Plavix®

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

Composition:

Active substance: clopidogrel;

One tablet contains 75 mg of clopidogrel hydrogen sulfate, expressed as base;

Excipients: mannite (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, iron oxide red (E 172)), carnauba wax.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: pink-colored, round, slightly biconvex film-coated tablets, engraved with "75" on one side and "1171" on the other.

Pharmacotherapeutic group. Antiplatelet agents, excluding heparin.

ATC code: B01AC04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Clopidogrel is a prodrug. One of clopidogrel's metabolites is an inhibitor of platelet aggregation. Clopidogrel must be biotransformed by cytochrome CYP450 enzymes to form the active metabolite, which inhibits platelet aggregation. 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 recovers at a rate consistent with platelet turnover. Aggregation of platelets induced by agonists other than ADP is also inhibited, due to the drug's blockade of platelet activation by released AD游戏副本.

Because the active metabolite is formed via cytochrome CYP450 enzymes, some of which are polymorphic or inhibited by other drugs, sufficient inhibition of platelet aggregation does not occur in all patients.

Pharmacodynamic effects. Significant slowing 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. At steady state, the average level of inhibition of aggregation with a daily dose of 75 mg ranges from 40% to 60%. Platelet aggregation and bleeding time return to baseline levels on average within 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, which compared clopidogrel with acetylsalicylic acid (ASA), and the CURE, CLARITY, COMMIT, CHANCE, POINT, and ACTIVE-A trials, which compared clopidogrel with placebo, both in combination with ASA and other standard therapies.

Recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease. The CAPRIE trial included 19,185 patients with atherothrombosis, manifested as recent myocardial infarction (<35 days prior), recent ischemic stroke (7 days to 6 months prior), 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 myocardial infarction subgroup, most patients received ASA in the first few days after MI onset.

Compared to ASA, clopidogrel significantly reduced the incidence of new ischemic events (a composite endpoint of myocardial infarction, ischemic stroke, and vascular death). 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 all-cause mortality as a secondary endpoint showed no significant differences between clopidogrel therapy (5.8%) and ASA (6%).

Subgroup analysis by underlying condition (myocardial infarction, ischemic stroke, and PAD) showed the greatest effect (statistically significant at p = 0.003) in patients with PAD (especially those with prior MI) (RRR = 23.7%; CI: 8.9–36.2), while a smaller effect (not statistically different from ASA) was observed in stroke patients (RRR = 7.3%; CI: -5.7–18.7 [p=0.258]). In patients enrolled based solely on recent MI, the effect of clopidogrel was numerically lower but not statistically different from ASA (RRR = -4%; CI: -22.5–11.7 [p=0.639]). Additionally, subgroup analysis by age suggests that the favorable effect of clopidogrel is lower in patients aged 75 years and older compared to those ≤75 years.

Since the statistical power of the CAPRIE trial was insufficient to assess efficacy in individual subgroups, it remains unclear whether true 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 myocardial infarction), 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 levels at least twice the upper limit of normal. Patients were randomized to receive clopidogrel (loading dose 300 mg, then 75 mg/day, n=6259) or placebo (n=6303), both in combination with ASA (75–325 mg once daily) and other standard therapies. Treatment duration was up to 1 year. In the CURE trial, 823 (6.6%) patients also received concomitant therapy with GPIIb/IIIa glycoprotein receptor antagonists. More than 90% of patients received heparins. This concomitant therapy did not significantly affect the relative frequency of bleeding events with clopidogrel versus placebo.

The number of patients reaching the primary endpoint [cardiovascular death (CVD), myocardial infarction (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) in the clopidogrel group (17% with conservative treatment, 29% if patients underwent percutaneous transluminal coronary angioplasty with or without stent placement, and 10% if they underwent 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 months 0–1, 1–3, 3–6, 6–9, and 9–12 of the study, respectively. Thus, beyond 3 months of treatment, the favorable effect observed in the clopidogrel + ASA group no longer increased, while the risk of bleeding remained (see section "Special precautions").

