Coplavix

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT COPLAVIX® (COPLAVIX®)

Composition:

Active substances: clopidogrel, acetylsalicylic acid;

One tablet contains 75 mg of clopidogrel hydrogen sulfate in the form of base and 75 mg of acetylsalicylic acid;

Excipients:

clopidogrel layer: mannitol (E 421), polyethylene glycol 6000, microcrystalline cellulose (low moisture content, 90 μm), low-substituted hydroxypropylcellulose, hydrogenated castor oil;

acetylsalicylic acid layer: maize starch, low-substituted hydroxypropylcellulose, stearic acid, microcrystalline cellulose (low moisture content, 90 μm), colloidal anhydrous silicon dioxide;

film coating: Opadry Yellow 32K22174: lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, yellow iron oxide (E 172);

polishing: carnauba wax.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: slightly convex oval-shaped yellow film-coated tablets, engraved with "C75" on one side and "A75" on the other.

Pharmacotherapeutic group. Antithrombotic agents, platelet aggregation inhibitors, excluding heparin. ATC code B01AC30.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. Clopidogrel belongs to prodrugs; one of its metabolites is an inhibitor of platelet aggregation. The active metabolite of clopidogrel responsible for inhibiting platelet aggregation is formed via metabolism of clopidogrel by enzymes of the cytochrome CYP450 system. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y12 receptor on the platelet surface and subsequent ADP-mediated activation of the glycoprotein IIb/IIIa complex, thereby suppressing platelet aggregation. Due to the irreversible nature of binding, platelets exposed to clopidogrel remain affected throughout their lifespan (approximately 7–10 days); normal platelet function recovers at a rate corresponding to platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking ADP-mediated amplification of platelet activation caused by released ADD.

Since the active metabolite is formed via enzymes of the cytochrome CYP450 system, and some of these enzymes are polymorphic or inhibited by other medicinal products, adequate platelet inhibition does not occur in all patients.

Pharmacodynamic effects. Repeated administration of clopidogrel at a dose of 75 mg daily significantly inhibited ADP-induced platelet aggregation from the first day of treatment; this effect gradually increased and reached a steady state by days 3–7. At steady state, the mean level of platelet inhibition observed with the 75 mg daily dose ranged from 40% to 60%. Platelet aggregation and bleeding time gradually returned to baseline levels within approximately 5 days.

Acetylsalicylic acid inhibits platelet aggregation by irreversible inhibition of cyclooxygenase prostaglandins, thus suppressing the formation of thromboxane A2, which induces platelet aggregation and vasoconstriction. This effect persists throughout the platelet lifespan.

Clinical efficacy and safety.

The safety and efficacy of the combination of clopidogrel with ASA were evaluated in three double-blind studies involving over 61,900 patients: in the CURE, CLARITY, and COMMIT studies, the combination of clopidogrel with ASA was compared to monotherapy with ASA, with both treatment regimens used in combination with other standard therapy.

The CURE study included 12,562 patients with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), who had experienced the last episode of chest pain or ischemic symptoms within the previous 24 hours. Patients had ECG changes indicating new ischemia or elevated levels of cardiac enzymes or troponin I or T at least twice the upper limit of normal. Patients were randomized into groups receiving clopidogrel (loading dose 300 mg, then 75 mg/day, N = 6,259) with ASA (75–325 mg once daily) or ASA monotherapy (75–325 mg once daily, N = 6,303), with both regimens combined with other standard therapy. Patients received treatment for up to one year. In the CURE study, 823 (6.6%) patients concurrently received a GPIIb/IIIa receptor antagonist. Heparins were used in over 90% of patients, and concomitant heparin therapy did not significantly affect the relative frequency of bleeding in the clopidogrel with ASA group versus the ASA monotherapy group.

The number of patients reaching the primary endpoint (cardiovascular death (CVD), myocardial infarction (MI), or stroke) was 582 (9.3%) in the clopidogrel with ASA group and 719 (11.4%) in the ASA monotherapy group; the relative risk reduction (RRR) was 20% (95% CI 10–28%; p = 0.00009) in the clopidogrel with ASA group (the relative risk reduction was 17% with conservative patient management, 29% with percutaneous transluminal coronary angioplasty (PTCA) with or without stenting, and 10% in patients who underwent coronary artery bypass grafting (CABG)). Prevention of new cardiovascular events (primary endpoint) occurred with a relative risk reduction of 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) during the periods 0–1, 1–3, 3–6, 6–9, and 9–12 months of the study, respectively. Thus, after more than 3 months of treatment, the favorable effect observed in the clopidogrel with ASA group did not further increase, while the risk of bleeding remained (see section "Special precautions for use").

Use of clopidogrel in the CURE study was associated with reduced need for thrombolytic therapy (RRR = 43.3%; CI: 24.3–57.5%) and use of GPIIb/IIIa receptor inhibitors (RRR = 18.2%; CI: 6.5–28.3%).

The number of patients reaching the combined primary endpoint (CVD, MI, stroke, or refractory ischemia) was 1,035 (16.5%) in the clopidogrel with ASA group and 1,187 (18.8%) in the ASA monotherapy group; the relative risk reduction was 14% (95% CI 6–21%, p = 0.0005) in the clopidogrel with ASA group. This effect was primarily due to a statistically significant reduction in the frequency of MI (287 (4.6%) in the clopidogrel with ASA group and 363 (5.8%) in the ASA monotherapy group). No effect on the frequency of rehospitalization for unstable angina was observed.

Results obtained in patient subgroups with various characteristics (e.g., unstable angina or non-Q-wave MI, low to high risk, diabetes, need for revascularization, age, sex, etc.) were consistent with the primary analysis results. In particular, during a retrospective analysis of 2,172 patients (17% of the total population participating in the CURE study) who underwent stenting (Stent-CURE), clopidogrel demonstrated a significant RRR of 26.2% compared to placebo in favor of clopidogrel for the combined endpoint (CVD, MI, stroke), as well as a significant RRR of 23.9% for the second combined primary endpoint (CVD, MI, stroke, or refractory ischemia). Moreover, the safety profile of clopidogrel in this subgroup did not raise particular concerns. Therefore, the results of this subgroup are consistent with the overall study results.

In patients with acute MI with ST-segment elevation, the safety and efficacy of clopidogrel were evaluated in two randomized, placebo-controlled, double-blind studies—CLARITY and COMMIT.

