Plavix®

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

Composition:

Active substance: clopidogrel;

One tablet contains 300 mg of clopidogrel hydrogen sulfate in the form of base;

Excipients: mannitol (E 421), microcrystalline cellulose, polyethylene glycol, low-substituted hydroxypropylcellulose, hydrogenated castor oil, coating: Opadry 32K14834, type II (lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, red iron oxide (E 172)), carnauba wax.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: pink, elongated, film-coated tablets, engraved with "300" on one side and "1332" on the other.

Pharmacotherapeutic group.

Antithrombotic agents. Platelet aggregation inhibitors excluding heparin. Clopidogrel.

ATC code: B01AC04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Clopidogrel is a prodrug; one of its metabolites is an inhibitor of platelet aggregation. In order to form the active metabolite that inhibits platelet aggregation, clopidogrel must undergo biotransformation by cytochrome CYP450 enzymes. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its P2Y12 receptors on the platelet surface and subsequent ADP-induced activation of the glycoprotein IIb/IIIa complex, thereby inhibiting platelet aggregation. Since the binding is irreversible, platelets exposed to clopidogrel remain modified throughout their lifespan (approximately 7–10 days), and normal platelet function recovery occurs at a rate consistent with platelet turnover. Platelet aggregation induced by other agonists besides ADP is also inhibited due to the drug blocking ADP-mediated platelet activation.

Since the active metabolite is formed under the influence of cytochrome CYP450 enzymes, some of which are polymorphic or inhibited by other medicinal products, adequate platelet aggregation inhibition does not occur in all patients.

Pharmacodynamic effects. Significant inhibition of ADP-induced platelet aggregation is observed from the first day of repeated daily doses of 75 mg of the drug. This effect progressively increases and stabilizes between days 3 and 7 of treatment. At steady state, the average level of aggregation inhibition with a daily dose of 75 mg ranges from 40 to 60%. Platelet aggregation and bleeding time return to baseline levels on average 5 days after discontinuation of treatment.

Clinical efficacy and safety. The safety and efficacy of clopidogrel were evaluated in 7 double-blind studies involving over 100,000 patients: the CAPRIE trial – comparing clopidogrel with acetylsalicylic acid (ASA), and the CURE, CLARITY, COMMIT, CHANCE, POINT, and ACTIVE-A trials, which compared clopidogrel and placebo, both in combination with ASA and other standard therapy.

Recent myocardial infarction (MI), stroke, or established peripheral arterial disease. The CAPRIE trial included 19,185 patients with atherosclerotic thrombosis, manifested as recent MI (<35 days ago), recent ischemic stroke (7 days to 6 months ago), or established peripheral arterial disease (PAD). Patients were randomized to receive clopidogrel 75 mg/day or ASA 325 mg/day and were followed for 1 to 3 years. In the MI subgroup, most patients received ASA in the first few days after the event.

Clopidogrel significantly reduced the incidence of new ischemic events (composite endpoint consisting of MI, ischemic stroke, and vascular death) compared to ASA. In the intention-to-treat analysis, there were 939 events in the clopidogrel group and 1020 events in the ASA group (relative risk reduction (RRR) 8.7% [95% CI: 0.2–16.4]; p = 0.045). Thus, for every 1000 patients treated for 2 years, an additional 10 [CI: 0–20] patients avoided a new ischemic event. Analysis of total mortality as a secondary endpoint showed no significant differences between clopidogrel therapy (5.8%) and ASA (6%).

Subgroup analysis by underlying condition (MI, ischemic stroke, and PAD) showed the greatest effect (statistically significant at p = 0.003) in patients with PAD (especially those who had experienced MI) (RRR = 23.7%; CI: 8.9–36.2), a smaller effect (not significantly different from ASA) in stroke patients (RRR = 7.3%; CI: -5.7–18.7 [p=0.258]). In patients recently experiencing MI included in the study, the numerical impact of clopidogrel was lower but not statistically significantly different from ASA (RRR = -4%; CI: -22.5–11.7 [p=0.639]). Additionally, subgroup analysis by age suggests that the beneficial effect of clopidogrel in patients over 75 years of age was lower than in those under 75.

Since the power of the CAPRIE trial was not sufficient to assess efficacy in individual subgroups, it remains unclear whether actual differences in relative risk reduction exist among patients with different conditions or whether the differences were due to chance.

Acute coronary syndrome. The CURE trial included 12,562 patients with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave MI), who had experienced chest pain or ischemic symptoms within the previous 24 hours. Patients had ECG changes indicating new ischemia or elevated cardiac enzyme activity or troponin I or T at least twice the upper limit of normal. Patients were randomized to receive clopidogrel (loading dose 300 mg followed by 75 mg daily, n=6259) or placebo (n=6303), both in combination with ASA (75–325 mg once daily) and other standard therapy. Treatment duration was up to one year. During the CURE trial, 823 (6.6%) patients also received concomitant therapy with a GPIIb/IIIa glycoprotein receptor antagonist. Over 90% of patients received heparins. This concomitant therapy did not statistically significantly affect the relative frequency of bleeding events with clopidogrel versus placebo.

The number of patients who reached the primary endpoint [cardiovascular death (CVD), MI, or stroke] was 582 (9.3%) in the clopidogrel group and 719 (11.4%) in the placebo group. The relative risk reduction was 20% (95% CI 10%–28%; p=0.00009) for the clopidogrel group (17% with conservative treatment, 29% with percutaneous transluminal coronary angioplasty with or without stent placement, and 10% with coronary artery bypass grafting). 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 0–1, 1–3, 3–6, 6–9, and 9–12 month periods of the study, respectively. Thus, after more than 3 months of treatment, the beneficial effect observed in the clopidogrel + ASA group no longer increased, while the risk of bleeding remained (see section "Special precautions for use").

Use of clopidogrel during the CURE trial reduced the need for thrombolytic therapy (RRR = 43.3%; CI: 24.3%–57.5%) and for GPIIb/IIIa glycoprotein receptor antagonists (RRR = 18.2%; CI: 6.5%–28.3%).

The number of patients who reached the combined primary endpoint (CVD, MI, stroke, or refractory ischemia) was 1035 (16.5%) in the clopidogrel group and 1187 (18.8%) in the placebo group. The relative risk reduction was 14% (95% CI: 6%–21%, p=0.0005) in the clopidogrel group. This effect was primarily due to a statistically significant reduction in the incidence of MI [287 (4.6%) in the clopidogrel group and 363 (5.8%) in the placebo group]. No changes in the frequency of rehospitalizations for unstable angina were observed.

Results obtained in patient groups with different 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. In particular, an additional analysis of 2,172 patients (17% of the total CURE group) who received a stent (Stent-CURE) showed a significant RRR (26.2%) favoring clopidogrel in preventing the primary endpoint (CVD, MI, stroke), as well as a significant RRR (23.9%) for the second combined primary endpoint (CVD, MI, stroke, or refractory ischemia). Moreover, the safety profile of clopidogrel in this subgroup raised no particular concerns. Thus, the results of the additional subgroup analysis are consistent with the overall trial results.

The beneficial effect of clopidogrel was demonstrated independently of receiving emergency and long-term treatment with other cardiovascular agents (such as heparin/low molecular weight heparin, GPIIb/IIIa glycoprotein receptor antagonists, lipid-lowering agents, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors). The efficacy of clopidogrel did not depend on the dose of ASA (75–325 mg once daily).

Myocardial infarction with ST-segment elevation. In patients with acute MI with ST-segment elevation (STEMI), the safety and efficacy of clopidogrel were evaluated in two randomized, placebo-controlled, double-blind trials: CLARITY and COMMIT, and a prospective subgroup analysis of CLARITY (CLARITY PCI).

