Clopidogrel

Per tablet:

Active substance: clopidogrel hydrosulfate - 97.88 mg, in terms of clopidogrel - 75.00 mg.

Excipients (kernel): lactose - 70.00 mg, microcrystalline cellulose - 17.00 mg, sodium croscarmellose - 5.52 mg, colloidal silicon dioxide - 1.80 mg, magnesium stearate - 1.80 mg.

Excipients (shell): hypromellose - 3.30 mg, macrogol-4000 - 0.90 mg, iron dye red oxide - 0.06 mg, titanium dioxide - 1.74 mg.

Pharmacotherapy group

Antiplatelet agent

ATX code

B01AC04

Pharmacodynamics:

Clopidogrel is a prodrug one of the active metabolites of which is a platelet aggregation inhibitor.

The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor P2Y12 and the subsequent activation of the glycoprotein complex IIb/IIIa caused by ADP, thereby suppressing platelet aggregation. Reduces platelet aggregation caused by other agonists (other than ADP) does not affect the activity of phosphodiesterase.

Due to the irreversibility of binding platelets exposed are damaged for the rest of their life (approximately 7-10 days) and the restoration of normal platelet function occurs at a rate corresponding to the platelet cycle. Platelet aggregation caused by agonists other than ADP is also inhibited by blocking the enhanced activation of platelets occurring under the influence of released ADP.

Since the active metabolite of clopidogrel is formed with the participation of the isoenzyme CYP2C19, some of which are polymorphic or inhibited by other drugs compounds, not all patients have enough platelet suppression.

When taking clopidogrel daily at a dose of 75 mg from the first day, there is a significant suppression of ADP-induced platelet aggregation, which gradually increases within 3-7 days and then achieves an equilibrium state (it reaches a constant level). In equilibrium, platelet aggregation is suppressed by an average of 40-60%. After stopping taking clopidogrel, platelet aggregation and bleeding time return to the initial level for an average of 5 days.

Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular in lesions of cerebral coronary or peripheral arteries.

In patients with recently suffered myocardial infarction, ischemic stroke and/or peripheral artery occlusion disease, taking clopidogrel at a dose of 75 mg per day significantly reduces the risk of developing vascular complications (myocardial infarction stroke cardiovascular mortality).

In acute coronary syndrome without lifting the ST segment on the ECG (unstable angina myocardial infarction), taking clopidogrel (load dose 300 mg once then 75 mg/day) in combination with acetylsalicylic acid at a dose of 75-325 mg/day and other standard therapy reliably and independently of other types of treatment reduces the risk of vascular complications.

In case of myocardial infarction with ST segment rise to the ECG, clopidogrel (load dose 300 mg once during the first 12 hours of the disease then 75 mg/day) in combination with acetylsalicylic acid (load dose 150-325 mg then 75-162 mg/day) fibrinolytic therapy and according to hepar

Patients who were not discharged for coronary angiography to take clopidogrel according to this scheme reduces the frequency of deaths and repeated myocardial infarction to 8 days of the disease or until discharge from the hospital.

In general, in case of myocardial infarction, regardless of ECG changes (upgrade of ST segment depression or first complete blockade of the left leg of the Gis beam), taking clopidogrel at a dose of 75 mg/day in combination with acetylsalicylic acid 162 mg per day leads to a decrease in total mortality and the

The results of the clinical study showed that in patients with atrial fibrillation who had at least one risk factor for vascular complications but were unable to take indirect anticoagulants clopidogrel in combination with acetylsalicylic acid (compared to the use of only one acetylsalicylic acid) reduced the total incidence of strokes of myocardial infarction of systemic thromboembolism outside the central nervous system or vascular death to a greater extent by reducing the risk of stroke.

Pharmacokinetics:

Suction and distribution: when taken regularly orally, clopidogrel at a dose of 75 mg/day, it is quickly absorbed.

The maximum concentration (Cmax) of unchanged clopidogrel after a single ingestion at a dose of 75 mg is about 22-25 ng/ml; the time to reach the maximum concentration (TSmah) of clopidogrel is about 45 minutes. Based on data on the elimination of clopidogrel metabolite by the kidneys, the absorption of clopidogrel is at least 50%.

In vitro clopidogrel and its main inactive metabolite circulating in the blood reversibly bind to plasma proteins (98% and 94%, respectively) this bond is unsaturated in a wide range of concentrations.