The CLARITY study included 3,491 patients. These patients had experienced MI with ST-segment elevation within the previous 12 hours and were scheduled for thrombolytic therapy. Patients received clopidogrel (loading dose 300 mg, then 75 mg/day, n = 1,752) plus ASA or ASA alone (loading dose 150–325 mg, then 75–162 mg/day, n = 1,739), a fibrinolytic agent, and, if needed, heparin. Patients were followed for 30 days. The primary endpoint was occlusion of the infarct-related artery on angiogram before hospital discharge or death, or recurrent MI before coronary angiography. In patients who did not undergo angiography, the primary endpoint was death or recurrent MI by day 8 or before hospital discharge. The patient population included 19.7% women and 29.2% patients aged ≥65 years. Overall, 99.7% of patients received fibrinolytics (fibrin-specific—68.7%, non-fibrin-specific—31.1%), 89.5% received heparin, 78.7% received beta-blockers, 54.7% received ACE inhibitors, and 63% received statins.

Fifteen percent (15%) of patients in the clopidogrel with ASA group and 21.7% in the ASA-only group reached the primary endpoint, representing an absolute reduction of 6.7% and a 36% reduction in risk in favor of clopidogrel (95% CI: 24–47%; p < 0.001), primarily due to a reduction in occlusion events in infarct-related arteries. This effect was observed in all predefined subgroups, including those defined by age and sex, infarct location, and type of fibrinolytic or heparin used.

The COMMIT study, using a 2×2 factorial design, included 45,852 patients who, within 24 hours of symptom onset suggestive of MI, showed ECG signs (i.e., ST-segment elevation, ST-segment depression, or left bundle branch block). Patients received clopidogrel (75 mg/day, n = 22,961) with ASA (162 mg/day) or ASA alone (162 mg/day, n = 22,891) for 28 days or until hospital discharge. Combined primary endpoints were death from any cause and first recurrence of MI, stroke, or death. The population included 27.8% women, 58.4% patients aged ≥60 years (26% aged ≥70 years), and 54.5% patients who received fibrinolytics.

Clopidogrel with ASA significantly reduced the relative risk of death from any cause by 7% (p = 0.029) and the relative risk of the combination of recurrent MI, stroke, or death by 9% (p = 0.002), representing an absolute reduction of 0.5% and 0.9%, respectively. This effect was observed in patients within the first 24 hours, regardless of age, sex, or use of fibrinolytics.

Switching from P2Y12 inhibitors in acute coronary syndrome (ACS).

Transitioning from a more potent P2Y12 receptor inhibitor to clopidogrel with aspirin after the acute phase of ACS was evaluated using two investigator-sponsored (ISS) randomized studies—TOPIC and TROPICAL-ACS—based on clinical outcomes.

The clinical benefits provided by more potent P2Y12 receptor inhibitors—ticagrelor and prasugrel—in pivotal studies were associated with significant reductions in recurrent ischemic events (particularly acute and subacute stent thrombosis (ST), myocardial infarction (MI), and urgent revascularization). Despite a stable benefit regarding ischemic events during the first year, a more pronounced reduction in recurrent ischemic events after ACS was observed during the first days after treatment initiation. Meanwhile, a retrospective analysis revealed a statistically significant increase in bleeding risk with more potent P2Y12 receptor inhibitors, occurring predominantly during the maintenance therapy phase one month after ACS. The TOPIC and TROPICAL-ACS studies were designed to investigate the possibility of minimizing bleeding while maintaining treatment efficacy.

TOPIC (Timing Of Platelet Inhibition after acute Coronary syndrome)

In this randomized open-label study, patients with ACS requiring PCI (percutaneous coronary intervention) were included. Patients who were receiving aspirin and a more potent P2Y12 receptor inhibitor and had no adverse events within one month were assigned to switch to treatment with fixed-dose aspirin plus clopidogrel (de-escalation dual antiplatelet therapy (DAPT)) or to continue their current medication regimen (unchanged DAPT).

Overall, the analysis included 645 of 646 patients with ST-segment elevation MI, non-ST-segment elevation MI, or unstable angina (de-escalation DAPT (n = 322); unchanged DAPT (n = 323)). One-year follow-up was conducted in 316 patients (98.1%) in the de-escalation DAPT group and 318 patients (98.5%) in the unchanged DAPT group. The mean follow-up duration for both groups was 359 days. Characteristics of the studied cohorts were similar between the two groups.

The primary outcome—combination of cardiovascular death, stroke, urgent revascularization, and bleeding ≥2 on the BARC (Bleeding Academic Research Consortium) scale at one year after ACS—occurred in 43 patients (13.4%) in the de-escalation DAPT group and 85 patients (26.3%) in the unchanged DAPT group (p < 0.01). This statistically significant difference was primarily due to fewer bleeding episodes, with no reported difference in ischemic disease endpoints (p = 0.36), while bleeding ≥2 on the BARC scale occurred less frequently in the de-escalation DAPT group (4.0%) compared to the unchanged DAPT group (14.9%, p < 0.01). Bleeding episodes defined as all bleeds on the BARC scale occurred in 30 patients (9.3%) in the de-escalation DAPT group and 76 patients (23.5%) in the unchanged DAPT group (p < 0.01).

TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes)

This randomized open-label study included 2,610 patients with biomarker-positive ACS after successful PCI.

Patients were randomized to receive either prasugrel 5 or 10 mg/day (days 0–14) (n = 1,306) or prasugrel 5 or 10 mg/day (days 0–7) followed by a switch to clopidogrel 75 mg/day (days 8–14) (n = 1,304) in combination with ASA (<100 mg/day). Platelet function testing (PFT) was performed on day 14. Patients receiving prasugrel monotherapy continued prasugrel for 11.5 months.

Patients switching to clopidogrel underwent testing for high on-treatment platelet reactivity (HPR). If HPR was ≥46 units, patients were switched back to prasugrel 5 or 10 mg/day for 11.5 months; if HPR was <46 units, patients continued clopidogrel 75 mg/day for 11.5 months. Thus, the de-escalation group under monitoring included patients receiving either prasugrel 5 mg (40%) or clopidogrel (60%). All patients continued aspirin and were followed for one year.

The primary endpoint (combination of cardiovascular death, MI, stroke, and bleeding ≥2 on the BARC scale at 12 months) was met, indicating non-inferiority. Ninety-five patients (7%) in the monitored de-escalation group and 118 patients (9%) in the control group experienced the event (p-value for non-inferiority = 0.0004). Monitored de-escalation did not lead to an increase in combined ischemic event risk (2.5% in the de-escalation group vs. 3.2% in the control group; p-value for non-inferiority = 0.0115) or the key secondary endpoint—bleeding ≥2 on the BARC scale (5% in the de-escalation group vs. 6% in the control group (p = 0.23)). Cumulative frequency of all bleeding events (classes 1–5 on the BARC scale) was 9% (114 events) in the monitored de-escalation group compared to 11% (137 events) in the control group (p = 0.14).

