Coplviks - instructions for use, doses, side effects, contraindications

Active substanceAcetylsalicylic acid + ClopidogrelAcetylsalicylic acid + Clopidogrel

Similar drugsTo uncover

Clopigrant® A

capsules inwards

Micro Labs Limited India

Coplavix®

pills inwards

Sanofi Pharma Bristol-Myers Squibb EsenSi France

Dosage form: & nbspfilm coated tablets

Composition:

One tablet contains:

active ingredients: clopidogrel hydrogen sulfate in the form II - 97,875 mg (in terms of clopidogrel - 75 mg), acetylsalicylic acid - 100 mg; Excipients:

core: Mannitol - 68,925 mg, macrogol-6000 - 34,000 mg, microcrystalline cellulose - 144,764 mg, low-substituted giprolose - 19.567 mg, castor oil hydrogenated - 3,300 mg, stearic acid - 1,161 mg, silicon colloidal dioxide - 0,631 mg, corn starch -11,111 mg;

shell: Opadrai® pink * - 20.0 mg, carnauba wax - traces.

* - Opadrai® pink contains lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, iron oxide red (E 172).

Description:Oval biconvex tablets covered with a filmy coating of light pink color with C75 engraving on one side and A100 on the other side.

Pharmacotherapeutic group:Antiaggregant agent

ATX: & nbsp

B.01.A.C Inhibitors of platelet aggregation (excluding heparin)

Pharmacodynamics:

Clopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation.Its active metabolite irreversibly binds to platelet ADP receptors (adenosine diphosphate receptors) and selectively inhibits the binding of ADP to ADP receptors of platelets and subsequent activation of the complex GPIIb/IIIa under the action of ADP, due to which ADP-induced aggregation of platelets is suppressed. Clopidogrel also inhibits platelet aggregation caused by other agonists, due to the fact that it blocks the activation of platelets by the released ADP. 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.

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

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

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

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

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

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

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

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

Pharmacokinetics:

Suction

Clopidogrel

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

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

ASA

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

Distribution

Clopidogrel

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

ASA

ASA weakly binds to proteins in the blood plasma and has a small volume of distribution (10 liters). Her metabolite - salicylic acid - binds well to blood plasma proteins, but its relationship to blood plasma proteins depends on its concentration in the blood plasma (nonlinear connection). At low 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

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo Clopidogrel is metabolized by 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: metabolism with several isoenzymes of the cytochrome P450 system. At the same time, in the beginning clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite.Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of an active metabolite of clopidogrel-thiol clopidogrel derivative. In vitro this pathway of metabolism occurs by means of isoenzymes CYP2C19, CYP1A2, CYP3A4 and CYP2B6. The active thiol metabolite of clopidogrel, which was isolated in studies in vitro, quickly and irreversibly binds to platelet receptors, inhibiting the aggregation of platelets.

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

ASA

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

Excretion

Clopidogrel

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

ASA

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

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

Pharmacogenetics

Using isoenzyme CYP2C19 formed as an active metabolite, and an intermediate metabolite - 2-oxo-clopidogrel. Pharmacokinetics and antiplatelet effect of the active metabolite clopidogrel in the study of platelet aggregation ex vivo (in vitro study of platelet aggregation in the blood taken from the patient taking clopidogrel inside, that is, after the metabolism of clopidogrel in the body) vary depending on the genotype of the isoenzyme CYP2C19. Allele of the isoenzyme gene CYP2C19*1 corresponds to fully functional metabolism, whereas alleles of isoenzyme genes CYP2C19*2 and CYP2C19*3 are non-functional. Alleles of isoenzyme genes CYP2C19*2 and CYP2C19*3 are the cause of a decrease in metabolism in the majority of representatives of the Caucasoid (85%) and Mongoloid races (99%).Other alleles that are associated with a lack or decrease in metabolism are less common and include but are not limited to alleles of isoenzyme genes CYP2C19M, * 5, * 6, * 7 and * 8. A patient with a low isoenzyme activity CYP2C19 will have the two alleles of the above gene with loss of function. Published frequencies of occurrence in general populations of people with a phenotype with a low isoenzyme activity CYP2C19 are: for Caucasians 2%, for Negroids 4% and for Chinese 14%. To determine the patient's isoenzyme genotype CYP2C19 there are corresponding tests.

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

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

Individual patient groups

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

- Elderly people

In elderly volunteers (older75 years), when compared with young volunteers, there was no difference in platelet aggregation and bleeding time. Do not require dose adjustment for the elderly.

- Children and teens

No data available.