In the CLARITY trial, 3491 patients with STEMI within the last 12 hours and planned thrombolytic therapy were included. Patients received clopidogrel (300 mg loading dose, then 75 mg/day, n=1752) or placebo (n=1739), both in combination with ASA (loading dose 150–325 mg, then 75–162 mg/day), a fibrinolytic agent, and, if necessary, heparin. Follow-up lasted 30 days. The primary endpoint was occlusion of the infarct-related artery, as seen on the angiogram before hospital discharge, death, or recurrent MI before coronary angiography. For patients not undergoing angiography, the primary endpoint was death or recurrent MI by day 8 or hospital discharge. Among the patients in this trial, 19.7% were women and 29.2% were aged 65 years or older. Overall, 99.7% of patients received fibrinolytic agents (fibrin-specific 68.7%, non-fibrin-specific 31.1%), 89.5% heparin, 78.7% beta-blockers, 54.7% ACE inhibitors, and 63% statins.

The primary endpoint was reached in 15% of patients in the clopidogrel group and 21.7% in the placebo group. Thus, the absolute reduction was 6.7%, with a 36% advantage in favor of clopidogrel (95% CI: 24–47%; p < 0.001), primarily due to reduced incidence of infarct-related artery occlusion. This advantage was observed in all predefined patient subgroups categorized by age, sex, infarct location, and type of fibrinolytic or heparin therapy received.

The CLARITY PCI subgroup analysis included 1863 patients with STEMI undergoing percutaneous coronary intervention (PCI). In patients receiving clopidogrel with a loading dose (LD) of 300 mg (n = 933), a significant reduction in the incidence of cardiovascular death, MI, or stroke after PCI was observed compared to patients receiving placebo (n = 930) (3.6% with prior clopidogrel treatment vs. 6.2% with placebo, HR: 0.54; 95% CI: 0.35–0.85; p = 0.008). In patients receiving clopidogrel with LD 300 mg, a significant reduction in the incidence of cardiovascular death, MI, or stroke within 30 days after PCI was observed compared to patients receiving placebo (7.5% with prior clopidogrel treatment vs. 12.0% with placebo, HR: 0.59; 95% CI: 0.43–0.81; p = 0.001). No significant difference in the frequency of major or minor bleeding was observed between the two treatments (2.0% with prior clopidogrel treatment vs. 1.9% with placebo, p > 0.99). The results of this analysis support early administration of a clopidogrel loading dose in STEMI and a standard pre-treatment strategy with clopidogrel when performing PCI.

The two-factor design of the COMMIT trial included 45,852 patients who developed symptoms suggestive of MI within the last 24 hours, confirmed by ECG abnormalities (e.g., ST-segment elevation or depression or left bundle branch block). Patients received clopidogrel (75 mg/day, n=22,961) or placebo (n=22,891) in combination with ASA (162 mg/day) for 28 days or until hospital discharge. Combined primary endpoints were all-cause mortality and first recurrence of MI, stroke, or death. The patient group included 27.8% women, 58.4% patients ≥60 years (26% ≥70 years), and 54.5% patients receiving fibrinolytic agents.

Clopidogrel significantly reduced the relative risk of all-cause mortality by 7% (p = 0.029) and the relative risk of the combination of recurrent MI, stroke, or death by 9% (p = 0.002), corresponding to an absolute reduction of 0.5% and 0.9%, respectively. This effect was observed in patients of different ages and sexes, regardless of fibrinolytic use, and occurred within the first 24 hours.

Loading dose of clopidogrel 600 mg in patients with acute coronary syndrome undergoing PCI.

Study CURRENT-OASIS-7 ("Use of Optimal Antiplatelet Doses of Clopidogrel and Aspirin to Reduce Recurrences – Organization to Assess Strategies in Ischemic Syndromes, 7th version")

This randomized factorial trial included 25,086 patients with acute coronary syndrome (ACS) and planned early PCI. Patients were randomized to receive double dose (600 mg on day 1, then 150 mg from day 2 to day 7, then 75 mg daily) versus standard dose (300 mg on day 1, then 75 mg daily) of clopidogrel, and high-dose (300–325 mg daily) versus low-dose (75–100 mg daily) aspirin. Coronary angiography was performed in 24,835 patients with ACS included in the study, and PCI in 17,263. In the 25,086 patients included in the study, similar rates of cardiovascular death, MI, or stroke were observed (4.2% with clopidogrel 600/150/75 mg vs. 4.4% with clopidogrel 300/75/75 mg, HR 0.94; 95% CI 0.83–1.06; p = 0.30). Major bleeding was more frequent with clopidogrel 600/150/75 mg (2.5%) compared to 300/75/75 mg (2.0%), HR 1.24; 95% CI 1.05–1.46; p = 0.01. However, among the 17,263 patients undergoing PCI, double-dose clopidogrel reduced the incidence of the primary endpoint compared to standard dose (3.9% vs. 4.5%, adjusted HR 0.86, 95% CI 0.74–0.99, p = 0.039). A significant reduction in stent thrombosis was observed among the 17,263 patients undergoing PCI with double-dose clopidogrel compared to standard treatment (1.6% vs. 2.3%, HR 0.68; 95% CI 0.55–0.85; p = 0.001). Major bleeding was more frequent with double-dose clopidogrel than with standard dose (1.6% vs. 1.1%, HR = 1.41, 95% CI 1.09–1.83, p = 0.009).

Study ARMYDA-6 MI ("Antiplatelet Therapy for Reducing Myocardial Damage during Angioplasty – Myocardial Infarction")

In this randomized prospective international multicenter study, pretreatment with clopidogrel loading dose (LD) 600 mg versus 300 mg was evaluated in emergency PCI for STEMI. Patients received clopidogrel LD 600 mg (n = 103) or clopidogrel LD 300 mg (n = 98) before PCI, then 75 mg/day from the day after PCI to 1 year. In patients receiving clopidogrel LD 600 mg, infarct size was significantly reduced compared to those receiving clopidogrel LD 300 mg. TIMI perfusion grade <3 after PCI was less frequent with LD 600 mg (5.8% vs. 16.3%, p = 0.031), LVEF at discharge was improved (52.1 ± 9.5% vs. 48.8 ± 11.3%, p = 0.026), and fewer major adverse cardiovascular events occurred within 30 days (5.8% vs. 15%, p = 0.049). No increase in bleeding or access site complications (secondary endpoints at 30 days) was observed.

Study HORIZONS-AMI ("Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction")

This study with post hoc analysis was conducted to evaluate whether LD 600 mg provides faster and stronger inhibition of platelet activation. The analysis assessed the impact of LD 600 mg versus 300 mg on 30-day clinical outcomes in 3311 patients from the main study (n = 1153; LD 300 mg group; n = 2158; LD 600 mg group) before cardiac catheterization, followed by 75 mg/day for ≥6 months after discharge. Results demonstrated significantly lower 30-day (uncorrected) mortality rates (1.9% vs. 3.1%, p = 0.03), recurrent MI (1.3% vs. 2.3%, p = 0.02), and definite or probable stent thrombosis (1.7% vs. 2.8%, p = 0.04) with LD 600 mg without higher bleeding rates. According to multivariate analysis, clopidogrel loading dose 600 mg was an independent predictor of reduced incidence of major adverse cardiac events within 30 days (HR 0.72 [95% CI 0.53–0.98], p = 0.04). The rate of major bleeding (not related to coronary artery bypass grafting) was 6.1% in the LD 600 mg group and 9.4% in the LD 300 mg group (p = 0.0005). The rate of minor bleeding was 11.3% in the LD 600 mg group and 13.8% in the LD 300 mg group (p = 0.03).