Metabolism: being a cure for clopidogrel is intensively metabolized in the liver. In vivo and in vitro, clopidogrel is metabolized in two ways: the first - through enzymes and subsequent hydrolysis to form an inactive derivative of carboxylic acid (85% of circulating metabolites) the second way - through the system of isoenzymes of cytochrome P450. Initially, 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 clopidogrel, a thiol derivative of clopidogrel. In vitro, this pathway of metabolism occurs using the isoenzymes CYP3A4 CYP2C19 CYP1A2 and CYP2B6.

Active thiol metabolite can only be isolated in in vitro studies; in vivo conditions, it binds quickly and irreversibly to the platelet P2Y12 receptor, thus inhibiting platelet aggregation.

Cmach of the active metabolite of clopidogrel after taking its load dose of 300 mg is 2 times higher than Cmach after 4 days of taking a supporting dose of clopidogrel 75 mg. At the same time, when taking 300 mg of clopidogrel, Cmach is achieved within about 30-60 minutes.

After re-intake of clopidogrel orally at a dose of 75 mg per day, Cmach of the main inactive metabolite is about 3 mg/l TSmah of inactive metabolite is achieved in 1 hour.

Excretion: within 120 hours after ingestion by a person of 14C-labeled clopidogrel, about 50% of the dose is excreted by the kidneys and about 46% - through the intestines.

After a single ingestion of a dose of 75 mg, the half-life (T1/2) is about 6 hours. After a single dose and repeated dose of T1/2, its main metabolite is 8 hours.

Pharmacogenetics

With the help of the isoenzyme CYP2C19, both the active metabolite and the intermediate metabolite - 2-oxo-clopidogrel - are formed. Pharmacokinetics and antiplatelet effect of the active metabolite clopidogrel in the study of platelet aggregation in vivo vary depending on the genotype of the isoenzyme CYP2C19. The allele of the CYP2C19*1 gene corresponds to fully functional metabolism, while the alleles of the genes CYP2C19*2 and CYP2C19*3 cause a decrease in metabolism in most representatives of the Caucasian (85%) and Mongoloid race (99%). Other alleles associated with the absence or decrease in metabolism are less common and include but are not limited to alleles of the genes CYP2C19*4 *5 *6 *7 and *8. Patients with low activity of the CYP2C19 isoenzyme should have two above alleles of the gene with loss of function. The published incidence of phenotypes of patients with low activity of the isoenzyme CYP2C19 is 2% in the Caucasian race in the Negroid race 4% and in the Chinese 14%.

There are tests to determine the patient's CYP2C19 genotype. These tests can be used as an auxiliary tool in determining treatment tactics.

In a cross-study involving 40 healthy volunteers (10 volunteers each with very fast extensive intermediate and delayed metabolism), pharmacokinetics and antiplatelet effect of clopidogrel was studied when used according to two schemes: 1) 300 mg once with subsequent administration at a dose of 75 mg per day for 5 days and 2) 600 mg once with subsequent administration at a No significant differences in the effects of active metabolite and the average level of platelet aggregation inhibition (IAT) between groups of volunteers with very rapid extensive and intermediate metabolism have been identified. In volunteers with reduced metabolic rate, the exposure to active metabolite was 63-71% lower than volunteers with extensively metabolizing clopidogrel.

When using the drug according to the 300 mg scheme once / 75 mg per day, the platelet response (when stimulating 5 μm ADP) in volunteers with delayed metabolism of clopidogrel was reduced: IAT was 24% (24 hours later) and 37% (Day 5). For comparison, volunteers with extensive metabolism had IAT 39% (in 24 hours) and 60% (Day 5).

When using clopidogrel according to the 600 mg scheme once /150 mg per day in volunteers with a reduced rate of clopidogrel metabolism, the effect of the drug was more pronounced than when using the drug at doses of 300 mg once /75 mg per day: IAT was 32% (in 24 hours) and 61% (Day 5), which is comparable to the indicators of IAT in groups of volunteers with a different rate of metabolism of clopidogrel who received the drug according to the scheme of 300 mg/75 mg. A suitable dosing regimen for a population of patients with reduced clopidogrel metabolism has not been established in clinical trials.