- Patients with impaired renal function

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

- Patients with impaired hepatic function

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

- Ethnicity

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

Based on the pharmacokinetics and metabolic peculiarities of both active substances of the Coplawix ® preparation, no clinically significant pharmacokinetic interactions are expected between them.

Indications:

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

Prevention of atherothrombotic complications

- In adults with acute coronary syndrome: without segment elevation ST (unstable angina or myocardial infarction without a tooth Q), including patients who underwent stenting with percutaneous coronary intervention; with segment lift ST (acute myocardial infarction) with drug treatment and the possibility of carrying out thrombolysis.

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

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

Contraindications:

Hypersensitivity to any of the auxiliaries of the drug.

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

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

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

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

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

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

Pregnancy and the period of breastfeeding (see distributed "Use during pregnancy and the period of breastfeeding").

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

Carefully:

With moderate hepatic insufficiency (7-9 points Po scale Child-Pugh), at which predisposition to bleeding is possible (limited clinical experience of use).

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

With injuries, surgical interventions, including invasive cardiological procedure or surgical intervention (see section "Special instructions").

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

At recently transferred transient infringement of a cerebral circulation or an ischemic stroke (see section "Species").

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

With the simultaneous use of warfarin, heparin, a glycoprotein inhibitor IIb/IIIa, selective serotonin reuptake inhibitors (SSRIs) of thrombolytic drugs (see the sections "Interaction of other drug means "and" Special instructions ") With bronchial asthma and an allergy in the anamnesis (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 isoenzyme activity CYP2C19 (see section "Pharmacokinetics", subsection "Pharmacokinetics", sections "Method of administration and dose", "Special instructions").

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

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

With history of allergic and hematologic reactions to other thienopyridine (such as ticlopidine, prasugrel) (the possibility of cross-allergic and hematological reactions, see the section "Special instructions").

Pregnancy and lactation:

Pregnancy

As a precaution, Coplawix® 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 volume and controlled studies in pregnant women were not conducted. ASC has been shown to be teratogenic, although clinical studies have found that doses of ASA to 100 mg / day, limited in obstetrics and requiring specialized monitoring, have shown themselves to be safe.

Breastfeeding period

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

Dosing and Administration:

The drug Coplawix® should be taken 1 time a day, regardless of food intake.

Doses

Adults and elderly patients with normal activity of isoenzyme СУР2С19

Acute coronary syndrome (ACS)

Treatment begins as soon as possible after the onset of symptoms. Reception of the drug Coplawix® begins after taking a single loading dose of clopidogrel in combination with ASA in the form of separate drugs, namely clopidogrel in a dose of 300 mg and ASA in doses of 75-325 mg per day, and with acute myocardial infarction with elevation of the segment S3 - in combination with thrombolytics or without them. Since the use of higher doses of ASA is associated with an increased risk of bleeding, the recommended dosage for ASA should not exceed 100 mg. With acute myocardial infarction with segment elevation ST in patients older than 75 years treated with clopidogrel should start without receiving a loading dose of it.

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

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

Atrial fibrillation

Coplawix® should be taken once a day, after starting treatment with clopidogrel 75 mg and ASA 100 mg in separate preparations.

Patients with genetically determined reduced isoenzyme activity CYP2C19

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

Special patient groups

Children

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

Elderly patients

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

Patients with hepatic insufficiency

The therapeutic experience of using the drug is limited to use in patients with mild liver disease, which may have a tendency to develop hemorrhagic diathesis. Therefore, when 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.

Side effects:

The safety of clopidogrel in clinical studies has been studied in more than 44,000 patients, including more than 12,000 patients taking it for a year or more, and 30,000 patients taking concomitantly clopidogrel and ASA; in the CURE clinical trial, 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 following are the clinically relevant adverse effects (NEs) observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT and ACTIVE A, and in the post-marketing application of the combination clopidogrel+ ASA, clopidogrel in monotherapy and ASA in monotherapy.

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 occurrence of NEs according to the available data.

Legend:

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

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

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

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

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

- Often: large bleeding¹ [life-threatening bleeding, requiring transfusion of 4 or more blood units; other large bleeding, requiring transfusion of 2-3 units of blood; not life-threatening large bleeding (according to the COMMIT study, the incidence of major non-cerebral bleeding and intracranial hemorrhage was "infrequent")]¹; small bleeding (according to the ACTIVE-A study, the incidence of small bleeding was "very frequent")¹, bleeding at the site of vascular puncture^1,2; bruising²; hematoma².