Children. The European Medicines Agency has waived the obligation to submit results of studies of Coplavix® in all pediatric subpopulations for the treatment of coronary atherosclerosis (see section "Dosage and administration").

Pharmacokinetics.

Clopidogrel.

Absorption. After single and repeated oral doses of 75 mg daily, clopidogrel is rapidly absorbed. The mean peak plasma concentration of unchanged clopidogrel (approximately 2.2–2.5 ng/mL after a single 75 mg oral dose) is reached about 45 minutes after administration. Absorption is at least 50% based on the amount of clopidogrel metabolites excreted in urine.

Distribution. In vitro, clopidogrel and its main circulating (inactive) metabolite reversibly bind to human plasma proteins (98% and 94%, respectively). Binding is non-saturable in vitro over a wide concentration range.

Metabolism. Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, clopidogrel metabolism occurs via two main metabolic pathways: one via esterase followed by hydrolysis to an inactive metabolite, a carboxylic acid derivative (85% of circulating metabolites), and the other via various cytochrome P450 enzymes. Initially, during clopidogrel metabolism, an intermediate metabolite, 2-oxo-clopidogrel, is formed. Further metabolism of the intermediate metabolite 2-oxo-clopidogrel leads to the formation of the active metabolite, a thiol derivative of clopidogrel. In vitro, this metabolic pathway is mediated by isoenzymes CYP3A4, CYP2C19, CYP1A2, and CYP2B6. The active thiol metabolite isolated in vitro rapidly and irreversibly binds to platelet receptors, thereby suppressing platelet aggregation.

After a single 300 mg loading dose of clopidogrel, the Cmax of the active metabolite is twice as high as after 4 days of maintenance dosing at 75 mg. Cmax is reached approximately 30–60 minutes after administration.

Elimination. Within 120 hours after oral administration of 14C-labeled clopidogrel to humans, approximately 50% is excreted in urine and approximately 46% in feces. After a single 75 mg oral dose, the elimination half-life is approximately 6 hours. The elimination half-life of the main circulating (inactive) metabolite is 8 hours after single or repeated administration.

Pharmacogenetics. CYP2C19 is involved in the formation of both the active metabolite and the intermediate metabolite 2-oxo-clopidogrel. Based on quantitative ex vivo platelet aggregation measurements, pharmacokinetic parameters and the antithrombotic effect of the active metabolite of clopidogrel vary according to CYP2C19 genotype.

The CYP2C19*1 allele corresponds to fully functional metabolism, while the CYP2C19*2 and CYP2C19*3 alleles correspond to reduced metabolism. The CYP2C19*2 and CYP2C19*3 alleles account for 85% of reduced-function alleles in Caucasians and 99% in Asians. Other alleles associated with reduced metabolism include CYP2C19*4, *5, *6, *7, and *8, but they are less common in the general population.

A patient with reduced metabolism has two non-functional alleles, as defined above. According to published data, CYP2C19 slow metabolizer genotypes occur in approximately 2% of Caucasians, 4% of African Americans, and 14% of Chinese. Tests are currently available to determine a patient's CYP2C19 genotype.

In a crossover study involving 40 healthy volunteers, 10 in each of four CYP2C19 metabolizer groups (ultrarapid, extensive, intermediate, and poor), pharmacokinetic and antiplatelet responses were evaluated after a 300 mg dose followed by 75 mg/day and after a 600 mg dose followed by 150 mg/day for 5 days (steady state). No significant differences in active metabolite concentrations and mean platelet aggregation inhibition (PAI) were observed between ultrarapid, extensive, and intermediate metabolizers. In poor metabolizers, the concentration of the active metabolite was reduced by 63–71% compared to extensive metabolizers. After the 300 mg/75 mg dosing regimen, antiplatelet responses were reduced in poor metabolizers—mean PAI (5 µM ADP) was 24% (at 24 hours) and 37% (on day 5) compared to 39% (at 24 hours) and 58% (on day 5) in extensive metabolizers and 37% (at 24 hours) and 60% (on day 5) in intermediate metabolizers. When poor metabolizers followed the 600 mg/150 mg regimen, the concentration of the active metabolite was higher than with the 300 mg/75 mg regimen. Additionally, PAI was 32% (at 24 hours) and 61% (on day 5), exceeding that in poor metabolizers on the 300 mg/75 mg regimen and comparable to that in other CYP2C19 metabolizer groups on the 300 mg/75 mg regimen. Based on clinical study results, the appropriate dosing regimen for this patient group has not been established.

Based on the above results, in a meta-analysis of 6 studies including 335 participants at steady state receiving clopidogrel treatment, it was shown that the concentration of the active metabolite decreased by 28% in intermediate metabolizers and by 72% in poor metabolizers, and platelet aggregation inhibition (5 µM ADP) was reduced by 5.9% and 21.4%, respectively, compared to extensive metabolizers.

The impact of CYP2C19 genotype on clinical outcomes in patients receiving clopidogrel has not been evaluated in prospective randomized controlled trials. However, several retrospective analyses have been conducted to assess this effect in patients receiving clopidogrel with available genotyping results: CURE (n = 2,721), CHARISMA (n = 2,428), CLARITY-TIMI 28 (n = 227), TRITON-TIMI 38 (n = 1,477), and ACTIVE-A (n = 601), as well as several published cohort studies.

In the TRITON-TIMI 38 study and three cohort studies (Collet, Sibbing, Giusti), the combined group of patients with intermediate or poor metabolism had a higher frequency of cardiovascular complications (death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolizers.

In the CHARISMA study and one cohort study (Simon), increased complication frequency was observed only in poor metabolizers compared to extensive metabolizers.

In the CURE, CLARITY, ACTIVE-A, and one cohort study (Trenk), no increase in complication frequency was observed according to metabolizer status.

None of these analyses included a sufficient number of patients to detect differences in clinical outcomes in poor metabolizers.

Special patient groups. Information on pharmacokinetic parameters of the active metabolite of clopidogrel in these patient groups is lacking.

Renal impairment. After repeated administration of clopidogrel 75 mg daily in patients with severe renal disease (creatinine clearance 5–15 mL/min), inhibition of ADP-induced platelet aggregation was lower (25%) than in healthy volunteers, although bleeding time prolongation was similar to that observed in healthy volunteers receiving 75 mg clopidogrel daily. Additionally, clinical tolerability was satisfactory in all patients.

Hepatic impairment. After repeated administration of clopidogrel 75 mg daily for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. Mean bleeding time prolongation in both groups was also similar.

Race. The prevalence of CYP2C19 alleles leading to moderate or marked reduction in CYP2C19-mediated metabolism depends on race/ethnicity (see section "Pharmacogenetics"). Published data on patients of Asian origin are limited, making it difficult to assess the clinical significance of CYP2C19 genotype for treatment outcomes.