In a meta-analysis (Vyas et al., 2014) evaluating the clinical benefit of clopidogrel LD 600 mg in patients with STEMI undergoing PCI, data from nine studies published between 2009 and 2012 were included. Primary efficacy and safety endpoints were major adverse cardiovascular events and major bleeding. A significant reduction in major adverse cardiovascular events was observed with LD 600 mg (OR 0.75; 95% CI 0.63–0.91; p = 0.003) compared to 300 mg without increased risk of major bleeding (600 mg [89 events in 3551 patients, 2.5%] vs. 300 mg [63 events in 2796 patients, 2.25%]; OR 0.84; 95% CI 0.60–1.16; p = 0.28).

In a meta-analysis (Siller-Matula et al., 2011), which included 5 randomized and 2 non-randomized studies, LD clopidogrel 300 mg (n = 11,148) was compared with 600 mg (n = 14,235) in patients undergoing PCI. Overall, LD 600 mg was associated with a 34% relative risk reduction in major adverse cardiovascular events (HR 0.66; 95% CI 0.52–0.84; p < 0.001). LD 600 mg clopidogrel was not associated with an increased risk of major bleeding (HR 0.91; 95% CI 0.73–1.15; p = 0.44).

Long-term (12 months) use of clopidogrel in patients with STEMI after PCI.

Study CREDO ("Clopidogrel to Reduce Events During Observation")

This randomized, double-blind, placebo-controlled trial was conducted to evaluate the benefit of long-term (12 months) clopidogrel treatment after PCI. 2116 patients were randomized to receive a 300 mg loading dose of clopidogrel (n = 1053) or placebo (n = 1063) 3–24 hours before PCI. After that, all patients in both groups received clopidogrel 75 mg/day until day 28. From day 29 to 12 months, patients in the clopidogrel group received clopidogrel 75 mg/day, while the control group received placebo. Both groups received aspirin throughout the study. After 1 year, a significant reduction in the combined risk of death, MI, or stroke was observed with clopidogrel (relative reduction 26.9%, 95% CI 3.9–44.4; p = 0.02; absolute reduction 3%) compared to placebo. No significant increase in the frequency of major bleeding (8.8% with clopidogrel vs. 6.7% with placebo, p = 0.07) or minor bleeding (5.3% with clopidogrel vs. 5.6% with placebo, p = 0.84) after 1 year was observed. The main conclusion from this study is that continuing clopidogrel and aspirin for at least 1 year leads to a statistically and clinically significant reduction in major thrombotic events.

Study EXCELLENT ("Efficacy of Xience/Promus and Cypher Stents in Reducing Late Loss after Stenting")

This prospective open-label randomized study was conducted to evaluate whether 6-month dual antiplatelet therapy (DAPT) would be no less effective than 12-month DAPT after drug-eluting stent implantation. The study included 1443 patients who underwent implantation and were randomized to receive 6-month DAPT (aspirin 100–200 mg/day plus clopidogrel 75 mg/day for 6 months, then aspirin alone until 12 months) or 12-month DAPT (aspirin 100–200 mg/day plus clopidogrel 75 mg/day for 12 months). No significant difference in the incidence of target vessel failure (composite measure of cardiac death, MI, or target vessel revascularization), the primary endpoint, was observed between the 6-month and 12-month DAPT groups (HR 1.14; 95% CI 0.70–1.86; p = 0.60). Additionally, the study did not demonstrate a significant difference in the safety endpoint (composite measure of death, MI, stroke, stent thrombosis, or major bleeding by TIMI scale) between the 6-month and 12-month DAPT groups (HR 1.15; 95% CI 0.64–2.06; p = 0.64). The main conclusion from this study was that 6-month DAPT was not inferior to 12-month DAPT regarding the risk of target vessel failure.

De-escalation of P2Y12 receptor inhibitors in acute coronary syndrome (ACS). Switching from a more potent P2Y12 receptor inhibitor to clopidogrel in combination with aspirin after the acute phase in patients with ACS was evaluated in two investigator-sponsored studies (ISS) – the TOPIC and TROPICAL-ACS trials – with data on clinical outcomes.

The clinical benefit provided by more potent P2Y12 receptor inhibitors, ticagrelor and prasugrel, in pivotal trials is due to a statistically significant reduction in the frequency of recurrent ischemic events (including acute and subacute stent thrombosis, MI, and emergency revascularization). Although benefits regarding ischemic events were consistently confirmed during the first year, the reduction in recurrent ischemic events after ACS was greater during the first days after treatment initiation. In contrast, post hoc analyses demonstrated a statistically significant increase in bleeding risk with more potent P2Y12 receptor inhibitors, occurring primarily during the maintenance phase, after the first month after ACS. The TOPIC and TROPICAL-ACS trials were designed to study the possibility of reducing bleeding events while maintaining clopidogrel efficacy.

Study TOPIC ("Timing of Platelet Inhibition after Acute Coronary Syndrome"). This randomized open-label study included patients with ACS requiring percutaneous coronary intervention (PCI). Patients who were on aspirin and a more potent P2Y12 receptor blocker and had no adverse events after one month were either switched to a combination of aspirin and clopidogrel at fixed doses (de-escalation dual antiplatelet therapy (DAPT)) or continued treatment according to the previous regimen (unchanged DAPT).

Overall, data from 645 of 646 patients with STEMI (ST-elevation MI) or NSTEMI (non-ST-elevation MI), or unstable angina (de-escalation DAPT (n = 322), unchanged DAPT (n = 323)) were analyzed. Follow-up visit at 1 year was conducted in 316 patients (98.1%) in the de-escalation DAPT group and 318 patients (98.5%) in the unchanged DAPT group. Median follow-up for both groups was 359 days. Characteristics of the study cohort were similar in the two groups.

The primary endpoint, a combination of events such as cardiovascular death, stroke, emergency revascularization, and bleeding events ≥2 by BARC (Bleeding Academic Research Consortium) criteria one year after ACS, was reached 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 events; no difference was reported for ischemic event endpoints (p = 0.36), while bleeding events ≥2 by BARC criteria occurred less frequently in the de-escalation DAPT group (4.0%) compared to 14.9% in the unchanged DAPT group (p < 0.01). Bleeding events defined as all events by BARC criteria were observed in 30 patients (9.3%) in the de-escalation DAPT group and 76 patients (23.5%) in the unchanged DAPT group (p < 0.01).

Study TROPICAL-ACS ("Testing Platelet Inhibition and Patient Outcomes in Long-term Antiplatelet Therapy for Acute Coronary Syndromes"). This randomized open-label study included 2610 patients with ACS with positive biomarker results who successfully underwent PCI. Patients were randomized to receive either prasugrel 5 or 10 mg/day (days 0–14) (n = 1306), or prasugrel 5 or 10 mg/day (days 0–7), followed by de-escalation to clopidogrel 75 mg/day (days 8–14) (n = 1304) in combination with ASA (<100 mg/day). Platelet function testing (PFT) was performed on day 14. Patients receiving only prasugrel continued prasugrel for 11.5 months.

In patients undergoing de-escalation, high on-treatment platelet reactivity (HPR) was assessed. 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, in the managed de-escalation group, patients received either prasugrel (40%) or clopidogrel (60%). All patients continued aspirin, and follow-up was conducted for one year.

The primary endpoint (composite endpoint of cardiovascular death, MI, stroke, and bleeding ≥2 by BARC criteria at 12 months) was reached, demonstrating at least non-inferior efficacy of clopidogrel. The primary endpoint event occurred in 95 patients (7%) in the managed de-escalation group and 118 patients (9%) in the control group (p for non-inferiority = 0.0004). Managed de-escalation did not lead to an increase in the combined risk of ischemic events (2.5% in the de-escalation group vs. 3.2% in the control group; p for non-inferiority = 0.0115), nor for the key secondary endpoint—the frequency of bleeding events ≥2 by BARC criteria (5% in the de-escalation group vs. 6% in the control group (p = 0.23)). The overall frequency of all bleeding events (1–5 by BARC criteria) was 9% (114 events) in the managed de-escalation group compared to 11% (137 events) in the control group (p = 0.14).