Similarly, a meta-analysis of six studies, which included data from 335 healthy volunteers who received clopidogrel and were in a state of achieving equilibrium concentration showed that in intermediate metabolizers the exposure of the active metabolite decreased by 28% and in weak metabolizers by 72%. Compared to intensive metabolizers, platelet aggregation inhibition in intermediate and weak metabolizers was reduced by 59% and 214%, respectively.

The impact of the genotype SUR2C19 on clinical outcomes in patients receiving clopidogrel in prospective randomized controlled studies was not assessed. Existing data from retrospective clinical trial analyses for which the results of genotyping of patients are available do not have sufficient capacity to assess the difference in clinical outcomes in weak clopidogrel metabolizers compared to intensive and intermediate metabolizers.

Special groups of patients

Elderly people

Elderly volunteers (over 75 years old) did not differ in platelet aggregation and bleeding time compared to young volunteers. Correction of the dose of clopidogrel in the elderly is not required.

Age under 18 years old

Pharmacokinetics of clopidogrel in children has not been studied.

Kidney dysfunction

After repeated administration of clopidogrel at a dose of 75 mg/day in patients with severe chronic renal failure (creatinine clearance (CC) 5-15 ml/min), inhibition of ADP-induced platelet aggregation was 25% lower than in healthy volunteers, but there was no elongation of bleeding time.

Liver dysfunction

After taking clopidogrel at a dose of 75 mg per day for 10 days in patients with severe liver damage, inhibition of ADP-induced platelet aggregation did not differ from that of healthy volunteers. The average bleeding time in patients with severe liver damage and healthy volunteers was comparable.

Race affiliation

The prevalence of alleles of the CYP2C19 isoenzyme genes responsible for intermediate or reduced metabolism differs in different racial groups. The available literary data are insufficient to assess the importance of genotyping of the isoenzyme CYP2C19 to predict the development of ischemic complications.

Prevention of atterotrombotic disorders in adult patients:

- after a myocardial infarction (with a prescription of several days to less than 35 days) of ischemic stroke (with a prescription of 7 days to less than 6 months) or with a diagnosis of occlusal disease of peripheral arteries;

- with acute coronary syndrome:

• without lifting the ST segment (unstable angina or myocardial infarction without tooth Q), including patients who have been stented during percutaneous coronary intervention (in combination with acetylsalicylic acid);
• with the rise of the ST segment (acute myocardial infarction with ST segment lifting) in medical treatment and the possibility of thrombolisis (in combination with acetylsalicylic acid);

Prevention of aterotromobotic and thromboembolic complications including stroke in atrial fibrillation (brillation arrhythmia)

- in adult patients with atrial fibrillation (fataltal arrhythmia) who have at least one risk factor for vascular complications cannot take indirect anticoagulants and have a low risk of bleeding (in combination with acetylsalicylic acid).

The use of Clopidogrel is not recommended during pregnancy due to the lack of clinical data on its use by pregnant women, although animal studies have not revealed either direct or indirect adverse effects on pregnancy, embryonic development of childbirth and postnatal development.

Studies on rats have shown that clopidogrel and/or its metabolites are excreted with milk of lactating rats. There are no data on the release of clopidogrel into breast milk. During Clopidogrel therapy, it is recommended to stop breastfeeding.

Fertility

Animal studies have not revealed the adverse effect of clopidogrel on fertility.

- Hypersensitivity to clopidogrel or any of the auxiliary substances included in the drug.

- Severe liver failure.

- Active bleeding (including peptic ulcer bleeding or intracranial hemorrhage).

- Pregnancy and breastfeeding period.

- Age up to 18 years (efficiency and safety of use are not established).

- Rare hereditary lactose intolerance to lactase deficiency and glucose-galactose malabsorption syndrome (due to the presence of lactose in the drug).

With caution:

- Moderate liver failure (7-9 points on the Child Pugh scale) (in which a predisposition to bleeding is possible) - clinical experience is limited;

- chronic renal failure (CPN) of mild to moderate severity (creatinine clearance 60-30 ml/min) - clinical experience is limited;

- diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal or intraocular) including surgical injuries;

- simultaneous administration of non-steroidal anti-inflammatory drugs (NSAIDs) (including cyclooxygenase-2 inhibitors (COX-2);

- simultaneous administration of oral anticoagulants heparin inhibitors of glycoprotein receptors IIb/IIIa selective serotonin reuptake inhibitors (SRI) and thrombolytic drugs;

- hereditary decrease in the activity of the isoenzyme CYP2C19 (since they have less active metabolite clopidogrel at the recommended doses and its antiplatelet effect is weaker, so when taking the usually recommended doses of clopidogrel in acute coronary syndrome or percutaneous coronary intervention, a higher incidence of cardiovascular complications is possible than in patients with normal activity of the isoenzyme CYP2C19);

- if there are hypersensitivity reactions to other thienopyridines (such as ticlopidine prasugrel) in the history due to the possibility of hypersensitivity cross reactions (see section "Special instructions").