Acetylsalicylic acid (ASA).

Absorption. ASA contained in Coplavix® is converted to salicylic acid via hydrolysis after absorption. Peak plasma levels of salicylic acid are reached within 1 hour after administration. Thus, ASA plasma levels are below the limit of detection 1.5–3 hours after administration.

Distribution. ASA binds poorly to plasma proteins and has a low volume of distribution (10 L). Its metabolite, salicylic acid, rapidly binds to plasma proteins, but binding is concentration-dependent (non-linear). At low concentrations (<100 µg/mL), approximately 90% of salicylic acid binds to albumin. Salicylic acid readily penetrates all body tissues and fluids, including the central nervous system, breast milk, and fetal tissues.

Metabolism and elimination. ASA contained in Coplavix® is rapidly converted via hydrolysis to salicylic acid, with a half-life of 0.3–0.4 hours at ASA doses of 75–100 mg. Salicylic acid is primarily conjugated in the liver, forming salicyluric acid, phenolic glucuronide, acyl glucuronide, and several secondary metabolites. The plasma half-life of salicylic acid in Coplavix® is approximately 2 hours. Salicylate metabolism is saturable; total body clearance decreases at high serum concentrations due to the liver's limited capacity to form both salicyluric acid and phenolic glucuronide. With toxic doses (10–20 g), the plasma half-life may exceed 20 hours. With high ASA doses, salicylic acid elimination follows zero-order kinetics (i.e., elimination rate is constant relative to plasma concentration), with an actual half-life of 6 hours or more. Renal excretion of unchanged active substance depends on urine pH. When urine pH exceeds 6.5, renal clearance of free salicylate increases from 5% to 80%. After therapeutic doses, approximately 10% is excreted in urine as salicylic acid, 75% as salicyluric acid, 10% as phenolic, and 5% as acyl glucuronide of salicylic acid.

Given the pharmacokinetic and metabolic characteristics of both compounds, clinically significant pharmacokinetic interactions are unlikely.

Preclinical safety data.

Clopidogrel.

In preclinical studies in rats and baboons, the most significant changes were observed in the liver. These occurred at doses at least 25 times higher than the concentration observed in humans receiving a 75 mg/day dose and resulted from effects on hepatic enzymes involved in metabolism. In humans receiving therapeutic doses of clopidogrel, no effects on hepatic metabolizing enzymes were observed.

At very high doses of clopidogrel in rats and baboons, poor gastrointestinal tolerability (gastritis, gastric erosions, and/or vomiting) was also observed.

There was no evidence of carcinogenic effects after administration of clopidogrel to mice for 78 weeks and to rats for 104 weeks at doses up to 77 mg/kg/day (at least 25 times the concentration observed in humans receiving the clinical dose of 75 mg/day).

Clopidogrel was tested in several in vitro and in vivo genotoxicity studies and did not show genotoxic activity.

Clopidogrel was found not to affect reproductive function in male and female rats and showed no teratogenic effects in rats or rabbits. Administration to lactating female rats caused a slight delay in offspring development. Special pharmacokinetic studies with radiolabeled clopidogrel showed that the parent compound or its metabolites penetrate into breast milk. Therefore, direct (minor toxicity) or indirect (low palatability) effects of the drug cannot be excluded.

Acetylsalicylic acid.

Single-dose studies showed that ASA has low toxicity upon oral administration. Repeated-dose toxicity studies showed that doses up to 200 mg/kg/day were well tolerated in rats; dogs were more sensitive, likely due to high sensitivity of dogs to the ulcerogenic effect of nonsteroidal anti-inflammatory drugs (NSAIDs). No issues with genotoxicity or clastogenicity were identified with ASA. Although no formal carcinogenicity studies of ASA were conducted, it has been shown not to be a factor promoting tumor growth.

Reproductive toxicity data indicate that ASA exhibits teratogenic properties in various laboratory animals.

In animals, administration of a prostaglandin synthesis inhibitor has been shown to increase fetal loss before and after implantation, as well as embryofetal lethality. Additionally, increased frequency of various developmental abnormalities, including cardiovascular, has been reported in animals receiving a prostaglandin synthesis inhibitor during the organogenesis period.

Clinical characteristics.

Indications.

Secondary prevention of atherothrombotic complications in adults already receiving clopidogrel and acetylsalicylic acid (ASA). Koplavix® is a fixed-dose combination medicinal product for continuation of therapy in cases of:

• Acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), including patients who have undergone stent placement during percutaneous coronary intervention;
• Acute ST-segment elevation myocardial infarction in patients receiving medical treatment, when thrombolysis is feasible.

Contraindications.

Hypersensitivity to the active substances or to any of the excipients.

Severe hepatic impairment.

Acute pathological bleeding, such as peptic ulcer bleeding or intracranial hemorrhage.

Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs), bronchial asthma, rhinitis, nasal polyps. Mastocytosis, in which administration of acetylsalicylic acid may provoke severe hypersensitivity reactions (including circulatory shock with flushing, arterial hypotension, tachycardia, and vomiting).

Severe renal impairment (creatinine clearance < 30 mL/min).

Acute peptic ulcers.

Hemorrhagic diathesis.

Severe heart failure.

Concomitant use of acetylsalicylic acid and methotrexate at doses of 15 mg/week or higher (due to increased hematological toxicity of methotrexate — salicylates reduce renal clearance of methotrexate and displace it from plasma protein binding).

Third trimester of pregnancy (see section "Use in pregnancy or lactation").

Interaction with other medicinal products and other forms of interaction.

Medicinal products associated with bleeding risk. There is an increased risk of bleeding due to potential additive synergy. Medicinal products whose concomitant use is associated with bleeding risk should be prescribed with caution (see section "Special precautions for use").

Oral anticoagulants. Concomitant use of Koplavix*®* with oral anticoagulants is not recommended, as it may enhance bleeding intensity (see section "Special precautions for use"). Although administration of clopidogrel at a dose of 75 mg/day in patients receiving long-term warfarin therapy did not alter the pharmacokinetics of S-warfarin or the international normalized ratio (INR), concomitant use of clopidogrel and warfarin increases the risk of bleeding due to independent effects of these agents on hemostasis.

Glycoprotein IIb/IIIa inhibitors. Koplavix*®* should be used with caution in patients concurrently receiving glycoprotein IIb/IIIa inhibitors (see section "Special precautions for use").

Heparin. In a clinical study conducted in healthy volunteers, clopidogrel did not require dose adjustment of heparin and did not alter heparin's effect on coagulation. Concomitant use of heparin does not affect the inhibitory effect of clopidogrel on platelet aggregation. A pharmacodynamic interaction between Koplavix*®* and heparin is possible, potentially increasing the risk of bleeding. Therefore, concomitant use requires caution (see section "Special precautions for use").