Use of clopidogrel during the CURE trial reduced the need for thrombolytic therapy (RRR = 43.3%; CI: 24.3–57.5%) and GPIIb/IIIa glycoprotein 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 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 largely due to a statistically significant reduction in the incidence of MI [287 (4.6%) in the clopidogrel group vs. 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) were consistent with the primary analysis. In particular, a subgroup analysis of 2172 patients (17% of the total CURE group) who received stents (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 this subgroup analysis are consistent with the overall trial results.

The favorable effect of clopidogrel was demonstrated independently of concomitant use of other cardiovascular agents (such as heparin/low molecular weight heparin, GPIIb/IIIa inhibitors, lipid-lowering agents, beta-blockers, and ACE inhibitors). The efficacy of clopidogrel was independent of ASA dose (75–325 mg once daily).

ST-segment elevation myocardial infarction (STEMI). In patients with acute 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).

The CLARITY trial included 3491 patients who had experienced STEMI within the previous 12 hours and were scheduled for thrombolytic therapy. 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. Patients were followed for 30 days. The primary endpoint was occlusion of the infarct-related artery detected on angiography 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. The patient population included 19.7% women, 29.2% patients ≥65 years of age. 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.

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 for clopidogrel (95% CI: 24–47%; p < 0.001), primarily due to a reduction in infarct-related artery occlusion. This advantage was observed across 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 who underwent percutaneous coronary intervention (PCI). In patients receiving clopidogrel with a 300 mg loading dose (LD) (n = 933), a significant reduction in the incidence of cardiovascular death, MI, or stroke after PCI was observed compared to placebo recipients (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 a 300 mg LD, a significant reduction in the incidence of cardiovascular death, MI, or stroke within 30 days after PCI was observed compared to placebo recipients (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 treatment groups (2.0% with prior clopidogrel treatment vs. 1.9% with placebo, p > 0.99). These results support the early use of a clopidogrel loading dose in STEMI and a standard pre-treatment strategy with clopidogrel when performing PCI.

The two-by-two factorial design of the COMMIT trial included 45,852 patients who developed symptoms suggestive of MI within the previous 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. The primary combined endpoints were all-cause mortality and the first recurrence of MI, stroke, or death. The patient population included 27.8% women, 58.4% patients ≥60 years (26% ≥70 years), and 54.5% patients receiving fibrinolytics.

Clopidogrel significantly reduced the relative risk of all-cause mortality by 7% (p = 0.029) and the relative risk of the composite endpoint 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 all ages and sexes, regardless of fibrinolytic use, and occurred within the first 24 hours.

Clopidogrel loading dose of 600 mg in patients with acute coronary syndrome undergoing PCI.

Study CURRENT-OASIS-7 (Optimal Antiplatelet Strategy for Reducing Recurrent Events – Organization to Assess Strategies in Ischemic Syndromes, version 7)

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) clopidogrel, and either high-dose (300–325 mg daily) or low-dose (75–100 mg daily) aspirin. Coronary angiography was performed in 24,835 of the 25,086 patients, and PCI in 17,263. In the 25,086 patients included in the study, the frequency of cardiovascular death, myocardial infarction, or stroke was similar (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 PCI patients with double-dose clopidogrel versus standard therapy (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 to Reduce Myocardial Damage During Angioplasty – Myocardial Infarction)