The frequency of adverse reactions is determined as follows: very often - more than 1/10 often - more than 1/100 and less than 1/10 infrequently - more than 1/1000 and less than 1/100 rarely - more than 1/10000 and less than 1/1000 very rarely - less than 1/10000 including individual messages unknown frequency (it is impossible to determine the frequency of occurrence of an unwanted reaction according to available data). Within each system-organ frequency class, unwanted effects are presented in descending order of severity.

On the part of the hematopoiesis organs: infrequently - thrombocytopenia leukopenia eosinophilia; rarely - neutropenia, including severe neutropenia; very rarely - thrombotic thrombocytopenic purple aplastic anemia pancitopenia agranulocytosis severe thrombocytopenia granulocytopenia anemia; frequency unknown - acquired hemophilia A.

From the immune system: unknown frequency - anaphylactoid reactions serum disease cross allergic and hematological reactions with other thiopyridines (such as ticlopidine prasugrel)

From the side of the blood clotting system: often - hematoma nasal bleeding gastrointestinal bleeding bruises at the puncture site; sometimes - intracranial bleeding, hemorrhage in the eye (conjunctival eye retinal) elongation of bleeding time; rarely - retroperitoneal bleeding; very

On the part of the nervous system: infrequently - intracranial hemorrhage, including lethal headache paresthesia dizziness; very rarely - taste disorders.

From the psyche side: very rarely - confusion of hallucination consciousness.

From the side of the visual organ: infrequently - eye hemorrhages (conjunctival in the tissue and retina of the eye).

From the hearing organ: rarely - vertigo.

From the cardiovascular system: often - hematoma; very rarely - severe bleeding from the operating wound vasculitis lower blood pressure.

From the respiratory system: often - nasal bleeding; very rarely - bronchospasm interstitial pneumonia pulmonary bleeding hemorrhage; eosinophilic pneumonia.

From the digestive system: very often - gastrointestinal bleeding diarrhea abdominal pain dyspepsia; infrequently - stomach ulcer and duodenal gastritis vomiting nausea constipation of flatulence; rarely - retroperitoneal bleeding; very rarely - gastrointest

From the liver and biliary tract: very rarely - hepatitis (non-infectious) acute liver failure hepatitis deviations from the norm of liver function indicators.

From the skin: often subcutaneous hemorrhages; infrequently - skin rash skin itching purple; very rarely / unknown frequency - bullous dermatitis (toxic epidermal necrolysis Stevens-Johnson syndrome multiform erythema) angioedema drug hypersensitivity syndrome medicinal rash with eosinophilia and systemic manifestations (DRESS syndrome) erythematous or exfoliative rash urticaria eczema red flat lichen

From the musculoskeletal system: very rarely - musculoskeletal hemorrhages (hemarthritis) arthralgia arthritis (join) myalgia.

From the genitourinary system: infrequently - hematuria; very rarely - glomerulopathy (including glomerulonephritis) hypercreatinemia.

Laboratory indicators: infrequently - elongation of bleeding time decrease in the number of platelet neutrophils in peripheral blood disorders of functional liver samples increase in creatinine concentration in blood plasma.

General disorders and disorders at the injection site: often - bleeding from the place of vascular puncture is very rare - fever.

Simultaneous administration of clopidogrel and peroral anticoagulants can increase the intensity of bleeding, so the use of this combination is not recommended. Clopidogrel at a dose of 75 mg per day does not affect the pharmacokinetics of warfarin and does not change the value of the International Normalized Ratity (INR) in patients taking warfarin for a long time. Nevertheless, simultaneous administration of warfarin with clopidogrel can increase the risk of bleeding due to the independent effect of these drugs on hemostasis.