Dual antiplatelet therapy in acute minor stroke or TIA with moderate to high risk.

Dual antiplatelet therapy with clopidogrel and ASA for stroke prevention after acute minor stroke or TIA with moderate to high risk was evaluated in two investigator-sponsored (ISS) randomized trials—CHANCE and POINT—based on clinical safety and efficacy outcomes.

CHANCE ("Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events").

In this randomized, double-blind, multicenter, placebo-controlled clinical trial, 5170 patients from China with acute TIA (ABCD2 score ≥4) or acute minor stroke (NIHSS score ≤3) participated. Patients in both groups received ASA openly on day 1 (75–300 mg at the treating physician's discretion). Patients randomly assigned to the clopidogrel-ASA group received clopidogrel loading dose 300 mg on day 1, then 75 mg/day from day 2 to day 90, and ASA 75 mg/day from day 2 to day 21. Patients randomly assigned to the ASA group received placebo version of clopidogrel from day 1 to day 90 and ASA 75 mg/day from day 2 to day 90.

The primary efficacy endpoint was any new stroke event (ischemic and hemorrhagic) within the first 90 days after acute minor stroke or TIA with high risk. These events occurred in 212 patients (8.2%) in the clopidogrel-ASA group compared to 303 patients (11.7%) in the ASA group (risk ratio [RR] 0.68; 95% confidence interval [CI] 0.57–0.81; p < 0.001). Ischemic stroke occurred in 204 patients (7.9%) in the clopidogrel-ASA group compared to 295 patients (11.4%) in the ASA group (RR 0.67; 95% CI 0.56–0.81; p < 0.001). Hemorrhagic stroke was observed in 8 patients in each of the two study groups (0.3% in each group). Moderate or severe bleeding was observed in 7 patients (0.3%) in the clopidogrel-ASA group and 8 (0.3%) in the ASA group (p = 0.73). The frequency of any bleeding events was 2.3% in the clopidogrel-ASA group compared to 1.6% in the ASA group (RR 1.41; 95% CI 0.95–2.10; p = 0.09).

POINT (Platelet Inhibition and Patient Outcomes in New TIA and Minor Ischemic Stroke).

In this randomized, double-blind, multicenter, placebo-controlled clinical trial, patients from around the world (4881 individuals) with acute TIA (ABCD2 score ≥4) or acute minor stroke (NIHSS score ≤3) participated. All patients in both groups received ASA openly from day 1 to day 90 (50–325 mg, depending on the treating physician's prescription). Patients randomly assigned to the clopidogrel group received clopidogrel loading dose 600 mg on day 1, then 75 mg/day from day 2 to day 90. Patients randomly assigned to the placebo group received placebo version of clopidogrel from day 1 to day 90.

The primary efficacy endpoint was a combination of major ischemic events (stroke, MI, or death from ischemic vascular event) on day 90. These events occurred in 121 patients (5.0%) in the clopidogrel-ASA combination group compared to 160 patients (6.5%) receiving ASA monotherapy (RR 0.75; 95% CI 0.59–0.95; p = 0.02). The secondary efficacy endpoint was ischemic stroke. It occurred in 112 patients (4.6%) receiving clopidogrel in combination with ASA compared to 155 patients (6.3%) receiving ASA monotherapy (RR 0.72; 95% CI 0.56–0.92; p = 0.01). The primary safety endpoint was major bleeding. It was observed in 23 of 2,432 patients (0.9%) receiving clopidogrel in combination with ASA and in 10 of 2,449 patients (0.4%) receiving ASA monotherapy (RR 2.32; 95% CI 1.10–4.87; p = 0.02). Minor bleeds occurred in 40 patients (1.6%) receiving clopidogrel in combination with ASA and in 13 patients (0.5%) receiving ASA monotherapy (RR 3.12; 95% CI 1.67–5.83; p < 0.001).

Analysis of the dynamics of the CHANCE and POINT studies.

No additional benefit in efficacy was observed with continuation of dual antiplatelet therapy beyond 21 days. The dynamics of serious ischemic events and major bleeds in treatment groups were analyzed to assess the impact of short-term DAPT.

Dynamics of serious ischemic events and major bleeds in treatment groups in the CHANCE and POINT studies

Atrial fibrillation. In the ACTIVE-W and ACTIVE-A studies, which were separate trials within the ACTIVE program, patients with atrial fibrillation (AF) who had at least one risk factor for vascular events were included. Based on inclusion criteria, physicians enrolled patients in the ACTIVE-W study if they were candidates for vitamin K antagonist (VKA) therapy (e.g., warfarin). The ACTIVE-A study included patients who could not receive VKA therapy due to contraindications or unwillingness to undergo such treatment.

The ACTIVE-W study demonstrated that anticoagulant therapy with vitamin K antagonists was more effective than treatment with clopidogrel plus acetylsalicylic acid (ASA).

The ACTIVE-A study (n = 7554) was a multicenter, randomized, double-blind, placebo-controlled trial comparing clopidogrel 75 mg daily + ASA (n = 3772) versus placebo + ASA (n = 3782). The recommended dose of ASA was 75–100 mg daily. Patients received treatment for up to 5 years.

Patients randomized in the ACTIVE program had documented AF, either permanent AF or at least two episodes of paroxysmal AF within the previous 6 months, and at least one of the following risk factors: age ≥75 years or age 55–74 years with diabetes requiring medication, documented history of myocardial infarction (MI), documented ischemic heart disease, treatment for systemic arterial hypertension, prior stroke, transient ischemic attack (TIA), or systemic embolism without central nervous system (CNS) structural involvement; left ventricular dysfunction with left ventricular ejection fraction <45%, or documented peripheral vascular disease. The mean CHADS2 score was 2 (range 0–6).

Key exclusion criteria included documented peptic ulcer disease within the past 6 months; history of intracranial hemorrhage; severe thrombocytopenia (platelet count <50 × 10⁹/L); requirement for clopidogrel or oral anticoagulants (OACs), or intolerance to either agent.

Seventy-three percent (73%) of patients enrolled in the ACTIVE-A study could not receive VKA therapy due to physician judgment related to inability to monitor international normalized ratio (INR), high risk of falls or head injury, or presence of specific bleeding risk factors; in 26% of patients, the physician's decision was based on patient refusal to take VKA.

Among the patients, 41.8% were women. The mean age was 71 years, and 41.6% were over 75 years of age. Overall, 23% of patients received antiarrhythmic drugs, 52.1% received beta-blockers, 54.6% received angiotensin-converting enzyme inhibitors, and 25.4% received statins.

The number of patients who reached the primary endpoint (time to first occurrence of stroke, MI, systemic embolism without CNS structural involvement, or vascular death) was 832 (22.1%) in the clopidogrel + ASA group and 924 (24.4%) in the placebo + ASA group (relative risk reduction of 11.1%, 95% CI: 2.4%–19.1%; p = 0.013), primarily due to a significant reduction in stroke incidence. Strokes occurred in 296 (7.8%) patients receiving clopidogrel + ASA and in 408 (10.8%) patients receiving placebo + ASA (relative risk reduction of 28.4%; 95% CI: 16.8%–38.3%, p = 0.00001).

Children. In a dose-escalation study conducted in 86 newborns or infants up to 24 months of age at risk of thrombosis (PICOLO), clopidogrel was administered at sequential doses of 0.01, 0.1, and 0.2 mg/kg to newborns and infants, and at a dose of 0.15 mg/kg only to newborns. At a dose of 0.2 mg/kg, the mean platelet aggregation inhibition was 49.3% (5 µM ADP-induced platelet aggregation), comparable to that observed in adults receiving Plavix® 75 mg daily.