This randomized, prospective, international, multicenter study evaluated pre-treatment with clopidogrel at a 600 mg loading dose (LD) versus 300 mg LD in emergency PCI for STEMI. Patients received clopidogrel at 600 mg LD (n = 103) or 300 mg LD (n = 98) before PCI, then 75 mg daily from the day after PCI to 1 year. In patients receiving clopidogrel at 600 mg LD, infarct size was significantly reduced compared to those receiving 300 mg LD. TIMI perfusion grade <3 after PCI occurred less frequently with 600 mg LD (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 a 600 mg LD provides faster and stronger inhibition of platelet activation. The analysis assessed the impact of 600 mg LD versus 300 mg LD on 30-day clinical outcomes in 3311 patients from the main study (n = 1153; 300 mg LD group; n = 2158; 600 mg LD group) before cardiac catheterization, followed by 75 mg daily 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 600 mg LD without higher bleeding rates. According to multivariate analysis, a 600 mg loading dose of clopidogrel 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 CABG) was 6.1% in the 600 mg LD group and 9.4% in the 300 mg LD group (p = 0.0005). The rate of minor bleeding was 11.3% in the 600 mg LD group and 13.8% in the 300 mg LD group (p = 0.03).

In a meta-analysis (Vyas et al., 2014) evaluating the clinical benefit of a 600 mg clopidogrel loading dose in patients with STEMI undergoing PCI, data from nine studies published between 2009 and 2012 were included. The primary efficacy and safety endpoints were major adverse cardiovascular events and major bleeding. A significant reduction in major adverse cardiovascular events was observed with the 600 mg LD (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), including 5 randomized and 2 non-randomized studies, 300 mg (n = 11,148) and 600 mg (n = 14,235) clopidogrel loading doses were compared in patients undergoing PCI. Overall, the 600 mg LD 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). The 600 mg clopidogrel LD 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 STEMI patients 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. Afterward, all patients in both groups received clopidogrel 75 mg daily until day 28. From day 29 to 12 months, patients in the clopidogrel group received clopidogrel 75 mg daily, while the control group received placebo. Both groups received aspirin throughout the study. After 1 year, clopidogrel use was associated with a significant reduction in the combined risk of death, MI, or stroke (relative reduction 26.9%, 95% CI 3.9–44.4; p = 0.02; absolute reduction 3%) compared to placebo. No significant increase in 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) was observed after 1 year. 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) is non-inferior to 12-month DAPT after drug-eluting stent implantation. 1443 patients undergoing stent implantation 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 rate of target vessel failure (a composite 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, no significant difference in the safety endpoint (composite of death, MI, stroke, stent thrombosis, or major TIMI bleeding) was observed 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 non-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 ACS patients was evaluated in two investigator-sponsored randomized trials (ISS)—TOPIC and TROPICAL-ACS—with clinical outcome data.

The clinical benefit provided by more potent P2Y12 receptor inhibitors, ticagrelor and prasugrel, in pivotal trials was due to a statistically significant reduction in recurrent ischemic events (including acute and subacute stent thrombosis, myocardial infarction, 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 of treatment. In contrast, post hoc analyses demonstrated a statistically significant increase in bleeding risk with more potent P2Y12 receptor inhibitors, occurring predominantly during the maintenance phase, after the first month post-ACS. The TOPIC and TROPICAL-ACS trials were designed to investigate the possibility of reducing bleeding events while maintaining clopidogrel's efficacy.

Study TOPIC (Timing of Platelet Inhibition Following Acute Coronary Syndrome). This randomized, open-label trial included ACS patients requiring percutaneous coronary intervention (PCI). Patients receiving aspirin and a more potent P2Y12 receptor blocker without adverse events after one month were either switched to a fixed-dose combination of aspirin and clopidogrel (de-escalation dual antiplatelet therapy [DAPT]) or continued on the previous regimen (unchanged DAPT).

Data from 645 of 646 patients with STEMI (ST-segment elevation myocardial infarction), NSTEMI (non-ST-segment elevation myocardial infarction), or unstable angina were analyzed (de-escalation DAPT [n = 322], unchanged DAPT [n = 323]). Follow-up visits at 1 year were completed 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. Baseline characteristics were similar in both groups.

