PLAVIX instructions for use, description of the medicinal product PLAVIX: contraindications, side effects, dosages, composition - tablets, coating. shell in the reference book of medicines

Instructions for use PLAVIX®

Platelet aggregation inhibitor.

Clopidogrel is a prodrug and must be metabolized by CYP2C19 enzymes to form its active metabolite. The active metabolite of clopidogrel selectively blocks platelet P2Y12 receptors, inhibiting the binding of ADP to these receptors and the subsequent ADP-mediated activation of the GPIIb/IIIa glycoprotein complex, thereby preventing platelet aggregation. The irreversibility of blockade of P2Y12 receptors persists for the entire remaining life of platelets (approximately 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the platelet cycle. Platelet aggregation induced by agonists other than ADP is also suppressed by blocking the increased platelet activation induced by released ADP.

Since the active metabolite is formed by the CYP2C19 isoenzyme, some of which are polymorphic or suppressed by other drug compounds, platelet suppression is not sufficient in all patients.

Regular use of the drug in a daily dose of 75 mg from the first day of use leads to significant inhibition of platelet aggregation caused by ADP. The inhibitory effect increases progressively and an equilibrium state is achieved after 3-7 days. At the same time, the average level of inhibition under the influence of a daily dose of 75 mg was from 40 to 60%. Platelet aggregation and bleeding time gradually returned to baseline levels, on average 5 days after cessation of treatment.

The safety and effectiveness of clopidogrel were assessed in a double-blind study in five clinical programs involving a total of over 80,000 patients:

CAPRIE, comparing clopidogrel with acetylsalicylic acid (ASA), and CURE, CLARITY and COMMIT and ACTIVE-A, which compared clopidogrel with placebo (comparison groups with ASA and other standard therapy).

Recent myocardial infarction, recent stroke, or diagnosed peripheral arterial occlusive disease

The CAPRIE study included 19,185 patients with atherothrombosis, manifested as recent myocardial infarction (less than 35 days), recent ischemic stroke (7 days to 6 months), or diagnosed peripheral arterial occlusive disease (PAD). Patients were randomized to receive 75 mg clopidogrel or 325 mg ASA/day and remained under observation for 1 to 3 years. In the subgroup of patients who had myocardial infarction, most patients received ASA from the first days after myocardial infarction.

Clopidogrel led to a statistically significant reduction in the incidence of new ischemic disorders (myocardial infarction, ischemic stroke and sudden death) compared with ASA: the number of ischemic disorders among patients who received at least one dose of the drug was 939 in the group receiving clopidogrel and 1020 in the ASA group. The percentage relative risk reduction was 8.7% in the ASA group [95% CI:

0.2-16.4];
(p=0.045), which corresponds to 10 [CI: 0-20] additional patients with success in preventing new ischemic events for every 1000 patients treated for 2 years. Analysis of overall mortality did not demonstrate a significant difference between clopidogrel (5.8%) and ASA (6%).

When analyzing subgroups using qualitative assessment of the condition (myocardial infarction, stroke and PAAD), the greatest beneficial effect (achieved statistical significance at p = 0.003) was in patients with PAAD (especially those with a history of myocardial infarction) (RRR = 23.7% ;CI:

8.9-36.2) and weaker (insignificant difference with ASA) in patients who had a stroke (RRR=7.3%;
CI: -5.7-18.7). In patients enrolled only on the basis of recent myocardial infarction, the outcome in the clopidogrel group was numerically better, but not statistically different from ASA (RRR= -4%;
CI: -22.5-11.7). In addition, subgroup analysis by age suggests that the success of clopidogrel in patients over 75 years of age was less than in patients under 75 years of age.

Because the CAPRIE study was not designed to evaluate the effectiveness of specific subgroups, it is unclear whether the difference in relative risk reduction between the qualifying conditions actually exists or is due to chance.

Acute coronary syndrome

The CURE study included 12,562 patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q wave myocardial infarction) within 24 hours of the last episode of chest pain or symptoms suggestive of ischemia. To be included in the study, patients were required to have either ECG changes indicating new ischemic events or elevated cardiac enzyme levels of at least 2 times the normal level:

troponin I or T. Patients were assigned to groups of clopidogrel (300 mg loading dose, followed by a dose of 75 mg/day, n=6259) or placebo (n=6303), both in combination with ASA (75-325 mg once a day). days) and other standard appointments. The course of therapy was carried out for up to one year. In this study, 823 (6.6%) patients were simultaneously treated with GPIIb/IIIa receptor antagonists. Heparins were prescribed to more than 90% of patients, and heparin therapy did not have a significant effect on the relative percentages of bleeding between clopidogrel and placebo.