In a randomized, double-blind, parallel-group study (CLARINET), 906 children (newborns and infants) with cyanotic congenital heart defects who underwent palliative surgery to create a systemic-to-pulmonary arterial shunt were randomized to receive clopidogrel 0.2 mg/kg (n = 467) or placebo (n = 439), along with standard background therapy until the second-stage surgery. The mean time between shunt creation and first study drug administration was 20 days. Approximately 88% of patients concurrently received ASA (1–23 mg/kg/day). There was no statistically significant difference between groups in achieving the primary composite endpoint, consisting of death, shunt thrombosis, or cardiac surgery due to thrombotic events by day 120 of life: 89 [19.1%] in the clopidogrel group and 90 [20.5%] in the placebo group (see section "Dosage and administration"). The most common adverse reaction in both the clopidogrel and placebo groups was bleeding, but there was no statistically significant difference in bleeding frequency between groups. During the subsequent long-term safety follow-up period, 26 patients with a patent shunt at 1 year of age continued to receive clopidogrel until 18 months of age. During this period, the safety profile of the drug remained unchanged.

In the CLARINET and PICOLO studies, a reconstituted solution of clopidogrel was used. In a relative bioavailability study in adults, the reconstituted solution showed similar extent and slightly faster absorption of the main circulating (inactive) metabolite compared to the registered tablet formulation.

Pharmacokinetics.

Absorption. After single and repeated oral doses of 75 mg daily, clopidogrel is rapidly absorbed. Peak plasma concentrations of unchanged clopidogrel (approximately 2.2–2.5 ng/mL after a single 75 mg oral dose) are reached about 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Distribution. Clopidogrel and the main (inactive) circulating metabolite are reversibly bound to human plasma proteins in vitro (98% and 94%, respectively). This binding remains non-saturable in vitro over a wide concentration range.

Metabolism. Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, two main metabolic pathways exist: one involves esterases leading to hydrolysis and formation of an inactive carboxylic acid derivative (accounting for 85% of all circulating metabolites in plasma), and the other involves cytochrome P450 enzymes. Clopidogrel is initially converted to the intermediate metabolite 2-oxo-clopidogrel. Further metabolism of 2-oxo-clopidogrel leads to the formation of a thiol derivative—the active metabolite. This active metabolite is formed predominantly by the enzyme CYP2C19, with contributions from other CYP enzymes such as CYP1A2, CYP2B6, and CYP3A4. The active metabolite of clopidogrel (thiol derivative), isolated in vitro, rapidly and irreversibly binds to platelet receptors, thereby inhibiting platelet aggregation.

The Cmax of the active metabolite is approximately twice higher after a single 300 mg loading dose of clopidogrel compared to that observed after 4 days of 75 mg maintenance dosing. Cmax is reached approximately 30–60 minutes after administration.

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

Pharmacogenetics. CYP2C19 is involved in the formation of both the active metabolite and the intermediate metabolite 2-oxo-clopidogrel. The pharmacokinetics of the active metabolite of clopidogrel and antiplatelet effects, measured by ex vivo platelet aggregation, vary depending on CYP2C19 genotype.

The CYP2C19*1 allele corresponds to fully functional metabolism, whereas the CYP2C19*2 and CYP2C19*3 alleles correspond to non-functional metabolism. CYP2C19*2 and CYP2C19*3 alleles account for most of the non-functional alleles in Caucasian (85%) and Mongoloid (99%) patients with reduced metabolism. Other alleles associated with absent or reduced metabolism are less common and include CYP2C19*4, *5, *6, *7, and *8. A patient with reduced metabolism has two non-functional alleles as described above. Published data indicate that CYP2C19 genotypes associated with reduced metabolism occur in 2% of Caucasian patients, 4% of African-American patients, and 14% of Chinese patients. Tests are currently available to determine CYP2C19 genotype.

In a crossover study involving 40 healthy volunteers (10 in each of four CYP2C19 metabolic phenotype groups: ultrarapid, extensive, intermediate, and poor), the pharmacokinetics and antiplatelet effects of a 300 mg dose followed by 75 mg daily, and a 600 mg dose followed by 150 mg daily, were evaluated. Each treatment regimen was administered for a total of 5 days (to reach steady state). No significant differences in active metabolite plasma concentrations or mean platelet aggregation inhibition (PAI) were observed between individuals with ultrarapid, extensive, and intermediate metabolism. In individuals with poor metabolism, active metabolite plasma concentrations were reduced by 63–71% compared to those with extensive metabolism. After administration of the 300 mg/75 mg regimen, antiplatelet effects in poor metabolizers were less pronounced, with mean PAI (5 µM ADP) of 24% (24 hours) and 37% (day 5), compared to 39% (24 hours) and 58% (day 5) in extensive metabolizers and 37% (24 hours) and 60% (day 5) in intermediate metabolizers. When the 600 mg/150 mg regimen was used in poor metabolizers, active metabolite plasma concentrations were higher than with the 300 mg/75 mg regimen. Furthermore, PAI values were 32% (24 hours) and 61% (day 5), higher than in poor metabolizers receiving 300 mg/75 mg and similar to values in other CYP2C19 metabolic phenotype groups receiving the 300 mg/75 mg regimen. Based on clinical effect studies, an optimal dosing regimen for this patient group has not been established.

Consistent with the above findings, a meta-analysis of six studies assessing steady-state data from 335 patients receiving clopidogrel showed that active metabolite plasma concentrations were reduced by 28% in intermediate metabolizers and by 72% in poor metabolizers; platelet aggregation inhibition (5 µM ADP) was also reduced, with PAI differences of 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 studied in prospective randomized controlled trials. However, several retrospective analyses have been conducted to assess this effect in patients receiving clopidogrel with available genotyping data: CURE (n = 2721), CHARISMA (n = 2428), CLARITY-TIMI 28 (n = 227), TRITON-TIMI 38 (n = 1477), and ACTIVE-A (n = 601). Additionally, results from several cohort studies have been published.

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

In analyses of CHARISMA and one cohort study (Simon), patients with poor metabolism had increased event rates compared to those with extensive metabolism.

Analyses of CURE, CLARITY, ACTIVE-A, and one cohort study (Trenk) showed no difference in cardiovascular event rates based on metabolic phenotype.

None of these analyses included a sufficient number of patients to definitively detect differences in clinical outcomes among patients with poor metabolism.

Special patient populations. The pharmacokinetics of the active metabolite of clopidogrel have not been studied in the special patient populations listed below.

Renal impairment. After repeated administration of 75 mg clopidogrel daily in patients with severe renal impairment (creatinine clearance 5–15 mL/min), ADP-induced platelet aggregation inhibition was less pronounced (25%) compared to healthy volunteers, while bleeding time was prolonged to a similar extent as in healthy volunteers receiving 75 mg clopidogrel daily. Clinical tolerability was good in all patients.

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

Racial origin. The prevalence of CYP2C19 alleles causing intermediate and poor metabolic activity varies by race/ethnicity (see section "Pharmacogenetics"). Limited data are available in Mongoloid race patients to assess the clinical significance of genotyping this CYP from the standpoint of clinical outcomes.

Preclinical safety data. The most commonly observed adverse effects during preclinical animal studies were hepatic changes. These occurred at doses leading to clopidogrel blood concentrations nearly 25 times higher than those observed in humans receiving the clinical dose of 75 mg clopidogrel daily and were due to the drug's effect on enzymes involved in hepatic metabolism. No effect on enzymes involved in hepatic metabolism was observed in humans receiving therapeutic doses of clopidogrel.

Poor gastric tolerance (gastritis, erosive gastric lesions, and/or vomiting) was observed in rats and baboons when high doses of clopidogrel were administered.

No evidence of carcinogenic potential was observed in mice after 78 weeks and in rats after 104 weeks of clopidogrel administration at doses up to 77 mg/kg daily (approximately 25 times higher than human plasma concentrations observed with the clinical dose of 75 mg daily).