Thrombolytics. The safety of concomitant use of clopidogrel with fibrin-specific or non-fibrin-specific thrombolytic agents and heparins was evaluated in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed with concomitant use of thrombolytics and heparin with ASA (see section "Adverse effects"). The safety of concomitant use of Koplavix*®* with other thrombolytic agents has not been officially established; such combinations require caution (see section "Adverse effects").

Nonsteroidal anti-inflammatory drugs (NSAIDs). In a clinical study involving healthy volunteers, concomitant use of clopidogrel and naproxen increased occult gastrointestinal blood loss. Therefore, concomitant use with nonsteroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors, is not recommended (see section "Special precautions for use").

Concomitant use of high-dose salicylates with NSAIDs (due to synergistic effects) increases the risk of ulceration and gastrointestinal bleeding.

Experimental data indicate that ibuprofen may inhibit the antiplatelet effect of low-dose aspirin when administered concomitantly. In one study, administration of a single 400 mg dose of ibuprofen 8 hours before or 30 minutes after immediate-release aspirin (81 mg) resulted in reduced effect of ASA on thromboxane formation or platelet aggregation. However, limitations of these data and statistical uncertainty regarding extrapolation of ex vivo findings to clinical situations mean that definitive conclusions about regular ibuprofen use cannot be drawn; clinically significant effects are unlikely with occasional ibuprofen use (see section "Pharmacodynamics").

Selective serotonin reuptake inhibitors (SSRIs). SSRIs affect platelet activation and increase bleeding risk; therefore, concomitant use of SSRIs with clopidogrel should be done with caution.

Metamizole. When used concomitantly with acetylsalicylic acid, metamizole may reduce the effect of ASA on platelet aggregation. Therefore, this combination should be prescribed with caution to patients receiving low-dose ASA for cardioprotective purposes.

Other medicinal products used concomitantly with clopidogrel.

Inducers of CYP2C19

Since clopidogrel metabolism into its active metabolite is partially mediated by CYP2C19, use of medicinal products that enhance the activity of this enzyme is likely to increase levels of the active metabolite of clopidogrel. The clinical significance of this interaction is not established.

Rifampicin — a potent inducer of CYP2C19 — increases both levels of the active metabolite of clopidogrel and platelet inhibition, potentially increasing bleeding risk. As a precaution, concomitant use of potent CYP2C19 inducers should be avoided (see section "Special precautions for use").

Inhibitors of CYP2C19

Since clopidogrel metabolism into its active metabolite is partially mediated by CYP2C19, use of medicinal products that inhibit this enzyme's activity is likely to reduce levels of the active metabolite of clopidogrel. The clinical significance of this interaction is not established. Concomitant use of medicinal products that strongly or moderately inhibit CYP2C19 activity should be avoided (see sections "Special precautions for use" and "Pharmacokinetics").

Medicinal products that are strong or moderate inhibitors of CYP2C19 include omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, efavirenz.

Proton pump inhibitors (PPIs). Administration of omeprazole 80 mg once daily, given either simultaneously with clopidogrel or with a 12-hour interval between the two drugs, reduced exposure to the active metabolite by 45% (after loading dose) and by 40% (during maintenance dosing). This reduction in exposure was associated with decreased platelet aggregation inhibition by 39% (after loading dose) and by 21% (during maintenance dosing). Esomeprazole is expected to have a similar interaction with clopidogrel.

Observational and clinical studies have yielded conflicting data regarding the clinical significance of this pharmacokinetic (PK)/pharmacodynamic (PD) interaction for the risk of serious cardiovascular events. As a precaution, concomitant use of omeprazole or esomeprazole should be avoided (see section "Special precautions for use").

With pantoprazole or lansoprazole, a less pronounced reduction in exposure to the clopidogrel metabolite was observed.

During concomitant treatment with pantoprazole 80 mg once daily, plasma concentrations of the active metabolite decreased by 20% (after loading dose) and by 14% (during maintenance dosing). This was associated with a reduction in platelet aggregation inhibition by 15% and 11%, respectively. These results suggest that clopidogrel can be used concomitantly with pantoprazole.

Currently, there is no evidence that other medicinal products reducing gastric acidity, such as histamine H2-receptor blockers (except cimetidine, which is a CYP2C19 inhibitor) or antacids, affect the antiplatelet activity of clopidogrel.

Booster antiretroviral therapy. In HIV patients receiving boosted antiretroviral therapy (ART), there is a high risk of vascular events.

Markedly reduced platelet inhibition has been observed in HIV patients receiving ART boosted with ritonavir or cobicistat. Although the clinical significance of these data is uncertain, spontaneous reports have described HIV-infected patients receiving ritonavir-boosted ART who experienced recurrent occlusive events after revascularization or thrombotic events despite high-dose clopidogrel regimens. Concomitant use of clopidogrel with ritonavir may reduce mean platelet inhibition.

Therefore, concomitant use of clopidogrel with boosted ART should be avoided.

Other medicinal products. No clinically significant pharmacodynamic interaction was observed when clopidogrel was used concomitantly with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, concomitant use of phenobarbital or estrogen has no significant effect on the pharmacodynamic activity of clopidogrel.

Pharmacokinetic parameters of digoxin or theophylline were not altered when administered concomitantly with clopidogrel. Antacid agents did not reduce clopidogrel absorption.

Data from studies using human liver microsomes indicate that the carboxylic acid metabolite of clopidogrel may inhibit cytochrome P450 2C9 activity. This could potentially increase plasma concentrations of certain medicinal products metabolized by cytochrome P450 2C9, such as phenytoin and tolbutamide, as well as NSAIDs. Data from the CAPRIE study suggest that concomitant use of phenytoin and tolbutamide with clopidogrel is safe.

Medicinal products that are substrates of CYP2C8. In a study involving healthy volunteers, administration of clopidogrel led to increased exposure to repaglinide. In vitro studies showed increased repaglinide exposure due to inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, clopidogrel should be used with caution when administered concomitantly with medicinal products primarily eliminated via CYP2C8 metabolism (e.g., repaglinide, paclitaxel) (see section "Special precautions for use").

Rosuvastatin. Repeated administration of clopidogrel 75 mg has been shown to increase rosuvastatin exposure by 1.4-fold (AUC) without affecting Cmax.

Other medicinal products used concomitantly with ASA.

Uricosuric agents (benzobromarone, probenecid, sulfinpyrazone) should be used with caution, as ASA may reduce their efficacy by competitive excretion of uric acid.