The number of patients with new cardiovascular events (cardiovascular death, myocardial infarction or stroke) was 582 (9.3%) in the clopidogrel group and 719 (11.4%) in the placebo group, with a 20% reduction in relative risk (95% CI 10-28%; p=0.00009) in the group receiving clopidogrel (17% relative risk reduction in patients receiving conservative treatment, 29% in patients after PLCA (percutaneous luminal coronary angioplasty) with or without stenting , and 10% after coronary artery bypass grafting.New cardiovascular events were prevented with the following relative risk reduction (RRR): 22% (CI: 8.6, 33.4), 32% (CI: 12.8, 46.4), 4% (CI : -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI:

-31.6, 44.2) for intervals of 0-1, 1-3, 3-6, 6-9 and 9-12 months, respectively. Thus, after 3 months of treatment, the benefit observed in the clopidogrel + ASA group no longer increased, while the risk of bleeding remained.

The use of clopidogrel in the CURE study was associated with a reduction in the need for thrombolytic therapy (relative risk reduction 43.3%; CI:

24.3%, 57.5%) and in GPIIb/IIIa inhibitors (RRR=18.2%;
CI: 6.5%, 28.3%).

The number of patients with overall cardiovascular events (cardiovascular death, myocardial infarction, stroke or refractory ischemia) was 1035 (16.5%) in the clopidogrel group and 1187 (18.8%) in the placebo group, with a relative risk reduction in the clopidogrel group of 14% (95% CI 6-21%, p=0.0005). This benefit is mainly explained by a statistically significant reduction in the incidence of myocardial infarction [287 (4.6%) in the clopidogrel group and 363 (5.8%) in the placebo group]. There was no effect on readmission rates for unstable angina.

The results obtained in the treatment of different groups of patients (unstable angina, non-Q wave myocardial infarction, low and high risk, diabetes mellitus, need for revascularization, age, gender) are consistent with the results of the primary analyses. Specifically, in a post-hoc analysis of 2172 patients (17% of the total treated population of the CURE study) undergoing stent placement (Stent-CURE), the results showed that clopidogrel compared with placebo clearly demonstrated a significant relative risk reduction of 26.2% in favor of clopidogrel for the primary endpoint (cardiovascular death, myocardial infarction, stroke), and a significant relative risk reduction of 23.9% for the second primary endpoint (cardiovascular death, myocardial infarction, stroke or refractory ischemia ). Moreover, the safety profile of clopidogrel in this subgroup of patients did not raise any particular concerns. Thus, the results in this subgroup are consistent with the overall results of the study.

Treatment benefits with clopidogrel were independent of other short- or long-term cardiovascular treatments (such as low molecular weight heparins or unfractionated heparin, GPIIb/IIIa receptor antagonists, lipid-lowering agents, beta-blockers and ACE inhibitors). The effectiveness of clopidogrel did not depend on the dose of acetylsalicylic acid (75-325 mg 1 time / day).

The safety and effectiveness of clopidogrel in patients with acute ST-segment elevation myocardial infarction was studied in two randomized, placebo-controlled, double-blind studies, CLARITY and COMMIT.

The CLARITY study included 3491 patients enrolled within 12 hours of ST-segment elevation myocardial infarction with thrombolytic therapy. Patients received clopidogrel (loading dose 300 mg, subsequently 75 mg/day, n=1752), or placebo (n=1739), both drugs in combination with ASA (150-325 mg as a loading dose, subsequently 75-162 mg /day), fibrinolytic drug and, if necessary, heparin. The patients were observed for 30 days. The primary endpoint was the presence of infarct-related artery occlusion on predischarge angiogram, or death or recurrent myocardial infarction occurring before coronary angiography (study day 30). For patients who did not undergo angiography, the primary end point was death or recurrent myocardial infarction up to 8 days or before discharge from the hospital. Among the patients, 19.7% were women and 29.2% of patients were over 65 years of age. A total of 99.7% of patients received fibrinolytics (fibrin-specific:

68.7%;
non-fibrin-specific: 31.1%), 89.5% - heparin, 78.7% - beta-blockers, 54.7% - ACE inhibitors and 63% - statins.

15% of patients in the clopidogrel group and 21.7% of patients in the placebo group met the primary endpoint, representing an absolute reduction of 6.7% and a reduction difference of 36% in favor of clopidogrel (95% CI, 24.47%; P < 0.001), mainly due to a decrease in the percentage of occlusion of the infarct-related artery. This benefit remained consistent across subgroups of patients prespecified by age, sex, infarct location, and type of fibrinolytic or heparin used.

The COMMIT factorial study design included 45,852 patients within 24 hours of the onset of symptoms suggestive of myocardial infarction, incl. ECG abnormalities (ST segment elevation, ST segment depression, or left bundle branch block). Patients received clopidogrel (75 mg/day, n=22961) or placebo (n=22891), in combination with ASA (162 mg/day), for 28 days or until discharge. Primary endpoints were death from any cause, first recurrent infarction, stroke, or death. The group included 27.8% women, 58.4% patients aged 60 years or older (26% aged 70 years or older), and 54.5% patients receiving fibrinolytics.

Clopidogrel significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the relative risk of the combination of recurrent heart attack, stroke or death by 9% (p=0.002), representing an absolute reduction of 0.5% and 0.9%, respectively. . This advantage remained constant in all age and gender groups of patients, and did not depend on the use of fibrinolytics, and was observed already 24 hours after the start of the drug.