A series of genotoxicity studies of clopidogrel were conducted in vitro and in vivo, none of which revealed any genotoxic effects.

Clopidogrel did not affect reproductive function in rats and showed no teratogenic effects in rats or rabbits. Administration to lactating rats resulted in minor developmental delay in offspring. Specific pharmacokinetic studies with radiolabeled clopidogrel demonstrated that the parent compound and its metabolites are excreted in breast milk. Therefore, both direct effects on offspring (minor toxicity) and indirect effects (due to impaired taste of milk) cannot be excluded.

Clinical characteristics.

Indications.

Secondary prevention of atherothrombotic events in adult patients:

• who have experienced myocardial infarction (treatment initiation – within a few days, but no later than 35 days after onset), ischemic stroke (treatment initiation – within 7 days, but no later than 6 months after onset), or who have been diagnosed with peripheral arterial disease;

• with acute coronary syndrome:

  • with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), including patients who have undergone percutaneous coronary intervention with stent placement, in combination with acetylsalicylic acid (ASA);

• with acute ST-segment elevation myocardial infarction, in combination with acetylsalicylic acid (ASA) in patients undergoing percutaneous coronary intervention (including patients receiving stents), or in patients receiving medical therapy eligible for thrombolytic/fibrinolytic therapy.

Transient ischemic attack (TIA) of moderate to high risk or minor ischemic stroke (IS)

Clopidogrel in combination with ASA is indicated in adult patients with TIA of moderate to high risk (ABCD2 score ≥ 4) or minor ischemic stroke (NIHSS score ≤ 3) within 24 hours of the TIA or IS event.

[1] Age, blood pressure, clinical features, duration, and diabetes diagnosis.

2 National Institutes of Health Stroke Scale.

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation. Clopidogrel in combination with ASA is indicated in adult patients with atrial fibrillation who have at least one risk factor for vascular events, in whom vitamin K antagonist (VKA) therapy is contraindicated and who have a low risk of bleeding, for the prevention of atherothrombotic and thromboembolic events, including stroke.

For additional information, see section "Pharmacological properties".

Contraindications.

Hypersensitivity to the active substance or to any component of the medicinal product. Severe hepatic impairment. Active bleeding (e.g., peptic ulcer or intracranial hemorrhage).

Interaction with other medicinal products and other forms of interaction.

MEDICINAL PRODUCTS ASSOCIATED WITH INCREASED BLEEDING RISK. Due to potential additive effects, there is an increased risk of hemorrhagic complications; therefore, concomitant use of such medicinal products with clopidogrel requires caution (see section "Special precautions for use").

Oral anticoagulants. Concomitant use of Plavix® with oral anticoagulants is not recommended, as this combination may increase the risk and severity of bleeding (see section "Special precautions for use"). Although administration of clopidogrel at a dose of 75 mg once daily does not alter the pharmacokinetic profile of S-warfarin or the international normalized ratio (INR) in patients receiving long-term warfarin therapy, concomitant use of clopidogrel and warfarin increases the risk of bleeding due to independent effects on hemostasis.

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

Acetylsalicylic acid (ASA). Acetylsalicylic acid does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but clopidogrel enhances the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg ASA twice daily for one day did not cause a clinically significant increase in bleeding time prolonged by clopidogrel. Since a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid with an increased risk of bleeding is possible, concomitant use of these agents requires caution (see section "Special precautions for use"). Nevertheless, clopidogrel and ASA have been used concomitantly for up to one year (see section "Pharmacological properties").

Heparin. Clinical study data in healthy volunteers indicate that clopidogrel does not require heparin dose adjustment and does not alter heparin's effect on coagulation. Concomitant administration of heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation. Since a pharmacodynamic interaction between clopidogrel and heparin with an increased risk of bleeding is possible, concomitant use of these agents requires caution (see section "Special precautions for use").

Thrombolytic agents. The safety of concomitant use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic agents, and heparin was evaluated in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed with concomitant use of thrombolytic agents and heparin with ASA (see section "Adverse reactions").

Non-steroidal anti-inflammatory drugs (NSAIDs). In a clinical study involving healthy volunteers, concomitant administration of clopidogrel and naproxen increased the number of occult gastrointestinal bleedings. However, due to the lack of interaction studies with other NSAIDs, it is not yet established whether the risk of gastrointestinal bleeding increases with all NSAIDs. Therefore, caution is required when using NSAIDs, particularly COX-2 inhibitors, concomitantly with clopidogrel (see section "Special precautions for use").

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

Concomitant use with other medicinal products.

Inducers of CYP2C19

Since clopidogrel is partially metabolized to its active metabolite via CYP2C19, administration of medicinal products that induce the activity of this enzyme is expected to increase the level of the active metabolite of clopidogrel.

Rifampicin strongly induces CYP2C19, leading to both increased levels of the active metabolite of clopidogrel and enhanced platelet inhibition, which may particularly increase the risk of bleeding. As a precaution, concomitant use of strong CYP2C19 inducers should be avoided (see section "Special precautions for use").

Inhibitors of CYP2C19

Since clopidogrel is partially converted to its active metabolite via CYP2C19, administration of medicinal products that reduce the activity of this enzyme will most likely lead to decreased plasma concentrations of the active metabolite of clopidogrel. The clinical significance of this interaction is not established. Therefore, as a precaution, concomitant use of strong and moderate CYP2C19 inhibitors should be avoided (see sections "Special precautions for use" and "Pharmacokinetics").

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

Proton pump inhibitors (PPIs). Omeprazole 80 mg once daily, when co-administered with clopidogrel or within 12 hours between doses of these two medicinal products, reduced the concentration of the active metabolite in blood by 45% (loading dose) and 40% (maintenance dose). This reduction was associated with a decrease in platelet aggregation inhibition by 39% (loading dose) and 21% (maintenance dose). A similar interaction is expected between clopidogrel and esomeprazole.

Observational and clinical studies have yielded conflicting data regarding the clinical consequences of these pharmacokinetic (PK) and pharmacodynamic (PD) interactions in terms of the development of major cardiovascular events. As a precaution, omeprazole or esomeprazole should not be used concomitantly with clopidogrel (see section "Special precautions for use").

A less pronounced reduction in metabolite concentrations in blood was observed with pantoprazole or lansoprazole.

When pantoprazole 80 mg once daily was co-administered, plasma concentrations of the active metabolite decreased by 20% (loading dose) and 14% (maintenance dose). This reduction was associated with a decrease in mean platelet aggregation inhibition by 15% and 11%, respectively. These results suggest that concomitant use of clopidogrel and pantoprazole is possible.

There is no evidence that other medicinal products that reduce gastric acid production, such as H2 blockers or antacids, affect the antiplatelet activity of clopidogrel.

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

Markedly reduced platelet inhibition was observed in HIV patients receiving ART boosted with ritonavir or cobicistat. Although the clinical significance of these data is not established, spontaneous reports have been received of HIV-infected patients receiving ART boosted with ritonavir who experienced recurrent occlusive events after de-obstruction or thrombotic events despite high-dose clopidogrel regimens. Concomitant use of clopidogrel and ritonavir may result in reduced mean platelet inhibition. Therefore, concomitant use of clopidogrel with boosted ART should be avoided.

Combination with other medicinal products. A number of clinical studies have been conducted with clopidogrel and other medicinal products to investigate potential pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interaction was observed when clopidogrel was administered concomitantly with atenolol, nifedipine, or both. Furthermore, the pharmacodynamic activity of clopidogrel remained virtually unchanged when administered concomitantly with phenobarbital and estrogen.

The pharmacokinetic properties of digoxin or theophylline were not altered when administered concomitantly with clopidogrel.

Antacid agents did not affect the absorption of clopidogrel.

