may lead to an increase in bleeding time with subsequent complications in the form of bleeding.

Treatment: when bleeding occurs, appropriate treatment is required. The antidote of clopidogrel is not established. If rapid correction of prolonged bleeding time is necessary, transfusion of platelet mass is recommended.

ASA

Symptoms: a moderate degree of overdose - dizziness, ringing in the ears, headaches, confusion and symptoms of 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 in the blood, metabolic acidosis develops. In addition, the following symptoms appear: hyperthermia and profuse 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.

Lethal dose of ASA 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, non-cardiogenic pulmonary edema may develop (see "Side effect").

Treatment: when diagnosing severe overdose, hospitalization is required. With moderate intoxication, one can try to induce vomiting, in case of failure, gastric lavage is indicated. After this, take inside (if the patient can swallow) or enter into the stomach through the probe activated charcoal (adsorbent) and salt laxative. For the purpose of forced alkalinization of urine, 250 mg of sodium bicarbonate is dripped intravenously for 3 hours under the control of the pH of the urine and the acid-base state to accelerate the elimination of salicylates. The preferred treatment for severe overdose is hemodialysis or peritoneal dialysis. If necessary, symptomatic treatment of other manifestations of intoxication is used.

Precautionary measures

Bleeding and blood disorders

In connection with the risk of bleeding and hematological adverse effects (see "Side effects"), if clinical symptoms that are suspect for bleeding occur during treatment, it is urgent to make a general clinical blood test, determine APTT, the number of platelets in peripheral blood, Functional activity of thrombocytes and to conduct other necessary studies.

The simultaneous use of the drug Coplavix® with warfarin is not recommended; This can increase the intensity of bleeding (see "Interaction").

Due to the presence of two antiplatelet agents in the preparation of Coplavix®, it should be used with caution in patients at increased risk of bleeding due to trauma, surgery or other pathological conditions, as well as in patients taking NSAID (including inhibitors COX-2), heparin, glycoprotein IIb / IIIa inhibitors, SSRIs and thrombolytics.

It is necessary to carefully monitor patients for the exclusion of signs of bleeding, incl. And latent, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgical intervention.

If the patient is scheduled surgical intervention and there is no need for an antithrombotic effect, clopidogrel should be discontinued 5-7 days before surgery. Coplavix® 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 cautioned that they may need more time to stop bleeding when taking Coplavix® to stop bleeding 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 starting any new drug, patients should inform the doctor (including the dentist) about Coplavix® treatment.

Recently suffered ischemic stroke

It has been shown that in patients with recent transient ischemic cerebrovascular disorders or stroke having an increased risk of developing a recurrent ischemic complication, the combination of ASA and clopidogrel increases the possibility of developing large bleeding. Therefore, the use of Coplawix ® in such patients should be carried out with caution and only in the case of clinical benefit from its use.

TTP

Very rarely, after the use of clopidogrel (sometimes even briefly), there have been cases of TTP development, 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 the confirmed isolated increase in APTT, accompanied or not accompanied by the development of bleeding, consideration should be given to the possibility of developing acquired hemophilia. Patients with a confirmed diagnosis of acquired hemophilia should be observed and treated by specialists in this disease and stop taking clopidogrel.

Atrial fibrillation (atrial fibrillation)

In patients with atrial fibrillation who had an increased risk of developing cardiovascular complications who could take indirect anticoagulants, the advantage of indirect anticoagulants compared to ASA monotherapy or the use of clopidogrel + ASA in reducing the risk of stroke was shown.

Cross-allergic and / or hematologic reactions between thienopyridines

Patients should collect anamnesis for the presence of previously allergic and / or hematologic reactions to other thienopyridine (such as ticlopidine, prasugrel), because they have a history. Reported the presence of cross-allergic and / or hematological reactions between thienopyridines (see "Side effects"). Tienopyridines can cause mild to severe allergic reactions (such as rash, angioedema) or hematologic reactions (such as thrombocytopenia and neutropenia). Patients who had 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 CYP2C19 isoenzyme, when clopidogrel is used in the recommended doses, less active clopidogrel metabolite is formed and its effect on platelet function is reduced. Therefore, such patients with ACS or patients undergoing percutaneous coronary intervention and taking clopidogrel may have a higher incidence of cardiovascular events than patients with normal CYP2C19 isoenzyme activity. There are tests to determine the genotype CYP2C19, these tests can be used to select a therapeutic strategy. The use of higher doses of clopidogrel in patients with a low activity of the isoenzyme CYP2C19 is considered (see "Pharmacokinetics", Pharmacogenetics, Precautions, "Method of administration and dose"), but the efficacy and safety of the use of increased doses of clopidogrel in patients with low activity of the isoenzyme CYP2C19 Have not been established to date.