Atrial fibrillation

The ACTIVE-W and ACTIVE-A studies, separate studies of the ACTIVE program, included patients with atrial fibrillation (AF) who had at least one risk factor for vascular complications. Based on inclusion criteria, physicians enrolled patients in the ACTIVE-W study if patients were eligible for vitamin K antagonist (VKA) therapy (eg, warfarin). The ACTIVE-A study included patients who were not eligible for VKA therapy because they were unwilling or unable to receive such treatment.

The ACTIVE-W trial showed that treatment with vitamin K antagonists was more effective when combined with clopidogrel and ASA.

The ACTIVE-A study (n=7554) was a multicenter, randomized, double-blind, placebo-controlled study comparing the clopidogrel 75 mg/day + ASA group (n=3772) with the placebo + ASA group (n=3782). The recommended dose of ASA was 75-100 mg/day. Patients received treatment for the entire duration of treatment, up to 5 years.

Patients randomized to the ACTIVE study program had documented history of MA, i.e. or persistent AF or at least 2 episodes of intermittent AF in the past 6 months, and also had at least one of the following risk factors:

age ≥75 years or age 55–74 years in combination with diabetes mellitus requiring drug therapy, documented myocardial infarction, or documented acute coronary disease;
treatment for systemic hypertension;
previous stroke, transient ischemic attack (TIA) or non-CNS systemic embolism;
left ventricular dysfunction with left ventricular stroke volume <45%;
or documented peripheral vascular disease. The mean CHADS2 score was 2 (range 0–6).

The main criteria for excluding patients from the study were:

gastric and duodenal ulcer within the previous 6 months, previous intracerebral hemorrhage, severe thrombocytopenia (platelet count <50 × 109/l), need for therapy with clopidogrel or anticoagulants, unresponsive to one of the two compounds.

73% of patients enrolled in the ACTIVE-A trial were unable to take vitamin K antagonists due to physician judgment, abnormal INR, fall or head injury, or specific bleeding risk; 26% of patients did not want to take vitamin K antagonists.

The patient group included 41.8% women. The average age of patients was 71 years, 41.6% of patients were over 75 years old. Overall, 23% of patients received antiarrhythmic drugs, 52.1% received beta-blockers, 54.6% received ACE inhibitors, and 25.4% received statins.

The number of patients who experienced the expected clinical outcome (first stroke, myocardial infarction, non-CNS systemic embolism, or death from vascular disease) was 832 (22.1%) in the clopidogrel+ASA group and 924 (24.4%) in the clopidogrel+ASA group. placebo+ASA group.

The beneficial effect of clopidogrel + ASA was observed in the early stages and persisted throughout the study period up to 5 years; The incidence of the primary outcome was consistently lower in the clopidogrel + ASA group than in the placebo + ASA group.

The reduction in the risk of major vascular complications in the clopidogrel + ASA treatment group was mainly due to a significant reduction in the incidence of stroke. Stroke was observed in 296 (7.8%) patients receiving clopidogrel + ASA and in 408 (10.8%) patients receiving placebo + ASA.

The incidence of ischemic stroke was significantly lower in the clopidogrel + ASA group than in the placebo + ASA group (6.2% and 9.1%, respectively; relative risk reduction, 32.4%; 95% confidence interval, 20.2-42.7%).

The risk of stroke of any severity decreased with the use of clopidogrel + ASA. In addition, it was reported that there were 46 fewer non-disabling strokes and 69 fewer disabling or fatal strokes in the clopidogrel + ASA group than in the placebo + ASA group.

There was a trend towards a reduction in the rate of myocardial infarction in the group receiving clopidogrel + ASA (relative risk reduction, 21.9%; 95% CI, -3% to 40.7%, p = 0.08). The incidence of vascular disease mortality was similar between the two groups.

The effectiveness of clopidogrel + ASA was maintained throughout the study period (5 years), the incidence of stroke was significantly lower in the clopidogrel + ASA group compared to the placebo + ASA group.

Pediatric patients

In a randomized, double-blind, parallel-group study (CLARINET), 906 pediatric patients (neonates and infants) with cyanotic congenital heart disease with systemic-pulmonary anastomosis received clopidogrel 0.2 mg/kg (n=467) or placebo (n =439) against the background of concomitant basic therapy before the second stage of the operation. The median time between palliative bypass surgery and study drug initiation was 20 days. About 88% of patients received concomitant ASA therapy (doses ranging from 1 to 23 mg/kg/day). There was no difference between the groups in the primary composite outcome measure, the sum of deaths, shunt thrombosis, or cardiac interventions up to 120 days after a thrombotic complication (relative risk reduction, 11.1%; 95% CI:

-19.2, 33.6;
p=0.43). The most commonly reported adverse reaction in both groups was hemorrhage;
however, there was no significant difference between the groups in the incidence of hemorrhage. During long-term safety follow-up, 26 patients 1 year of age with a bypass were treated with clopidogrel until 18 months of age. No new security risks were identified during this monitoring.