Methotrexate. Due to the presence of acetylsalicylic acid in Koplavix*®*, concomitant use of methotrexate at doses exceeding 20 mg/week requires caution due to the potential for reduced renal clearance of methotrexate, which may lead to myelotoxicity.

Tenofovir. Concomitant use of tenofovir disoproxil fumarate and nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of renal impairment.

Valproic acid. Concomitant use of salicylates and valproic acid may lead to reduced protein binding of valproic acid and inhibition of its metabolism, resulting in increased total and free valproic acid levels in serum. When used concomitantly with valproic acid, ASA displaces it from plasma protein binding, increasing its toxicity.

Varicella vaccine. Salicylates are not recommended for patients within six weeks after varicella vaccination. Cases of Reye’s syndrome have occurred following salicylate administration during varicella infection.

Acetazolamide. Salicylates should be used with caution concomitantly with acetazolamide due to increased risk of metabolic acidosis.

Concomitant use of high-dose acetylsalicylic acid and antidiabetic sulfonylurea derivatives enhances the hypoglycemic effect of the latter due to displacement of protein-bound sulfonylurea by acetylsalicylic acid.

Concomitant use of ASA and digoxin increases digoxin plasma concentration due to reduced renal excretion.

Systemic glucocorticoids (including hydrocortisone used for replacement therapy in Addison’s disease) reduce salicylate blood levels and increase the risk of overdose.

Angiotensin-converting enzyme (ACE) inhibitors in combination with high-dose acetylsalicylic acid reduce glomerular filtration due to inhibition of vasodilatory prostaglandin effects and reduced antihypertensive efficacy.

Nicorandil. In patients concurrently taking nicorandil and nonsteroidal anti-inflammatory drugs (NSAIDs), including ASA and lysine acetylsalicylate (LAS), there is an increased risk of severe complications such as gastrointestinal ulcers, perforation, and gastrointestinal bleeding (see section "Special precautions for use").

Other interactions with ASA.

Interactions have also been reported with medicinal products used concomitantly with ASA at higher (anti-inflammatory) doses: angiotensin-converting enzyme (ACE) inhibitors, acetazolamide, anticonvulsants (phenytoin and valproic acid), beta-blockers, diuretics, and oral hypoglycemic agents.

Alcohol promotes damage to the gastrointestinal mucosa and prolongs bleeding time due to synergism between ASA and alcohol. Patients should be informed of the risk of gastrointestinal mucosal damage and bleeding when taking the drug concomitantly with alcohol, especially if alcohol consumption is chronic or substantial (see section "Special precautions for use").

Diuretics in combination with high-dose acetylsalicylic acid reduce glomerular filtration due to decreased renal prostaglandin synthesis.

Other interactions with clopidogrel and ASA.

Over 30,000 patients participated in clinical trials of the combination of clopidogrel with ASA at maintenance doses not exceeding 325 mg, receiving various concomitant medications, including diuretics, beta-blockers, ACE inhibitors, calcium antagonists, lipid-lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptics, and GP IIb/IIIa antagonists, without evidence of clinically significant adverse interactions.

In addition to the information on interactions with specific medicinal products listed above, data on interactions between Koplavix*®* and some commonly used medicinal products prescribed to patients with atherothrombotic disease are lacking, as studies have not been conducted.

As with other oral P2Y12 inhibitors, concomitant administration of opioid agonists may delay and reduce clopidogrel absorption, likely due to delayed gastric emptying. The clinical significance is unknown. Consideration should be given to using parenteral antithrombotic agents in patients with acute coronary syndrome who require concomitant administration of morphine or other opioid agonists.

Special precautions for use.

Bleeding and hematological disorders. Due to the risk of bleeding and hematological adverse reactions, if clinical symptoms associated with bleeding occur during treatment, urgent blood count and/or monitoring of other relevant parameters should be performed (see section "Adverse reactions"). Since Coplavix*®* is an antithrombotic agent containing two active substances, it should be used with caution in patients with an increased risk of bleeding related to trauma, surgery, or other pathological conditions, as well as when used in combination therapy with other non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors, heparin, glycoprotein IIb/IIIa inhibitors, selective serotonin reuptake inhibitors (SSRIs), potent CYP2C19 inducers, thrombolytics, or other medicinal products that increase the risk of bleeding, such as pentoxifylline (see section "Interaction with other medicinal products and other forms of interaction"). Triple antiplatelet therapy (clopidogrel + aspirin + dipyridamole) is not recommended for secondary prevention of stroke in patients with acute non-cardioembolic ischemic stroke or transient ischemic attack (TIA) due to an increased risk of bleeding (see section "Interaction with other medicinal products and other forms of interaction"). Careful monitoring of the patient is required to detect any signs of bleeding, including occult bleeding, particularly during the first weeks of treatment and/or after invasive cardiovascular procedures or surgery. Concomitant use of Coplavix*®* with oral anticoagulants is not recommended, as this may increase the severity of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Before any planned surgery, and before starting any new medication, patients should inform their physicians, including dentists, about taking Coplavix*®. When elective surgery is planned, the necessity of dual antiplatelet therapy should be reconsidered in favor of using a single antithrombotic agent. If temporary discontinuation of antiplatelet therapy is required, Coplavix®* should be discontinued 7 days prior to surgical intervention.

Coplavix*®* prolongs bleeding time; it should be used with caution in patients with lesions that increase the predisposition to bleeding (particularly gastrointestinal and intraocular).

Patients should also be warned about the possible prolonged time required to stop bleeding while taking Coplavix*®*, and the necessity to inform their physician about any unusual bleeding (in terms of location or duration).

Thrombotic thrombocytopenic purpura (TTP). Very rare cases of TTP have been reported with clopidogrel use, sometimes even after short-term treatment. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia, often associated with neurological symptoms, renal dysfunction, or fever. TTP may be life-threatening and requires immediate therapeutic interventions, including plasmapheresis.

Acquired hemophilia. Cases of acquired hemophilia have been reported following clopidogrel use. In cases of confirmed isolated prolongation of activated partial thromboplastin time (aPTT), with or without bleeding, the diagnosis of acquired hemophilia should be considered. Patients with confirmed diagnosis of acquired hemophilia should be under physician supervision and receive appropriate treatment; clopidogrel use should be discontinued in such patients.

Recent transient ischemic attack or stroke. The use of clopidogrel in combination with acetylsalicylic acid (ASA) in patients who recently experienced a transient ischemic attack or stroke and have a high risk of recurrent ischemic events has been associated with an increased risk of major bleeding. Therefore, additional use of this combination should be approached with caution, except in cases where a favorable effect has been demonstrated.