The appointment of glycoprotein IIb\IIIa receptor inhibitors together with clopidogrel requires caution, especially in patients with an increased risk of bleeding (in injuries and surgical interventions or other pathological conditions).

Acetyl salicylic acid (ACS) does not affect platelet aggregation suppression caused by induced by ADP but clopidogrel potentiates the action of ASK on collagen-induced platelet aggregation. However, simultaneous administration of 500 mg of ASK 2 times a day did not have a significant impact on the increase in bleeding time caused by taking clopidogrel. Pharmacodynamic interaction is possible between clopidogrel and ASK, which leads to an increased risk of bleeding. Therefore, caution should be taken when used simultaneously, although in clinical trials patients received combined therapy with clopidogrel and ASK for one year.

When used simultaneously with heparin, according to a clinical study conducted on healthy volunteers, no change in the dose of heparin was required when taking clopidogrel and the anticoagulant effect of heparin did not change.

The combined use of heparin did not change the inhibitory effect of clopidogrel on platelet aggregation. Pharmacodynamic interaction is possible between clopidogrel and heparin, which can increase the risk of bleeding, so the use of this combination requires caution.

The safety of joint use of clopidogrel fibrin-specific or non-specific thrombolytics and heparin has been studied in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the case of joint use of thrombolytics and heparin with ASK.

The appointment of NSAIDs (including COX-2 inhibitors) together with clopidogrel requires caution. In a clinical study conducted with the participation of healthy volunteers, the combined use of clopidogrel and naproxen increased hidden gastrointestinal bleeding. However, due to the lack of research on the interaction of clopidogrel with other NSAIDs, it is not currently known whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel along with other NSAIDs.

Selective serotonin reuptake inhibitors (SRI)

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

Since clopidogrel is metabolized before its active metabolite partially with the participation of the isoenzyme CYP2C19, the use of drugs that inhibit the activity of this enzyme can lead to a decrease in the level of active metabolite. The clinical significance of this interaction is unknown. As a precaution, it is recommended to avoid taking clopidogrel simultaneously with drugs inhibiting the isoenzyme CYP2C19 (omeprazole esomeprazole fluvoxamine fluoxetine moclobemide voriconazole fluconazole ticlopidine ciprofloxacin If it is necessary to prescribe proton pump inhibitors simultaneously with clopidogrel, drugs with the least inhibition of the CYP2C19 isoenzyme (e.g. pantoprazole or lansoprazole) should be used.

There is no evidence that other drugs that reduce the acidity of gastric juice, such as H2 blockers (except for cimetidine, which is an inhibitor of the isoenzyme CYP2C19) or antacids, affect the antiplatelet properties of clopidogrel.

A number of clinical studies were conducted with clopidogrel and other simultaneously prescribed drugs in order to study possible pharmacodynamic and pharmacokinetic interactions, which showed that:

• there is no clinically significant pharmacodynamic interaction when using clopidogrel together with athenolol and/or nifedipine;
• simultaneous use of phenobarbital cimetidine and estrogens does not have a significant effect on the pharmacodynamics of clopidogrel;
• antacid drugs do not reduce the absorption of clopidogrel;
• phenytoin and tolbutamide can be safely used simultaneously with clopidogrel it is unlikely that clopidogrel can affect the metabolism of other drugs such as phenytoin and tolbutamide and NSAIDs that are metabolized with the CYP2C19 isoenzyme of the cytochrome P450 group.

In addition to the information provided above, no other drug interaction has been conducted. Nevertheless, patients participating in clinical trials with clopidogrel received a number of other drugs at the same time including diuretics beta-adrenoblockers ACE inhibitors calcium channel blockers hypolipidemic agents (including insulin) coronary vasodilators antiepileptics and glycoprotein IIb/IIIa

Clopidogrel should be taken orally regardless of the time of meals.

Adults and elderly patients with normal activity of the CYP2C19 isoenzyme:

Myocardial infarction ischemic stroke and diagnosed peripheral artery occlusal disease

Clopidogrel is taken 75 mg once a day.

Acute coronary syndrome without lifting the ST segment (unstable angina angina myocardial infarction without tooth Q)

Treatment with Clopidogrel begins with a single dose of 300 mg and then taken 75 mg/day (in combination with acetylsalicylic acid at doses of 75-325 mg/day). Since the use of higher doses of acetylsalicylic acid is associated with an increase in the risk of bleeding, the recommended dose of acetylsalicylic acid should not exceed 100 mg. The maximum favorable effect develops in 3 months. The results of clinical studies confirm the expediency of taking the drug up to 12 months after the development of acute coronary syndrome without lifting the ST segment.