Plavix®

Data obtained from clinical studies

The safety of clopidogrel has been studied in more than 44,000 patients, including more than 12,000 patients treated for a year or more. Overall, the tolerability of clopidogrel 75 mg/day in the CAPRIE study was similar to that of ASA 325 mg/day. regardless of the age, gender and race of patients. The following are clinically significant adverse events observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT and ACTIVE A.

Bleeding and hemorrhage

Comparison of monotherapy with clopidogrel and ASA

In the CAPRIE clinical trial, the overall incidence of all bleeding in patients taking clopidogrel and in patients taking ASA was 9.3%. The incidence of severe bleeding with clopidogrel and ASA was comparable: 1.4% and 1.6%, respectively.

In general, the incidence of gastrointestinal bleeding in patients taking clopidogrel and in patients taking ASA. was (2.0% and 2.7%, respectively), including the frequency of gastrointestinal bleeding requiring hospitalization was (0.7% and 1.1%, respectively).

The overall incidence of bleeding from other sites was higher when taking clopidogrel compared to taking ASA (7.3% versus 6.5%, respectively). However, the incidence of severe bleeding with clopidogrel and ASA was comparable (0.6% or 0.4%, respectively). The most commonly reported bleeding events were purpura/bruising, epistaxis. Less commonly reported were the development of hematomas, hematuria and ocular hemorrhages (mainly conjunctival). The incidence of intracranial hemorrhage with clopidogrel and ASA was comparable (0.4% or 0.5%, respectively).

Comparison of combination therapy clopidogrel + ASA and placebo + ASA

In the CURE clinical trial, patients taking clopidogrel + ASA, compared with patients taking placebo + ASA, had an increased incidence of major bleeding (3.7% vs. 2.7%) and minor bleeding (5.1% vs. compared to 2.4%). Mainly, the sources of major bleeding were the gastrointestinal tract (GIT) and arterial puncture sites.

The incidence of life-threatening bleeding in patients taking clopidogrel + ASA compared with patients taking placebo + ASA was not significantly different (2.2% and 1.8%, respectively), the incidence of fatal bleeding was the same (0.2% for both types of therapy).

The incidence of non-life-threatening major bleeding was significantly higher in patients taking clopidogrel + ASA compared with patients taking placebo + ASA (1.6% and 1%, respectively), but the incidence of intracranial hemorrhage was the same (0.1 % for both types of therapy).

The incidence of major bleeding in the clopidogrel + ASA group depended on the dose of ASA (< 100 mg: 2.6%; 100-200 mg: 3.5%; > 200 mg: 4.9%), as did the incidence of major bleeding in placebo+ASA group (<100 mg: 2.0%; 100-200 mg: 2.3%; >200 mg: 4.0%).

In patients who stopped antiplatelet therapy more than 5 days before coronary artery bypass grafting, there was no increase in the incidence of major bleeding within 7 days after the intervention (4.4% in the clopidogrel + ASA group and 5.3% in the placebo + ASA group). In patients who continued antiplatelet therapy during the last five days before coronary artery bypass surgery, the incidence of these events after surgery was 9.6% (in the clopidogrel + ASA group) and 6.3% (in the placebo + ASA group).

In the CLARITY clinical trial, the incidence of major bleeding (defined as intracranial bleeding or bleeding with a decrease in hemoglobin > 5 g/dL) in both groups (clopidogrel + ASA and placebo + ASA) was comparable in both treatment groups (1.3% vs. 1% in the clopidogrel+ASA group and the placebo+ASA group, respectively). It was similar in subgroups of patients divided by baseline characteristics and by type of fibrinolytic therapy or heparin therapy.

The incidence of fatal bleeding (0.8% vs. 0.6%) and intracranial hemorrhage (0.5% vs. 0.7%) during treatment with clopidogrel + ASA and placebo + ASA, respectively, was low and comparable in both treatment groups.

In the COMMIT clinical trial, the overall incidence of noncerebral major bleeding or cerebral bleeding was low and similar (0.6% in the clopidogrel+ASA group and 0.5% in the placebo+ASA group).

In the ACTIVE-A clinical trial, the incidence of major bleeding was higher in the clopidogrel + ASA group than in the placebo + ASA group (6.7% versus 4.3%, respectively). Major bleeding was mostly extracranial in both groups (5.3% vs. 3.5%), mainly from the gastrointestinal tract (3.5% vs. 1.8%). There were more intracranial hemorrhages in the clopidogrel + ASA group compared to the placebo + ASA group (1.4% versus 0.8%, respectively). There were no statistically significant differences between these treatment groups in the incidence of fatal bleeding (1.1% vs. 0.7%) and hemorrhagic stroke (0.8% vs. 0.6%).

Blood disorders

In the CAPRIE study, severe neutropenia (<0.45*109/L) was observed in 4 patients (0.04%) taking clopidogrel and 2 patients (0.02%) taking ASA.

Two of the 9599 patients taking clopidogrel had a complete absence of neutrophils in the peripheral blood, which was not observed in any of the 9586 patients taking ASA. Although the risk of myelotoxicity with clopidogrel is low, if a patient taking clopidogrel develops a fever or other signs of infection, the patient should be monitored for possible neutropenia.