The primary endpoint, a composite of cardiovascular death, stroke, emergency revascularization, and bleeding events ≥ grade 2 according to BARC (Bleeding Academic Research Consortium) criteria at 1 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 events; no difference was reported for ischemic event endpoints (p = 0.36), while bleeding events ≥ grade 2 according to 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 according to BARC criteria 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).

Study TROPICAL-ACS (Testing Platelet Reactivity to Guide Maintenance Antiplatelet Therapy in Acute Coronary Syndromes). This randomized, open-label trial included 2610 ACS patients 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 guided de-escalation group, patients received either prasugrel (40%) or clopidogrel (60%). All patients continued aspirin, and follow-up was conducted for 1 year.

The primary endpoint (composite of cardiovascular death, MI, stroke, and bleeding ≥ grade 2 according to BARC criteria at 12 months) was reached, demonstrating at least non-inferior efficacy of clopidogrel. The endpoint occurred in 95 patients (7%) in the guided de-escalation group and 118 patients (9%) in the control group (p for non-inferiority = 0.0004). Guided de-escalation did not increase 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 did it increase the key secondary endpoint—frequency of bleeding events ≥ grade 2 according to BARC criteria (5% in the de-escalation group vs. 6% in the control group; p = 0.23). The overall frequency of all bleeding events (grades 1–5 according to BARC) was 9% (114 events) in the guided de-escalation group vs. 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 plus ASA for stroke prevention after acute minor stroke or TIA with moderate to high risk was evaluated in two investigator-sponsored randomized trials (ISS)—CHANCE and POINT—with clinical safety and efficacy data.

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

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

The primary efficacy endpoint was any new stroke event (ischemic or 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 vs. 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 vs. 295 patients (11.4%) in the ASA group (RR 0.67; 95% CI 0.56–0.81; p < 0.001). Hemorrhagic stroke occurred in 8 patients in each of the two study groups (0.3% in each group). Moderate or severe bleeding occurred 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 vs. 1.6% in the ASA group (RR 1.41; 95% CI 0.95–2.10; p = 0.09).

POINT (Platelet Inhibition for New TIA and Minor Ischemic Stroke).

This randomized, double-blind, multicenter, placebo-controlled clinical trial included patients worldwide (4881 patients) with acute TIA (ABCD2 score ≥4) or acute minor stroke (NIHSS score ≤3). All patients in both groups received ASA openly from day 1 to day 90 (50–325 mg, depending on physician's prescription). Patients randomly assigned to the clopidogrel group received clopidogrel 600 mg loading dose on day 1, then 75 mg daily 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 composite of major ischemic events (stroke, MI, or death due to ischemic vascular event) on day 90. These events occurred in 121 patients (5.0%) in the clopidogrel plus ASA group vs. 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 plus ASA vs. 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 occurred in 23 of 2,432 patients (0.9%) receiving clopidogrel plus ASA vs. 10 of 2,449 patients (0.4%) receiving ASA monotherapy (RR 2.32; 95% CI 1.10–4.87; p = 0.02). Minor bleeding occurred in 40 patients (1.6%) receiving clopidogrel plus ASA vs. 13 patients (0.5%) receiving ASA monotherapy (RR 3.12; 95% CI 1.67–5.83; p < 0.001).

Analysis of the temporal patterns in the CHANCE and POINT trials.

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

Temporal patterns of serious ischemic events and major bleeding in treatment groups in the CHANCE and POINT trials

Number of cases
Results from CHANCE and POINT studies	Treatment group distribution	Total	1st week	2nd week	3rd week
Major ischemic events	ASA (n = 5,035)	458	330	36	21
	Clopidogrel + ASA (n = 5,016)	328	217	30	14
	Difference	130	113	6	7
Major bleeding	ASA (n = 5,035)	18	4	2	1
	Clopidogrel + ASA (n = 5,016)	30	10	4	2
	Difference	-12	-6	-2	-1

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

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 multicentre, randomized, double-blind, placebo-controlled trial comparing clopidogrel 75 mg once daily + ASA (n = 3772) versus placebo + ASA (n = 3782). The recommended dose of ASA was 75 to 100 mg daily. Patients were treated for up to 5 years.