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

Patients who discontinued treatment more than 5 days before 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 one 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 hemoglobin of more than 5 g / dl (according to the CLARITY clinical trial, the frequency of their development was "often")¹; bleeding requiring surgery¹; intracranial hemorrhages (hemorrhagic strokes) (according to the CLARITY clinical study, the 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 unknown (postmarketing experience): severe bleeding events², mainly, hemorrhage in the skin tissue², in the bones, muscles and cavity of the joints (hemarthrosis), in the eye tissues (conjunctival, in the internal environment and the retina of the eye), bleeding from the respiratory tract², hemoptysis², nasal bleeding, hematuria, bleeding from the operating wound²; intracranial hemorrhage³, including fatal cases³, especially in elderly patients; other cases of bleeding with a fatal outcome (in particular, bleeding from the gastrointestinal tract and retroperitoneal hemorrhage)².

Violations of the blood and lymphatic system

- Infrequent: decrease in the number of platelets in peripheral blood¹, severe thrombocytopenia with a platelet count in peripheral blood <80x10%, but> 30x10%¹; leukopenia¹; decrease in the number of neutrophils in peripheral blood¹, eosinophilia¹, prolongation of bleeding time¹.

- Rarely: neutropenia¹, including severe neutropenia (<0.45 x 109 / L)¹. Although the risk of myelotoxic effects when using clopidogrel is low enough, its potential should be considered when the patient receiving clopidogrel, develops fever and other infectious manifestations.

- Very rarely: aplastic anemia¹, severe thrombocytopenia with a platelet count in peripheral blood <3 Ox 109 / L¹.

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

Disorders from the central and peripheral nervous system

- infrequently: headache¹, dizziness¹ and paresthesia¹.

- Rarely: vertigo¹.

- Frequency unknown (postmarketing experience): changes in taste sensations².

Disorders from the digestive system

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

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

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

Disturbances from the liver and bile ducts

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

Disturbances from the skin and subcutaneous tissues

- Infrequent: skin rash¹, itching¹.

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

Immune system disorders

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

Disorders of the psyche

- Frequency unknown (postmarketing experience): confusion², hallucinations².

Vascular disorders

- Frequency unknown (post-marketing experience): vasculitis², lowering blood pressure².

Disturbances from the respiratory system, chest and mediastinal organs

- The frequency is unknown (post-marketing experience): bronchospasm², interstitial pneumonitis², eosinophilic pneumonia², non-cardiogenic pulmonary edema in chronic drug administration associated with a hypersensitivity reaction³.

Disturbances from musculoskeletal and connective tissue

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

Disorders from the kidneys and urinary tract

Frequency unknown (post-marketing experience): glomerulopathy, including glomerulonephritis², acute renal dysfunction (especially in patients with pre-existing renal failure, decompensation of chronic heart failure,nephritic syndrome or in patients taking diuretics simultaneously)³, kidney failure³.

General disorders

- Frequency unknown (post-marketing experience): fever².

Laboratory and instrumental data

- The frequency is unknown (postmarketing experience): deviation from the norm of biochemical indicators of the functional state of the liver², an increase in the concentration of creatinine in the blood².

Disorders from the metabolism and nutrition

- Frequency unknown (post-marketing experience): hypoglycaemia³, gout³.

Hearing disorders and labyrinthine disorders

- The frequency is unknown (post-marketing experience of application): hearing loss³, noise in ears³.

Overdose:

Symptoms and treatment of clopidogrel overdose

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

Symptoms and treatment of ASA overdose

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

When there are signs of severe intoxication, severe acid-base disturbances occur. Initially, the resulting hyperventilation leads to the development of respiratory alkalosis. Then, respiratory acidosis develops, as a consequence of the inhibitory effect of respiratory alkalosis on the respiratory center. Also, due to the presence of salicylates, metabolic acidosis develops in the blood. In addition, the following symptoms appear: hyperthermia and 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.

The lethal dose of acetylsalicylic acid is 25 - 30 g.

Plasma salicylate concentration above 300 mg / l (1.67 mmol / l) confirms the presence of intoxication.

Overdose of salicylates, especially in young children, can lead to severe hypoglycemia and potentially fatal poisoning.

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

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

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

Interaction:

Thrombolytics

Security the joint 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 when combined thrombolytic agents and heparin with ASA. Due to the lack of clinical data on the joint use of the drug Coplawix® and thrombolytic agents when used together, caution should be used (see section "Special instructions").

Inhibitors of glycoprotein IIb / IIIa

Between inhibitors of glycoprotein IIb/IIIand the Coplawix® preparation may have pharmacodynamic interaction, which requires caution in their joint use in patients who have an increased risk of bleeding (with trauma and surgical interventions or other pathological conditions) (see section "Special instructions").