During treatment with clopidogrel, the development of aplastic anemia was observed in one case.

The incidence of severe thrombocytopenia (<80*109/L) was 0.2% in patients taking clopidogrel and 0.1% in patients taking ASA, and very rare cases of platelet counts ≤30*109/L were reported.

The CURE and CLARITY studies observed comparable numbers of patients with thrombocytopenia or neutropenia in both treatment groups.

Other clinically significant adverse
reactions observed during clinical studies CARRIE , CURE , CLARITY COMMIT and ACTIVE - A
The frequency of adverse reactions was determined in accordance with the classification of the World Health Organization: very often (≥ 1/10); often (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 and < 1/100); rare (≥ 1/10000 and < 1/1000); very rare (< 1/10000), frequency unknown (cannot be calculated based on available data).

Nervous system disorders:

infrequently - headache, dizziness, paresthesia; rarely - vertigo.

Gastrointestinal disorders:

often - dyspepsia, abdominal pain, diarrhea; uncommon - nausea, gastritis, bloating, constipation, vomiting, stomach ulcer, duodenal ulcer.

Disorders of the skin and subcutaneous tissues:

Uncommon: skin rash, itching.

Blood and lymphatic system disorders:

uncommon - increased bleeding time, decreased platelet count in peripheral blood; leukopenia, decreased number of neutrophils in peripheral blood, eosinophilia.

Post-marketing experience with
the drug
Blood and lymphatic system disorders:

frequency is unknown - cases of serious bleeding, mainly subcutaneous, musculoskeletal, ocular hemorrhages (conjunctival, tissue and retinal), bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage), nosebleeds, hematuria and bleeding from postoperative wounds and cases of bleeding from lethal outcome (especially intracranial hemorrhage, gastrointestinal bleeding and retroperitoneal hemorrhage); agranulocytosis, granulocytopenia, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A.

Heart disorders

: frequency unknown - Kounis syndrome (vasospastic allergic angina/allergic myocardial infarction), caused by a hypersensitivity reaction to clopidogrel.

Immune system disorders:

frequency unknown - anaphylactoid reactions, serum sickness; cross-allergic and hematological reactions with other thienopyridines (such as ticlopidine, prasugrel) (see section "Special instructions"), autoimmune insulin syndrome (can lead to serious hypoglycemia, especially in patients with the HLA DRA4 serotype).

Mental disorders:

frequency unknown - confusion, hallucinations.

Nervous system disorders:

frequency unknown - taste disturbances, ageusia.

Vascular disorders:

frequency unknown - vasculitis, decreased blood pressure.

Disorders of the respiratory system, chest and mediastinal organs:

frequency unknown - bronchospasm, interstitial pneumonia, eosinophilic pneumonia.

Gastrointestinal disorders:

frequency unknown - colitis (including ulcerative colitis or lymphocytic colitis), pancreatitis, stomatitis.\

Disorders of the liver and biliary tract:

frequency unknown - hepatitis (non-infectious), acute liver failure.

Disorders of the skin and subcutaneous tissues:

frequency unknown - maculopapular erythematous or exfoliative rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), acute generalized exanthematous pustulosis, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations ( DRESS syndrome), eczema, lichen planus.

Musculoskeletal and connective tissue disorders:

frequency unknown - arthralgia (joint pain), arthritis, myalgia.

Renal and urinary tract disorders:

frequency unknown - glomerulonephritis.

Disorders of the genital organs and breast:

frequency unknown - gynecomastia.

General disorders and disorders at the injection site:

frequency unknown - fever.

Laboratory and instrumental data:

frequency unknown - deviation from the norm in laboratory parameters of the functional state of the liver, increased concentration of creatinine in the blood.

Plavix, 100 pcs., 75 mg, film-coated tablets

Data obtained from clinical studies

The safety of clopidogrel has been studied in more than 44,000 patients, incl. in more than 12,000 patients treated for a year or more. Overall tolerability of clopidogrel 75 mg/day in the CAPRIE

corresponded to the tolerability of ASA at a dose of 325 mg/day, regardless of the age, gender and race of patients.
The following are clinically significant adverse effects observed in five large clinical trials:
CAPRIE , CURE, CLARITY, COMMIT, ACTIVE A.

Bleeding and hemorrhage

Comparison of monotherapy with clopidogrel and ASA

In the CAPRIE

the overall incidence of all bleeding in patients taking clopidogrel and patients taking ASA was 9.3%. The incidence of severe bleeding with clopidogrel and ASA was comparable - 1.4% and 1.6%, respectively.

Overall, the incidence of gastrointestinal bleeding in patients taking clopidogrel and in patients taking ASA was 2% and 2.7%, respectively, incl. the incidence of gastrointestinal bleeding requiring hospitalization was 0.7% and 1.1%, respectively. The overall incidence of bleeding from other sites when taking clopidogrel compared to taking ASA was higher - 7.3% versus 6.5%. However, the incidence of severe bleeding with clopidogrel and ASA was comparable (0.6% and 0.4%, respectively). The most commonly reported bleeding events were purpura/bruising, epistaxis. Less commonly reported were the development of hematomas, hematuria and ocular hemorrhages (mainly conjunctival).