Results from the CAPRIE study indicate that phenytoin and tolbutamide, which are metabolized by cytochrome CYP 2C9, can be safely used concomitantly with clopidogrel.

MEDICINAL PRODUCTS THAT ARE SUBSTRATES OF THE CYP2C8 ENZYME. It has been shown that clopidogrel increases exposure to repaglinide in healthy volunteers. In vitro studies have demonstrated that this increased exposure to repaglinide is due to inhibition of the CYP2C8 enzyme by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant use of clopidogrel with medicinal products primarily eliminated via metabolism mediated by the CYP2C8 enzyme (e.g., repaglinide, paclitaxel) requires caution (see section "Special precautions for use").

Except for the information on interactions with specific medicinal products mentioned above, interaction studies between clopidogrel and medicinal products commonly prescribed to patients with atherothrombosis have not been conducted. However, patients participating in clinical trials with clopidogrel were concurrently using other medicinal products, including diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, calcium antagonists, cholesterol-lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, and GPIIb/IIIa antagonists, without evidence of clinically significant adverse effects.

As with other oral P2Y12 inhibitors, concomitant use of opioid agonists may potentially delay and reduce the absorption of clopidogrel, likely due to delayed gastric emptying. The clinical significance of this is unknown. Consider using parenteral antiplatelet agents in patients with acute coronary syndrome who require concomitant administration of morphine or other opioid agonists.

Rosuvastatin. It has been shown that after administration of clopidogrel 300 mg, rosuvastatin exposure increases twofold (AUC) and 1.3-fold (Cmax), and after repeated administration of clopidogrel 75 mg, rosuvastatin exposure increases 1.4-fold (AUC) without affecting Cmax.

Special precautions for use.

Hemorrhage and hematological disorders. Due to the risk of hemorrhage and hematological adverse reactions, a complete blood count and/or other appropriate tests should be performed immediately if symptoms indicating possible bleeding occur during treatment (see section "Adverse reactions"). As with other antiplatelet agents, clopidogrel should be used with caution in patients with an increased risk of bleeding due to trauma, surgical procedures, or other pathological conditions, and also when patients are receiving acetylsalicylic acid (ASA), heparin, glycoprotein IIb/IIIa inhibitors, NSAIDs including COX-2 inhibitors, selective serotonin reuptake inhibitors (SSRIs), strong CYP2C19 inducers, or other medicinal products such as pentoxifylline, which are associated with an increased risk of hemorrhagic events (see section "Interaction with other medicinal products and other forms of interaction"). Triple antiplatelet therapy (clopidogrel + ASA + dipyridamole) is not recommended for secondary prevention of stroke in patients with acute non-cardioembolic ischemic stroke or transient ischemic attack (TIA) due to increased risk of bleeding (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Patients should be carefully monitored for signs of bleeding, including occult bleeding, particularly during the first weeks of treatment and/or after invasive cardiac procedures or surgery. Concomitant use of clopidogrel 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").

For planned surgical procedures where antiplatelet effect is temporarily undesirable, clopidogrel treatment should be discontinued 7 days prior to surgery. Patients should inform their physician (including dentist) that they are taking clopidogrel before any surgical procedure or before starting any new medicinal product. Clopidogrel prolongs bleeding time; therefore, it should be used cautiously in patients with an increased risk of bleeding (particularly gastrointestinal and intraocular).

Patients should be advised that bleeding may take longer than usual to stop during treatment with clopidogrel (alone or in combination with ASA), and they should inform their physician of any unusual bleeding (in site or duration).

A loading dose of clopidogrel 600 mg is not recommended in patients aged ≥75 years with acute coronary syndrome without ST-segment elevation due to increased risk of bleeding in this population.

Due to limited clinical data in patients aged ≥75 years with ST-segment elevation acute coronary syndrome (STEMI) undergoing percutaneous coronary intervention (PCI) and at increased risk of bleeding, administration of a 600 mg loading dose of clopidogrel should only be considered after individual assessment of bleeding risk by the physician.

Thrombotic thrombocytopenic purpura (TTP). Very rare cases of thrombotic thrombocytopenic purpura (TTP) have been reported following 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 is a potentially life-threatening condition that may be fatal and requires immediate treatment, including plasma exchange.

Recent ischemic stroke.

Initiation of treatment

• Dual antiplatelet therapy (clopidogrel and ASA) should be initiated as early as possible and no later than 24 hours after the onset of symptoms in patients with acute minor ischemic stroke or moderate- to high-risk TIA.
• There are no data on the benefit-risk ratio of short-term dual antiplatelet therapy in patients with acute minor ischemic stroke or moderate- to high-risk TIA who have a history of (non-traumatic) intracranial hemorrhage.
• Monotherapy with clopidogrel in patients with non-minor ischemic stroke should be initiated only 7 days after the event.

Patients with non-minor ischemic stroke (NIHSS score > 4)
Due to lack of data, dual antiplatelet therapy is not recommended (see section "Indications").

Patients with recent minor ischemic stroke or moderate- to high-risk TIA scheduled for or undergoing interventional procedures

There are no data supporting the use of dual antiplatelet therapy in patients scheduled for carotid endarterectomy or endovascular thrombectomy, or in patients undergoing thrombolysis or anticoagulant therapy. Dual antiplatelet therapy is not recommended in these situations.

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

Cytochrome P450 2C19 (CYP2C19).

Pharmacogenetics. Patients with genetically reduced CYP2C19 function have lower plasma concentrations of the active metabolite of clopidogrel and a diminished antiplatelet effect when standard doses of clopidogrel are administered. Currently available tests can identify the CYP2C19 genotype in patients.

Since clopidogrel is partially converted to its active metabolite by CYP2C19, concomitant use of medicinal products that reduce the activity of this enzyme will most likely result in reduced plasma concentrations of the active metabolite of clopidogrel. However, the clinical significance of this interaction has not been fully established. Therefore, as a precaution, concomitant use of strong and moderate CYP2C19 inhibitors should be avoided (see section "Interaction with other medicinal products and other forms of interaction"; list of CYP2C19 inhibitors is provided in section "Pharmacokinetics").

Concomitant use of medicinal products that induce CYP2C19 activity is expected to increase levels of the active metabolite of clopidogrel and may increase the risk of bleeding. As a precaution, concomitant use of strong CYP2C19 inducers should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Substrates of CYP2C8 enzyme. Caution is advised in patients receiving clopidogrel concomitantly with medicinal products that are substrates of the CYP2C8 enzyme (see section "Interaction with other medicinal products and other forms of interaction").

Cross-reactivity among thienopyridines. Patients should be screened for history of hypersensitivity to other thienopyridines (such as clopidogrel, ticlopidine, prasugrel), as cross-reactivity has been reported (see section "Adverse reactions"). Thienopyridines may cause allergic reactions ranging from mild to severe, such as rash, angioedema, or hematological cross-reactions such as thrombocytopenia and neutropenia. Patients with a history of allergic and/or hematological reactions to one thienopyridine may have an increased risk of similar or other reactions to another thienopyridine. Monitoring for signs of hypersensitivity is recommended in patients with known allergy to thienopyridines.

Renal function impairment. Experience with clopidogrel use in patients with renal impairment is limited; therefore, the drug should be used with caution in such patients (see section "Dosage and administration").

Hepatic function impairment. Experience with clopidogrel use in patients with moderate hepatic disease and risk of hemorrhagic diathesis is limited. Therefore, clopidogrel should be used with caution in these patients (see section "Dosage and administration").

Excipients. Each tablet of Plavix® contains 12 mg of lactose. Patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Each tablet of Plavix® contains 13.2 mg of hydrogenated castor oil, which may cause gastrointestinal discomfort and diarrhea.

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

Use during pregnancy or breastfeeding.