Renal insufficiency

Clopidogrel + ASA should not be used in patients with severe renal failure (see section "Contraindications"). The experience of using clopidogrel in patients with mild and moderate renal failure is limited. Therefore, in this group of patients the combination of clopidogrel + ASA should be used with caution.

Liver failure

Clopidogrel + ASA should not be used in patients with severe hepatic impairment (see "Contraindications"). The experience of using clopidogrel in patients with moderate liver disease, which may have a predisposition to bleeding, is limited. Therefore, in this group of patients, clopidogrel + ASA should be used with caution.

Caution required due to the presence of ASA in the formulation

- in patients with bronchial asthma or other allergic diseases in the anamnesis, t. They have an increased risk of developing hypersensitivity reactions;

- in patients with gout, t. Low doses of ASA increase the concentration of urate in the blood;

- there may be an association between ASA and the development of Reye's syndrome, a rare and life-threatening disease commonly seen in the prodromal period of infections in children, resulting in the development of encephalopathy and acute fatty liver disease and the rapid development of liver failure that can lead to death;

- Ethanol may increase the risk of GI loss when taking it against the background of ASA treatment. Therefore, care should be taken when using alcohol (ethanol) during the treatment of ASA (see "Interaction"). In addition, patients should be warned about the risk of bleeding due to chronic use of large amounts of alcohol (ethanol) during the administration of a combination of clopidogrel + ASA;

- Coplavix® should be used under close medical supervision in patients with glucose-6-phosphate dehydrogenase deficiency (G6FD) because of the risk of hemolysis (see "With caution", "Side effects");

- simultaneous administration of levothyroxine and salicylates should be avoided, especially at doses above 2 g / day (see "Interaction").

Effect on the digestive tract

Coplavix® should be used with caution in patients with gastric ulcer and duodenal ulcer or gastrointestinal hemorrhage in the history or patients with even minor symptoms from the upper gastrointestinal tract, which may be manifestations of ulcerative gastric lesions that can lead to gastric bleeding.

When treating Coplavix® at any time, there may be symptoms from the upper parts of the digestive tract, such as gastralgia, heartburn, nausea, vomiting and gastrointestinal bleeding. Despite the fact that in the treatment of Coplavix®, 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 GI tract and are instructed that, if they occur, they should immediately seek medical help.

Other

The drug contains hydrogenated castor oil, which can cause gastric upset or diarrhea.

Influence on the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. Usually Coplavix® does not significantly affect the ability to drive vehicles and engage in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions. However, in the case of unfavorable adverse reactions from the nervous system and the psyche (see "Side effects"), the concentration and speed of psychomotor reactions may decrease, 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.

Release form

Tablets, film-coated, 100 mg + 75 mg. By 7 tab. In PA / Al / PVC / aluminum blister. By 1, 2 or 4 bl. Placed in a cardboard box.

For 10 tab. In PA / Al / PVC / / aluminum blister. At 10 bl. Placed in a cardboard box.

Manufacturer

Sanofi Winthrop Industry, France.

Sanofi Wintrop Industrie, France. 1 rue de la Vierge, Ambares et Lagrave F-33565, Carbon Blanc Cedex, France.

The owner of the registration certificate: Sanofi Pharma Bristol-Myers Squibb EsenSi, France.

Claims of consumers should be sent to the address in Russia: 125009, Moscow.

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Coplavix

At a temperature no higher than 25 ° C.

Keep out of the reach of children.

The shelf life of the drug Coplavix

2 years.

Do not use beyond the expiration date printed on the package.