The incidence of intracranial hemorrhage with clopidogrel and ASA was comparable (0.4% and 0.5%, respectively).

Comparison of combination therapy with clopidogrel + ASA and placebo + ASA

In the CURE

in patients taking clopidogrel + ASA, compared with patients taking placebo + ASA, there was an increase in the incidence of major bleeding (3.7% versus 2.7%) and minor bleeding (5.1% versus 2.4%). Mainly, the sources of major bleeding were the gastrointestinal tract and arterial puncture sites.

The incidence of major bleeding in the clopidogrel + ASA group depended on the dose of ASA (<100 mg - 2.6%; 100-200 mg - 3.5%; >200 mg - 4.9%), as did the incidence of major bleeding in placebo + ASA group (<100 mg - 2%; 100-200 mg - 2.3%; >200 mg - 4%). In patients who stopped antiplatelet therapy more than 5 days before coronary artery bypass grafting, there was no increase in the incidence of major bleeding within 7 days after the procedure (4.4% in the clopidogrel + ASA group and 5.3% in the placebo + ASA group). In patients who continued antiplatelet therapy during the last five days before coronary artery bypass surgery, the incidence of these events after surgery was 9.6% (clopidogrel + ASA) and 6.3% (placebo + ASA).

In the CLARITY

The incidence of major bleeding (defined as intracranial hemorrhage or bleeding with a decrease in hemoglobin >5 g/dL) in both groups (clopidogrel + ASA and placebo + ASA) was comparable in both treatment groups (1.3 vs 1.1% in the clopidogrel + ASA group). ASA and the placebo + ASA group). It was similar in subgroups of patients divided by baseline characteristics and by type of fibrinolytic therapy or heparin therapy.

The incidence of fatal bleeding (0.8% vs. 0.6%) and intracranial hemorrhage (0.5% vs. 0.7%) with clopidogrel + ASA and placebo + ASA, respectively, was low and comparable in both treatment groups.

In the COMMIT

the overall incidence of noncerebral major bleeding or cerebral bleeding was low and similar (0.6% in the clopidogrel + ASA group and 0.5% in the placebo + ASA group).

In the ACTIVE-A

the incidence of major bleeding in the clopidogrel + ASA group was higher than in the placebo + ASA group (6.7% versus 4.3%, respectively). Major bleeding was mainly extracranial in both groups (5.3% vs 3.5%), and gastrointestinal bleeding was mainly observed (3.5% vs 1.8%). There were more intracranial hemorrhages in the clopidogrel + ASA group compared to the placebo + ASA group (1.4% versus 0.8%, respectively). There were no statistically significant differences between these treatment groups in the incidence of fatal bleeding (1.1% vs. 0.7%) and hemorrhagic stroke (0.8 vs. 0.6%).

Blood disorders

In the CAPRIE

severe neutropenia (<0.45·109/l) was observed in 4 patients (0.04%) taking clopidogrel and 2 patients (0.02%) taking ASA.

During treatment with clopidogrel, the development of aplastic anemia was observed in one case. The incidence of severe thrombocytopenia (<80 109/L) was 0.2% in patients taking clopidogrel and 0.1% in patients taking ASA; very rare cases of platelet counts <30 109/L were reported .

In CURE

and
CLARITY,
there were comparable numbers of patients with thrombocytopenia or neutropenia in both treatment groups.

Other clinically significant adverse reactions observed in clinical studies CAPRIE, CURE, CLARITY COMMIT, ACTIVE-A

The frequency of adverse reactions that were observed during the above clinical studies is presented in accordance with the following WHO classification: very common ≥10%; often ≥1% and <10%; uncommon ≥0.1% and <1%; rarely ≥ 0.01% and <0.1%; very rare <0.01%; frequency unknown - it is not possible to determine the frequency of occurrence of an adverse reaction from the available data.

From the nervous system:

uncommon - headache, dizziness, paresthesia; rarely - vertigo.

From the gastrointestinal tract:

often - dyspepsia, abdominal pain, diarrhea; uncommon - nausea, gastritis, bloating, constipation, vomiting, stomach ulcer, duodenal ulcer.

From the skin and subcutaneous tissue:

uncommon - rash, itching.

From the blood and lymphatic system:

uncommon - increased bleeding time, decreased platelet count in peripheral blood, leukopenia, decreased number of neutrophils in peripheral blood, eosinophilia.

Post-marketing experience with the drug

From the blood and lymphatic system:

frequency is unknown - cases of serious bleeding, mainly subcutaneous, musculoskeletal, ocular hemorrhages (conjunctival, tissue and retinal), bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage), nosebleeds, hematuria and bleeding from postoperative wounds and cases of bleeding from fatal outcome (especially intracranial hemorrhage, gastrointestinal bleeding and retroperitoneal hemorrhage), agranulocytosis, granulocytopenia, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A.

From the immune system:

frequency unknown - anaphylactoid reactions, serum sickness, cross-allergy with other thienopyridines (such as ticlopidine, prasugrel - see "Special Instructions").