Acute coronary syndrome with ST segment rise (acute myocardial infarction with ST segment rise)

Clopidogrel should be taken once a day at a dose of 75 mg with an initial single dose of 300 mg in combination with acetylsalicylic acid in combination with thrombolytics or without a combination with thrombolytics.

In patients over 75 years of age, treatment with Clopidogrel should begin without taking his load dose. Combined therapy begins as early as possible after symptoms appear and continue for at least 4 weeks.

The effectiveness of combined therapy with Clopidogrel and acetylsalicylic acid with this indication for more than 4 weeks has not been studied.

Atrial fibrillation (brillation arrhythmia)

Clopidogrel should be taken once a day at a dose of 75 mg. In combination with Clopidogrel, you should start and then continue taking acetylsalicylic acid (75-100 mg/day).

Skipping the next dose

• if less than 12 hours have passed since missing another dose of the drug, you should immediately take the missed dose of the drug and then take the following doses at normal times.
• if more than 12 hours have passed since missing another dose of the drug, the patient should take the next dose of the drug at normal times (do not double the dose).

Patients with genetically conditioned reduced activity of the CYP2C19 isoenzyme

Low activity of the CYP2C19 isoenzyme is associated with a decrease in the antiplatelet effect of Clopidogrel.

The mode of use of higher doses (600 mg - load dose then 150 mg once a day daily) in patients with low activity of the isoenzyme CYP2C19 increases the antiplatelet effect of clopidogrel.

Currently, clinical studies taking into account clinical outcomes do not establish an optimal clopidogrel dosing regimen for patients with reduced metabolism due to genetically determined low activity of the CYP2C19 isoenzyme.

Special groups of patients

Elderly patients

Elderly volunteers (over 75 years old) did not differ in platelet aggregation and bleeding time compared to young volunteers. For the elderly, no correction of the dose of clopidogrel is required.

Patients with kidney dysfunction

After repeated administration of Clopidogrel at a dose of 75 mg/day in patients with severe kidney disorders (creatinine clearance (CC) from 5 to 15 ml/min), inhibition of ADP-induced platelet aggregation (25%) was lower than in healthy volunteers, but the lengthening of bleeding time was the same as healthy volunteers receiving clopidogrel at a dose of 75 mg/day.

Patients with liver disfunction

The experience of using clopidogrel in patients with liver failure is limited. After the daily use of clopidogrel at a daily dose of 75 mg in patients with severe liver disfunction, inhibition of ADP-induced platelet aggregation was similar to that of healthy volunteers. The average bleeding time was comparable in both groups.

Ethnicity

The prevalence of alleles of genes of CYP2C19 isoenzymes responsible for intermediate and reduced metabolism of clopidogrel to its active metabolite varies in different ethnic groups.

There are limited data available only for members of the Mongoloid race to assess the effect of the genotype of the isoenzyme CYP2C19 on clinical outcomes (see Pharmacogenetics).

Female and male patients

In a small study comparing the pharmacodynamic properties of clopidogrel in men and women, women showed less inhibition of ADP-induced platelet aggregation, but there were no differences in bleeding time elongation.

In a controlled clinical study of CAPRIE (clopidogrel compared to acetylsalicylic acid in patients at risk of ischemic complications), the frequency of clinical outcomes of side effects and deviations of clinical laboratory indicators from the norm was the same in men and women.

Symptoms: an overdose of clopidogrel can lead to lengthening the bleeding time and subsequent hemorrhagic complications in the form of bleeding.

Treatment: if bleeding is detected, appropriate treatment should be carried out.

The clopidogrel antidote is not installed.

If a quick correction of the elongated bleeding time is necessary, a platelet transfusion is recommended.

It should be clarified that patients have hypersensitivity to other thienopyridine derivatives (ticlopidine prasugrel) in patients, as cases of cross-allergic reactions between thiopyridines are described. Patients who have previously experienced hypersensitivity to other thyenopyridines require careful monitoring throughout the therapy period to detect signs of hypersensitivity to clopidogrel.

During treatment, it is necessary to monitor the indicators of the he