Heparin

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

Indirect anticoagulants

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

NSAIDs

In a clinical study conducted with the participation of healthy volunteers, the combined use of clopidogrel and naproxen increased latent blood loss through the gastrointestinal tract. Therefore, the use of NSAIDs, including cyclooxygenase-2 (COX-2) inhibitors, in combination with the Coplviks® preparation is not recommended (see section "Specific guidance"). Experimental evidence suggests that ibuprofen (with a single dose of 400 mg between 8 h and 30 min after the immediate administration of ASA in a dose of 81 mg in the form of immediate release) can inhibit the effect of low doses of ASA on platelet aggregation.However, with irregular intake of ibuprofen, no clinically significant effects of it on the antiaggregant effect of ASA are expected.

Selective serotonin reuptake inhibitors (SSRIs)

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

Another combination therapy with clopidogrel

Strong and moderate inhibitors of the isoenzyme CYP2C9

As 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 precaution, simultaneous use of clopidogrel and strong or moderate inhibitors of the CYP2C9 isoenzyme should be avoided. Strong and moderate inhibitors of the isoenzyme CYP2C9 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 simultaneously with the administration of Coplawix®, then a proton pump inhibitor with a slight effect on the activity of the CYP2C19 isoenzyme, such as pantoprazole or lansoprazole.

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

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

- simultaneous use of phenobarbital, cimetidine and estrogens 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 data from studies with human liver microsomes suggest that the carboxylic metabolite of clopidogrel may inhibit the activity of the CYP2C9 isoenzyme, which can lead to an increase in the concentrations in the the blood plasma of certain 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 has been reported:

- uricosuric agents (drugs that promote the excretion of uric acid) (benzbromarone, probenecid, sulfinpirazone): ASA can suppress their uricosuric effect due to competition with uric acid at the elimination level;

- Methotrexate: methotrexate, taken in doses of more than 20 mg / week,should be used with caution when combined with the preparation of Coplavix® (due to the presence of ASA in the preparation of Coplavix®), since ASA can reduce the renal clearance of methotrexate, which in turn can increase its myelotoxic effect (see section "C caution "); - metamizole: metamizole with simultaneous application with ASA can reduce the effect of ASA on platelet aggregation. Therefore, this combination should be used with caution in patients taking a low dose of ASA for cardioprotective action;

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

- ethanol: with simultaneous use with ASA, the risk of bleeding increases with chronic use of large amounts of alcohol (ethanol) (see section "Special instructions").

Other interactions with clopidogrel and ASA

- ACE inhibitors, diuretics, beta-blockers,blockers of "slow" calcium channels, hypolipidemic drugs, vasodilators, hypoglycemic drugs (including insulin), antiepileptic drugs, hormone replacement therapy and glycoprotein receptor blockers GPIIb / IIIa - in clinical studies on the use of clopidogrel in combination with ASA in maintenance doses <325 mg, conducted with the participation of more than 30,000 patients, there were no clinically relevant undesirable interactions.

Special instructions:

Bleeding and hematologicue violations

In connection with the risk of bleeding and hematologic adverse effects (see the section "Side effect") in the event of the appearance during the treatment of clinical symptoms, suspicious of bleeding, it is urgent to make a clinical blood test to determine APTT (activated partial thromboplastin time), the number of platelets at peripheral blood, indicators functional activity thrombocytes and conduct other necessary studies.

Due to the presence of two antiplatelet agents in the preparation of Coplawix®, it should beuse with caution in patients prone to increased risk of bleeding due to trauma, surgical interventions or other pathological conditions, as well as in patients taking NSAIDs (including COX-2 inhibitors), heparin, glycoprotein inhibitors IIb/IIIa, SSRIs and thrombolytic drugs. It is necessary to carefully monitor patients for the exclusion of signs of bleeding, including hidden, especially during the first weeks of treatment and / or after invasive cardiological

procedures / surgical intervention. Simultaneous use of Coplawix® from indirect anticoagulants are not recommended, as this may increase the intensity bleeding (see section "Interaction with other medicinal products ").

If the patient is scheduled surgical intervention, and there is no need for permanent antiaggregant therapy, then 5-7 days before the surgical interventions clopidogrel should be canceled.

Coplawix® improves bleeding time and should be used with caution. patients with diseases and conditions predisposing to the development of bleeding (especially bleeding from the gastrointestinal tract and intraocular hemorrhages).