Cytochrome P450 2C19 (CYP2C19). Pharmacogenetics. In patients who are poor metabolizers of CYP2C19, administration of clopidogrel at recommended doses results in lower levels of the active metabolite and reduced effect on platelet function. Tests are available to determine the CYP2C19 genotype of a patient.

Since the metabolism of clopidogrel to its active metabolite is partially mediated by CYP2C19, concomitant use of medicinal products that inhibit this enzyme's activity is likely to reduce the levels of the active metabolite of clopidogrel. The clinical significance of this interaction is not fully established. Concomitant use of medicinal products that inhibit CYP2C19 activity should be avoided (list of CYP2C19 inhibitors, see section "Interaction with other medicinal products and other forms of interaction"; also see "Pharmacokinetics").

It is likely that the use of medicinal products that induce CYP2C19 activity will increase the levels of the active metabolite of clopidogrel and may increase the risk of bleeding. As a precaution, concomitant use of potent CYP2C19 inducers should be avoided (see section "Adverse reactions").

CYP2C8 substrates. Clopidogrel should be used with caution when administered concomitantly with medicinal products that are substrates of CYP2C8 (see section "Interaction with other medicinal products and other forms of interaction").

Cross-reactivity among thienopyridines. Patients should be screened for a history of hypersensitivity to other thienopyridines (e.g., ticlopidine, prasugrel), as cross-reactivity among thienopyridines has been reported (see section "Adverse reactions"). Thienopyridine use may lead to mild to severe allergic reactions such as rash, angioedema (Quincke's edema), or hematological reactions such as thrombocytopenia and neutropenia. Patients with a history of allergic or hematological reactions to one thienopyridine may have an increased risk of similar or different reactions to another thienopyridine. Monitoring for cross-reactivity is recommended.

ASA should be used with caution:

• in patients with a history of bronchial asthma or allergic reactions, as the risk of hypersensitivity reactions is increased in such patients;
• in patients with gout, as ASA, even at low doses, may increase uric acid concentration;
• in children (under 18 years of age), due to a possible association between ASA use and Reye's syndrome. Reye's syndrome is a very rare but potentially life-threatening condition;
• in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to the risk of hemolysis (see section "Adverse reactions"); in such cases, this medicinal product should be used under strict medical supervision;
• in patients who abuse alcohol. Alcohol may increase the risk of gastrointestinal tract injury when taken with ASA. Patients should be advised about the risk of gastrointestinal injury and bleeding when consuming alcohol while taking clopidogrel and ASA, especially if alcohol consumption is chronic or heavy (see section "Interaction with other medicinal products and other forms of interaction").

Gastrointestinal tract (GIT) disorders. Coplavix*®* should be used with caution in patients with a history of peptic ulcer, gastroduodenal bleeding, or other symptoms of upper gastrointestinal disorders, as these may be manifestations of gastric ulceration, which could lead to gastrointestinal bleeding. Adverse effects related to the GIT, including stomach pain, heartburn, nausea, vomiting, and gastrointestinal bleeding, may occur. Although other upper gastrointestinal symptoms such as dyspepsia are common and may occur at any time during treatment, physicians should remain vigilant for signs of ulcer development and bleeding, even in the absence of prior gastrointestinal symptoms. Patients should be informed about symptoms of gastrointestinal adverse effects and measures to be taken if they occur.

Patients concurrently taking nicorandil and non-steroidal anti-inflammatory drugs (NSAIDs), including ASA and L-arginine salicylate (LAS), have an increased risk of severe complications such as peptic ulcer, perforation, and gastrointestinal bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Excipients. One tablet of Coplavix*®* contains 7 mg of lactose. Patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product also contains 3.3 mg of hydrogenated castor oil, which may cause gastrointestinal discomfort and diarrhea.

Special precautions for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Use during pregnancy or breastfeeding.

Pregnancy. Clinical data on the use of Coplavix*®* during pregnancy are lacking. Coplavix*®* should not be used during the first and second trimesters of pregnancy, except when the clinical condition of the woman requires treatment with clopidogrel/ASA.

Due to the presence of acetylsalicylic acid in Coplavix*®*, its use during the third trimester of pregnancy is contraindicated.

Clopidogrel. As clinical data on clopidogrel use during pregnancy are currently unavailable, as a precautionary measure, clopidogrel should preferably not be used during pregnancy.

Animal studies have not shown any direct or indirect harmful effects of the drug on pregnancy, embryonic/fetal development, delivery, or postnatal development.

ASA.

Low doses (up to 100 mg/day). Clinical data confirm that doses up to 100 mg/day, used for limited indications in obstetrics requiring specialized monitoring, are safe.

Doses 100–500 mg/day. Clinical experience with doses exceeding 100 mg/day up to 500 mg/day is limited. Therefore, recommendations for doses equal to or exceeding 500 mg/day also apply to this dose range.

Doses equal to or exceeding 500 mg/day. Inhibition of prostaglandin synthesis may have adverse effects on pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage, congenital heart defects, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of congenital heart defects increased from less than 1% to approximately 1.5%. The risk is considered to increase with dose and duration of treatment. In animal studies, prostaglandin synthesis inhibitors caused reproductive toxicity. Acetylsalicylic acid should not be prescribed until 24 weeks of amenorrhea (5th month of pregnancy) unless clinically necessary. If acetylsalicylic acid is taken by a woman trying to conceive or before 24 weeks of amenorrhea (5th month of pregnancy), the lowest possible dose should be used for the shortest possible duration.

Starting from the sixth month of pregnancy, all prostaglandin synthesis inhibitors may cause in the fetus:

• pulmonary and cardiac toxicity (with premature closure of the arterial duct and pulmonary hypertension);
• impaired renal function, which may progress to renal failure with oligohydramnios;

in the woman and fetus at the end of pregnancy:

• possible prolongation of bleeding time, antiplatelet effect, which may occur even at very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

Breastfeeding. It is unknown whether clopidogrel passes into breast milk. It has been established that ASA passes into breast milk in limited amounts. Breastfeeding should be discontinued during treatment with Coplavix*®*.

Fertility. Data on the effect of Coplavix*®* on fertility are lacking. Animal studies have shown that clopidogrel does not alter fertility. It is unknown whether ASA affects fertility.

Ability to influence reaction speed when driving or operating machinery. Clopidogrel has no effect or a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

Method of Administration

For oral use. The medication can be taken independently of food intake.

Dosage

Adults and elderly patients

Coplavix®, a fixed-dose combination medicinal product, should be initiated after treatment with clopidogrel and acetylsalicylic acid (ASA) as separate agents has already begun. Coplavix® is administered once daily.

Patients with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction). The optimal duration of treatment has not been definitively established. Clinical trial data support the use of the drug for up to 12 months, with the maximum beneficial effect observed within the first 3 months (see section "Pharmacological Properties"). If treatment with Coplavix® is discontinued, it may be beneficial for patients to continue therapy with a single antiplatelet agent.