Mental disorders:

frequency unknown - confusion, hallucinations.

From the nervous system:

frequency unknown - disturbances in taste perception.

From the side of blood vessels:

frequency unknown - vasculitis, decreased blood pressure.

From the respiratory system, chest and mediastinal organs:

frequency unknown - bronchospasm, interstitial pneumonia, eosinophilic pneumonia.

From the gastrointestinal tract:

frequency unknown - colitis (including ulcerative or lymphocytic), pancreatitis, stomatitis.

From the liver and biliary tract:

frequency unknown - hepatitis (non-infectious), acute liver failure.

For the skin and subcutaneous tissues:

frequency unknown - maculopapular erythematous or exfoliative rash, urticaria, itching, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), acute generalized exanthematous pustulosis, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations (
DRESS
syndrome), eczema, lichen planus.

From the musculoskeletal and connective tissue side:

frequency unknown - arthralgia (joint pain), arthritis, myalgia.

From the kidneys and urinary tract:

frequency unknown - glomerulonephritis.

General disorders and disorders at the injection site:

frequency unknown - fever.

From the genital organs and breast:

frequency unknown - gynecomastia.

Laboratory and instrumental data:

frequency unknown - deviation from the norm in laboratory parameters of the functional state of the liver, increased concentration of creatinine in the blood.

Coplavix®

Clinical research experience

Clopidogrel

The safety of clopidogrel has been studied in more than 44,000 patients, incl. in more than 12,000 patients treated for a year or more, and 30,000 patients treated simultaneously with clopidogrel and ASA. The following are clinically significant adverse effects observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT and ACTIVE A. The safety of clopidogrel in combination with ASA was assessed in more than 6200 patients treated for 1 year or more in the CURE clinical trial .

Bleeding and hemorrhage

In the CAPRIE clinical trial

The overall incidence of all bleeding in patients receiving either clopidogrel or ASA was 9.3%. The incidence of severe bleeding with clopidogrel was 1.4%, and with ASA - 1.6%.

In patients receiving clopidogrel and in patients receiving ASA, gastrointestinal bleeding occurred in 2% and 2.7% of cases, respectively, and hospitalization was required in 0.7% and 1.1% of cases.

The incidence of other bleeding events was higher in patients receiving clopidogrel than in patients receiving ASA (7.3% versus 6.5%, respectively). However, the incidence of major bleeding was similar in both groups (0.6% vs 0.4%). The most common symptoms observed in both groups were purpura/bruising and epistaxis. Hematomas, hematuria and ocular hemorrhages (mainly conjunctival) were less common.

The incidence of intracranial hemorrhage was 0.4% in patients receiving clopidogrel and 0.5% in patients receiving ASA.

In the CURE clinical trial

There was an increase in the incidence of major and minor bleeding in patients receiving clopidogrel + ASA compared with patients receiving placebo + ASA (with the incidence of these bleeding being 3.7% versus 2.7% for major bleeding and 5.5% versus 2.4% for minor bleeding, respectively) . The main sites of bleeding were the gastrointestinal tract and arterial puncture sites.

The increase in the incidence of life-threatening bleeding in patients receiving clopidogrel + ASA compared with patients receiving placebo + ASA was not statistically significant (2.2% vs. 1.8%). There was no difference between the two groups in the incidence of fatal bleeding (0.2% in both groups). The incidence of non-life-threatening major bleeding was significantly higher in patients receiving clopidogrel + ASA compared with patients receiving placebo + ASA (1.6% vs. 1%), and the incidence of intracranial hemorrhage in both groups was 0.1%.

The incidence of major bleeding when using the combination of clopidogrel + ASA depended on the dose of the latter (<100 mg - 2.6%; 100-200 mg - 3.5%, >200 mg - 4.9%), as well as their frequency when using ASA alone (< 100 mg - 2%, 100-200 mg - 2.3%, >200 mg - 4%).

In patients who stopped taking the drug more than 5 days before coronary artery bypass surgery, there was no increase in the incidence of major bleeding within 7 days after this intervention (4.4% when taking clopidogrel + ASA versus 5.3% when taking ASA alone). In patients who remained on antiplatelet therapy during the last five days before coronary artery bypass surgery, the incidence of these events after surgery was 9.6% (clopidogrel + ASA) and 6.3% (ASA alone).

In the CLARITY clinical trial

The incidence of major bleeding (such as intracranial hemorrhage or bleeding with a decrease in hemoglobin of more than 5 g/dL) was similar in both treatment groups (1.3% and 1.1% in the clopidogrel + ASA group and placebo + ASA group, respectively) and was essentially independent on the baseline characteristics of the patients and the type of fibrinolytic or heparin therapy. The incidence of fatal bleeding (0.8% and 0.6% in the clopidogrel + ASA and placebo + ASA groups, respectively) and intracranial hemorrhage (0.5% and 0.7% in the clopidogrel + ASA and placebo + ASA groups, respectively) was low and did not differ significantly in both treatment groups.

In the COMMIT clinical trial

The overall incidence of non-cerebral major bleeding or cerebral bleeding was low and did not differ significantly between the two groups (0.6% and 0.5% in the clopidogrel + ASA and placebo + ASA groups, respectively).