Patients should be warned that when taking Copapwix ® to stop bleeding, they may It takes more time than usual, and that in the case of any unusual (for localization or duration) bleeding they should inform their own doctor about this.

Before any future surgical intervention and before proceeding to receive any new medication, patients should inform the doctor (including the dentist) about Copvalix® treatment.

Recently suffered ischemic stroke

It was shown that in patients with recent ischemic transient cerebral infarction or stroke having an increased risk of developing ischemic complications, the combination of ASA and clopidogrel increases the possibility of developing large bleeding. Therefore, the use of Coplawix® in such patients should be conducted with caution and only in the case of proven clinical benefit from itapplication.

Thrombotic thrombocytopenic purpura

Very rarely, after application clopidogrel (short), there have been cases of thrombotic thrombocytopenic purpura (TTP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever. TTP is potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

Acquired hemophilia

The cases of development of acquired hemophilia with the use of clopidogrel were reported. With a confirmed isolated increase in activated partial thromboplastin time, accompanied or not accompanied by development bleeding, should consider 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.

Cross-allergic and / or hematologic reactions between thienopyridines

Patients should collect anamnesis for any previously allergic and / or hematologic reactions to other thienopyridine (such as ticlopidine, prasugrel), since it has been reported that there are cross-allergic and / or hematological reactions between thienopyridines (see "Side effect" section). Tienopyridines can cause mild to severe allergic reactions (such as rash, angioedema) or hematologic reactions (such as thrombocytopenia and neutropenia). Patients who have previously experienced allergic and / or hematologic reactions to one of the drugs of the thienopyridine group may have an increased risk of developing similar reactions to another drug of the thienopyridine group. It is recommended to monitor cross-allergic and / or hematological reactions.

Functional activity of the isoenzyme CYP2C19

In patients with low metabolic activity of the isoenzyme CYP2C19 when clopidogrel is used in recommended doses, less active metabolite of clopidogrel is formed and its effect on platelet function is reduced. Therefore, such patients with acute coronary syndrome or patients undergoing percutaneous coronary intervention and taking clopidogrel, may have a greater incidence of cardiovascular events than patients with normal isoenzyme activity CYP2C1.

There are tests to determine the genotype CYP2C19, these tests can be used to help choose a therapeutic strategy. The use of higher doses of clopidogrel in patients with low isozyme activity CYP2C19 (see the section "Pharmacokinetics", "Pharmacokinetics", sections "With caution", "Methods of administration and doses"), but the effectiveness and safety of the use of increased doses of clopidogrel in patients with low isoenzyme activity CYP2C19 have not been established to date.

Effect on the gastrointestinal tract

The preparation of Coplawix® trace should be used with caution in patients with peptic ulcer and duodenal ulcer or gastrointestinal hemorrhages in the history or patients with even minor symptoms from the upper gastrointestinal tract, which may be manifestations of ulcerative lesions of the stomach, capable of leading to gastric bleeding.

When treated with Coplawix®, symptoms at the top of the digestive tract may occur at any time, such as gastralgia, heartburn, nausea, vomiting, and gastrointestinal bleeding.Despite the fact that in the treatment of Coplawix ® minor side effects gastrointestinal tract, such as dyspeptic disorders, often occur, 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 are informed about the symptoms of unwanted reactions from the digestive tract.

Other

There may be a relationship between ASA and the emergence of a life-threatening Ray syndrome (encephalopathy and acute fatty liver dystrophy with rapid development of the hepatic insufficiency), usually observed in the prodromal period of infections in children.

In connection with the presence of the drug ASA preparation Coplawiks should be prescribed to patients with a deficiency of glucose-6-phosphate dehydrogenase under thorough medical observation (due to the risk of hemolysis) (see the sections "With caution", "Side act").

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

Due to the presence of ASA in the preparation of Coplavix®, patients should be warnedon the increased risk of bleeding in chronic use of large amounts of alcohol (ethanol).

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

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

Form release / dosage:Tablets, film-coated, 100 mg + 75 mg.

Packaging:For 7 tablets in PA / Al / PVC / / Aluminum blister.
For 1, 2 or 4 blisters together with instructions for use in a cardboard box.
For 10 tablets in PA / Al / PVC / / Aluminum blister. For 10 blisters together with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-000163

Date of registration:13.01.2011

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

Manufacturer: & nbsp

SANOFI WINTHROP INDUSTRIE France

Representation: & nbspSanofi Aventis GroupSanofi Aventis Group

Information update date: & nbsp15.12.2014

Illustrated instructions

Instructions

Coplavix® (Coplavix®)