Patients with acute ST-elevation myocardial infarction. Treatment should be initiated as early as possible after symptom onset and continued for at least 4 weeks. The benefits of using the clopidogrel and ASA combination for longer than 4 weeks in this condition have not been studied (see section "Pharmacological Properties"). If treatment with Coplavix® is discontinued, it may be beneficial for patients to continue therapy with a single antiplatelet agent.

Missed dose:

• If less than 12 hours have passed since the missed dose was due, the patient should take the missed dose immediately and take the next dose at the usual time;
• If more than 12 hours have passed, the patient should take the next dose at the usual scheduled time, without doubling the dose.

Pharmacogenetics

Reduced CYP2C19-mediated metabolism leads to diminished clopidogrel effect. An optimal dosing regimen for patients with reduced metabolism has not been established (see sections "Pharmacological Properties" and "Pharmacokinetics").

Renal impairment

Coplavix® must not be used in patients with severe renal impairment (see section "Contraindications"). Therapeutic experience with Coplavix® in patients with mild or moderate renal dysfunction is limited (see section "Special Warnings and Precautions for Use"). Therefore, Coplavix® should be prescribed with caution in such patients.

Hepatic impairment

Coplavix® must not be used in patients with severe hepatic impairment (see section "Contraindications"). Therapeutic experience in patients with moderate liver disease and potential for hemorrhagic diathesis is limited (see section "Special Warnings and Precautions for Use"). Therefore, Coplavix® should be prescribed with caution in such patients.

Children
The safety and efficacy of Coplavix® in children (under 18 years of age) have not been established. The use of Coplavix® is not recommended in this patient group.

Overdose

Clopidogrel

Overdose with clopidogrel may lead to prolonged bleeding time and bleeding complications. Appropriate therapy should be administered in case of bleeding.

There is no known antidote for the pharmacological activity of clopidogrel. If rapid correction of prolonged bleeding time is required, platelet transfusion may be effective.

ASA (Acetylsalicylic acid)

Symptoms of mild to moderate intoxication include: dizziness, headache, tinnitus, confusion, and gastrointestinal symptoms (nausea, vomiting, epigastric pain).

In severe intoxication, significant acid-base imbalance occurs. Initial hyperventilation leads to respiratory alkalosis. Over time, due to respiratory center depression, respiratory acidosis develops. Additionally, the presence of salicylates causes metabolic acidosis. Since infants and young children often present to physicians at the late stage of intoxication, they usually already exhibit acidosis.

Other possible symptoms include: hyperthermia and sweating leading to dehydration, restlessness, seizures, hallucinations, and hypoglycemia. Central nervous system depression may progress to coma, cardiovascular collapse, and respiratory arrest. The lethal dose of acetylsalicylic acid is 25–30 g. A plasma salicylate concentration exceeding 300 mg/L (1.67 mmol/L) indicates intoxication.

Overdose with a fixed-dose combination of ASA and clopidogrel may result in enhanced bleeding and subsequent hemorrhagic complications due to the pharmacological activity of both clopidogrel and ASA.

Acute and chronic overdose with acetylsalicylic acid may lead to non-cardiogenic pulmonary edema (see section "Adverse Reactions").

In case of ingestion of a toxic dose, hospitalization is required. In cases of moderate intoxication, vomiting should be induced; if unsuccessful, gastric lavage is indicated. Activated charcoal (adsorbent) and sodium sulfate (cathartic) should then be administered. Urine alkalization is recommended (250 mmol sodium bicarbonate over 3 hours) with monitoring of urine pH. In cases of severe intoxication, hemodialysis should be performed. Other symptoms of intoxication should be treated symptomatically.

Adverse reactions.

Short description of the safety profile. The assessment of clopidogrel's safety profile was based on data from more than 42,000 patients participating in clinical trials, including over 30,000 patients receiving clopidogrel and aspirin (ASA) concomitantly, and over 9,000 patients treated for one year or longer. Clinically significant adverse reactions observed in four major studies—CAPRIE (a study comparing clopidogrel monotherapy with ASA), and CURE, CLARITY, and COMMIT (studies comparing combination therapy with clopidogrel and ASA versus ASA monotherapy)—are listed below. Overall, in the CAPRIE study, the effect of clopidogrel 75 mg/day was similar to that of ASA 325 mg/day, regardless of patient age, sex, or race. In addition to the experience accumulated from clinical trials, spontaneous reports of adverse reactions have been received.

Bleeding is the most commonly reported adverse reaction both during clinical studies and in the post-marketing period, occurring primarily during the first month of treatment.

In the CAPRIE study, among patients receiving either clopidogrel or ASA, the overall incidence of bleeding was 9.3%. The incidence of severe bleeding was similar with both clopidogrel and ASA.

In the CURE study, no excess of major bleeding was observed with the combination of clopidogrel and ASA during the 7 days following coronary artery bypass grafting (CABG) in patients who discontinued therapy more than five days prior to surgery. In patients who continued therapy within five days of CABG, the incidence of bleeding events was 9.6% in the clopidogrel plus ASA group and 6.3% in the placebo plus ASA group.

In the CLARITY study, there was an overall increase in bleeding events in the clopidogrel plus ASA group compared to the ASA monotherapy group. However, the rate of major bleeding was similar in both groups. These findings were consistent across patient subgroups defined at study entry and according to type of fibrinolytic or heparin therapy.

In the COMMIT study, the overall incidence of non-cerebral major bleeding or cerebral hemorrhage was low and similar in both treatment groups.

List of adverse reactions in table form.

The table below presents data on adverse reactions occurring during clopidogrel monotherapy, ASA monotherapy, or clopidogrel in combination with ASA in clinical trials, as well as those reported spontaneously. Adverse reactions are categorized by frequency as follows: common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). Within each organ system class, adverse reactions are listed in decreasing order of severity.

* «Frequency not known» corresponds to information reported in published data on ASA.

** Information regarding clopidogrel with frequency category «frequency not known».

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions through national reporting systems.

Shelf life. 2 years.

Storage conditions. Keep out of reach of children. Store in the original packaging at a temperature not exceeding 25 °C.

Packaging. No. 28 (7 × 4): 7 tablets in a blister, 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. SANOFI WINTHROP INDUSTRIE.

Manufacturer's address and location of its operations.

1 rue de la Vierge Ambarès et Lagrave, 33565 CARBON BLANC CEDEX, France.

Marketing Authorization Holder. LLC «Sanofi-Aventis Ukraine».

Address of the Marketing Authorization Holder. 48-50A Zhylianska Street, Kyiv, 01033, Ukraine.