In the ACTIVE-A clinical trial

The incidence of major bleeding was greater in patients receiving clopidogrel + ASA than in patients receiving placebo + ASA (6.7% vs 4.3%). Major bleeding was mostly extracranial in both groups of patients (5.3% in the clopidogrel + ASA group; 3.5% in the placebo + ASA group), mainly bleeding from the gastrointestinal tract (3.5% vs. 1.8%). Patients taking clopidogrel + ASA had more intracranial hemorrhage than patients taking placebo + ASA (1.4% vs 0.8%, respectively). There were no statistically significant differences in the incidence of fatal bleeding and hemorrhagic stroke (0.8% and 0.6%, respectively) between these groups of patients.

Hematological disorders

In the CAPRIE clinical trial

Severe neutropenia (<0.45×109/l) was observed in 4 patients (0.04%) receiving clopidogrel, and in 2 patients (0.02%) receiving ASA.

Two of the 9599 patients receiving clopidogrel had a complete absence of neutrophils in the peripheral blood, which was not observed in any of the 9586 patients receiving ASA. Although the risk of myelotoxicity with clopidogrel is very low, the possibility should be considered when fever or other signs of infection occur in patients receiving clopidogrel.

One case of aplastic anemia was observed during treatment with clopidogrel. The incidence of severe thrombocytopeia (<80×109/L) was 0.2% in the clopidogrel group and 0.1% in the ASA group; in very rare cases, platelet counts ≤30×109/L have been reported).

In the CURE and CLARITY clinical studies

The number of patients with thrombocytopenia or neutropenia was similar in both groups.

Other clinically significant side effects

Below are other side effects observed in the CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE-A clinical studies.

The incidence of side effects was determined according to the WHO classification: very common ≥10%; often ≥1% and <10%; uncommon ≥0.1% and <1%; rarely ≥0.01% and <0.1%; very rare <0.01%; unknown frequency - it is not possible to determine the frequency of side effects from the available data.

From the central and peripheral nervous system:

infrequently - headache, dizziness and paresthesia; rarely - vertigo.

From the gastrointestinal tract:

often - dyspepsia, abdominal pain, diarrhea; uncommon - nausea, gastritis, flatulence, constipation, vomiting, gastric ulcer and duodenal ulcer.

From the blood coagulation system: uncommon - prolongation of bleeding time, decrease in the number of platelets in the peripheral blood.

For the skin and subcutaneous tissues:

uncommon - rash, itching.

From the hematopoietic system:

uncommon - leukopenia, decreased number of neutrophils in peripheral blood, eosinophilia.

Adverse effects observed in the post-marketing period

Clopidogrel

Adverse reactions are divided into system-organ classes and are indicated in accordance with the above classification of their frequency of occurrence.

From the blood and lymphatic system:

very rarely - cases of severe hemorrhages, mainly in skin tissue, muscles and joints, eye tissue (conjunctival, internal media and retina) and bleeding from the respiratory tract, nosebleeds, hematuria and bleeding from the surgical wound; cases of fatal bleeding (in particular intracranial hemorrhage, gastrointestinal bleeding and retroperitoneal hemorrhage), agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP).

From the immune system:

very rarely - anaphylactoid reactions, serum sickness.

Mental disorders:

very rarely - confusion, hallucinations.

From the nervous system:

very rarely - changes in taste sensations.

From the cardiovascular system:

very rarely - vasculitis, decreased blood pressure.

From the respiratory system:

very rarely - bronchospasm, interstitial pneumonitis.

From the gastrointestinal tract:

very rarely - colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis.

From the liver and biliary tract:

very rarely - hepatitis (non-infectious nature), acute liver failure.

For the skin and subcutaneous tissues:

very rarely - maculopapular or erythematous rash, urticaria, itching, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), eczema and lichen planus.

From the musculoskeletal and connective tissue side:

very rarely - arthralgia, arthritis, myalgia.

From the kidneys and urinary tract:

very rarely - glomerulopathy.

General disorders and disorders at the injection site:

very rarely - fever.

Laboratory and instrumental data:

very rarely - deviation from the norm in biochemical indicators of the functional state of the liver, an increase in the concentration of creatinine in the blood.

ASK

The following adverse reactions have been reported in published information on the use of ASA; their frequency of occurrence is classified as “unknown frequency.”

From the immune system:

anaphylactic shock, increased symptoms of food allergy.

From the nervous system:

intracranial hemorrhages.

Metabolism and nutrition:

hypoglycemia, gout.

Hearing and labyrinth disorders:

hearing loss, tinnitus.

From the gastrointestinal tract:

ulcer or ulcerative perforation of the stomach and/or duodenum, symptoms of damage to the upper gastrointestinal tract, such as gastralgia.

From the liver and biliary tract:

increased activity of liver enzymes, liver damage, mainly hepatocellular.

From the kidneys and urinary tract:

acute renal failure (especially in patients with pre-existing renal failure, decompensated heart failure, nephritic syndrome or while taking diuretics).