Due to lack of clinical data on clopidogrel use during pregnancy, the drug should not be used during pregnancy (precautionary measure).

Animal studies have not shown direct or indirect adverse effects on pregnancy, embryonic/fetal development, parturition, or postnatal development.

It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion in milk; therefore, breastfeeding should be discontinued during treatment with Plavix®.

Fertility. Studies in laboratory animals have not shown any adverse effect of clopidogrel on fertility.

Ability to affect 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.

Adults and elderly patients. The 300 mg tablet is intended for use as a loading dose in patients with acute coronary syndrome. The drug is administered orally, independently of food intake.

Treatment with clopidogrel in patients with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction) should begin with a single loading dose of 300 mg or 600 mg, followed by continued administration of Plavix® at the 75 mg dosage once daily (together with acetylsalicylic acid at a dose of 75–325 mg daily). A 600 mg loading dose may be used in patients under 75 years of age when percutaneous coronary intervention (PCI) is required (see section "Special Instructions"). Since higher doses of acetylsalicylic acid increase the risk of bleeding, it is recommended not to exceed an acetylsalicylic acid dose of 100 mg. The optimal duration of treatment has not been formally established. Clinical trial data support treatment for up to 12 months, with maximum effect observed after 3 months of therapy (see section "Pharmacological Properties").

In patients with acute myocardial infarction with ST-segment elevation, who are receiving medical treatment and for whom thrombolytic/fibrinolytic therapy is indicated, clopidogrel should be administered at 75 mg once daily, beginning with a single 300 mg loading dose in combination with ASA, with or without thrombolytic agents. Treatment in patients over 75 years of age should be initiated without a clopidogrel loading dose. Combined therapy should be started as early as possible after symptom onset and continued for at least four weeks. The benefit of using clopidogrel in combination with ASA for more than four weeks in this condition has not been studied (see section "Pharmacological Properties").

If percutaneous coronary intervention (PCI) is planned:

• In patients undergoing primary PCI, and in patients undergoing PCI more than 24 hours after receiving fibrinolytic therapy, clopidogrel therapy should be initiated with a 600 mg loading dose. The 600 mg loading dose should be administered with caution in patients aged 75 years and older (see section "Special Instructions");
• In patients undergoing PCI within 24 hours after receiving fibrinolytic therapy, a 300 mg clopidogrel loading dose should be administered.

Clopidogrel treatment should be continued at a dose of 75 mg once daily in combination with ASA. In clinical practice, the prescribed maintenance dose range of ASA is 75 mg to 325 mg daily. Since higher ASA doses increase the risk of bleeding, it is recommended not to exceed an ASA dose of 100 mg. Combined therapy should be initiated as early as possible after symptom onset and continued for up to 12 months (see section "Pharmacological Properties").

Adult patients with moderate to high-risk TIA or minor ischemic stroke

Adult patients with moderate to high-risk TIA (ABCD2 score ≥ 4) or minor ischemic stroke (NIHSS score ≤ 3) should receive a clopidogrel loading dose of 300 mg, followed by continued treatment with 75 mg clopidogrel once daily and ASA at a dose of 75–100 mg once daily. Treatment with clopidogrel and ASA should be initiated within 24 hours of the event and continued for 21 days, followed by antiplatelet monotherapy.

In patients with atrial fibrillation, clopidogrel should be administered at a single daily dose of 75 mg. ASA (75–100 mg daily) should be initiated and continued together with clopidogrel (see section "Pharmacological Properties").

In case of a 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 scheduled dose at the usual time and should not double the dose to compensate for the missed dose.

Renal impairment. Therapeutic experience with the use of the drug in patients with renal impairment is limited (see section "Special Instructions").

Hepatic impairment. Therapeutic experience with the use of the drug in patients with moderate liver disease and potential for hemorrhagic diathesis is limited (see section "Special Instructions").

Children. Clopidogrel should not be used in children (under 18 years of age), as efficacy studies have not been conducted (see section "Pharmacodynamics").

Overdose.

In case of clopidogrel overdose, prolonged bleeding time with subsequent complications may occur. If bleeding occurs, symptomatic treatment is recommended.

There is no known antidote for the pharmacological activity of clopidogrel. If immediate correction of prolonged bleeding time is required, the effect of clopidogrel can be reversed by platelet transfusion.

Adverse Reactions

Short description of the safety profile

The safety of clopidogrel has been evaluated in more than 44,000 patients who participated in clinical trials (including over 1,200 individuals treated for 1 year or longer). Clinically significant adverse effects observed in the CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE-A trials are described below. In the CAPRIE trial, the overall tolerability of clopidogrel 75 mg once daily was comparable to that of acetylsalicylic acid (ASA) 325 mg once daily, regardless of patient age, gender, or race.

In addition to clinical trial data, spontaneous reports of adverse reactions during clinical use of the drug were also considered.

Bleeding was the most commonly observed adverse reaction, both during clinical trials and in the post-marketing period, and most frequently occurred during the first month of treatment.

In the CAPRIE trial, the overall incidence of bleeding in patients receiving clopidogrel or ASA was 9.3%. The frequency of major bleeding events was similar for clopidogrel and ASA.

In the CURE trial, no increased incidence of major bleeding was observed with clopidogrel + ASA combination therapy within 7 days after coronary artery bypass graft (CABG) surgery in patients who discontinued treatment more than 5 days prior to surgery. In patients who continued treatment up to 5 days before CABG, the incidence of major bleeding was 9.6% in the clopidogrel + ASA group versus 6.3% in the placebo + ASA group.

In the CLARITY trial, an overall increased incidence of bleeding was observed in the clopidogrel + ASA group compared to the placebo + ASA group. However, the frequency of major bleeding was similar in both groups. This finding remained consistent across patient subgroups defined by baseline characteristics and type of fibrinolytic or heparin therapy.

In the COMMIT trial, the overall incidence of severe non-cerebral major bleeding or cerebral bleeding was low and similar between treatment groups.

In the ACTIVE-A trial, the incidence of major bleeding was higher in the clopidogrel + ASA group compared to the placebo + ASA group (6.7% vs. 4.3%). In both groups, most major bleeds were extracranial (5.3% in the clopidogrel + ASA group vs. 3.5% in the placebo + ASA group), primarily gastrointestinal bleeding (3.5% vs. 1.8%). An increased incidence of intracranial hemorrhage was observed in the clopidogrel + ASA group compared to placebo + ASA (1.4% vs. 0.8%, respectively). There was no statistically significant difference between groups in the incidence of fatal bleeding (1.1% in clopidogrel + ASA vs. 0.7% in placebo + ASA) or hemorrhagic stroke (0.8% vs. 0.6%, respectively).

In the TARDIS trial, patients with recent ischemic stroke who received intensive triple antiplatelet therapy (ASA + clopidogrel + dipyridamole) experienced significantly more bleeding events and severe bleeding compared to those receiving clopidogrel monotherapy or ASA plus dipyridamole (adjusted overall RR 2.54, 95% CI 2.05–3.16, p < 0.0001).

List of adverse reactions in tabular form

Adverse reactions observed during clinical trials or during clinical use based on spontaneous reporting are listed in the table below. Adverse reactions are categorized by system organ class, and frequency is defined 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), and frequency not known (cannot be estimated from available data). Within each organ system class, adverse effects are listed in descending order of severity.

* Information regarding clopidogrel with frequency "frequency not known".

Reporting of suspected adverse reactions.

Reporting of adverse reactions after drug registration is important. It allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of drug efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Keep out of the reach of children.

Store in the original packaging.

Packaging.

No. 10 (10x1): 10 tablets in a blister, 1 blister in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

SANOFI WINTHROP INDUSTRIE.

Manufacturer's address and site of activity.

1, rue de la Vierge AMBARÉS ET LAGRAVE 33565 – CARBON BLANC Cedex, France.