Patients randomized in the ACTIVE programme had documented AF, i.e. 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 to 74 years, or diabetes mellitus requiring medication, or documented history of myocardial infarction (MI), or documented ischaemic heart disease; previous treatment for systemic arterial hypertension; prior stroke, transient ischaemic attack (TIA), 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 previous 6 months; history of intracranial haemorrhage, severe thrombocytopenia (platelet count <50×109/L); need for clopidogrel or oral anticoagulants (OAC), or intolerance to either of these two substances.

73% of patients included in the ACTIVE-A study could not receive VKA due to physician assessment, inability to monitor international normalized ratio (INR), risk of falls or head injury, or presence of a specific bleeding risk factor; in 26% of patients, the physician's decision was based on patient unwillingness to receive VKA.

41.8% of patients were women. The mean age was 71 years, and 41.6% of patients were aged 75 years or older. Overall, 23% of patients received antiarrhythmic agents, 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 death) was 832 (22.1%) in the group receiving clopidogrel + ASA and 924 (24.4%) in the placebo + ASA group (relative risk reduction 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 28.4%; 95% CI: 16.8–38.3%, p = 0.00001).

Children. In a dose-escalation study involving 86 neonates 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 in neonates and infants, and at a dose of 0.15 mg/kg in neonates only. At a dose of 0.2 mg/kg, the mean platelet aggregation inhibition was 49.3% (5 µM ADP-induced platelet aggregation), which was comparable to that observed in adults receiving Plavix® at a dose of 75 mg daily.

In a randomized, double-blind, parallel-group study (CLARINET) involving 906 children (neonates and infants) with cyanotic congenital heart disease undergoing palliative surgery to create a systemic-to-pulmonary arterial shunt, patients were randomized to receive clopidogrel 0.2 mg/kg (n = 467) or placebo (n = 439), with concomitant background therapy, until the second stage of surgery. The mean time between the palliative shunt surgery and the first administration of the investigational drug was 20 days. Approximately 88% of patients concurrently received ASA (1 to 23 mg/kg/day). No significant differences between groups were observed regarding achievement of the primary composite endpoint, consisting of death, shunt thrombosis, or cardiac surgery due to thrombotic events by day 120 of life, which occurred in 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 no significant differences in bleeding frequency were observed between groups. During a subsequent long-term follow-up period for adverse events, 26 patients with a shunt present at 1 year of age received clopidogrel until 18 months of age. During this observation period, the safety profile of the drug remained unchanged.

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

Pharmacokinetics.

Absorption. After single and multiple 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 urinary excretion of clopidogrel metabolites.

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

Metabolism. Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, there are two main metabolic pathways: one involving esterases leading to hydrolysis and formation of an inactive carboxylic acid derivative (which accounts for 85% of circulating metabolites in plasma), and another involving cytochrome P450 enzyme system. Initially, clopidogrel is 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 CYP2C19 enzyme, with contributions from several 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 as high 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 radiolabelled 14C-clopidogrel in humans, approximately 50% of the dose was excreted in urine and about 46% in faeces. After a single 75 mg oral dose, the elimination half-life of clopidogrel is approximately 6 hours. The elimination half-life of the main circulating (inactive) metabolite is 8 hours after both single and multiple dosing.

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, as measured by ex vivo platelet aggregation, vary depending on the CYP2C19 genotype.

The CYP2C19*1 allele corresponds to fully functional metabolism, whereas the CYP2C19*2 and CYP2C19*3 alleles correspond to non-functional metabolism. The CYP2C19*2 and CYP2C19*3 alleles constitute the majority of 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 specified above. According to published data, CYP2C19 genotypes corresponding to reduced metabolism occur in 2% of Caucasians, 4% of African descent 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 groups corresponding to a specific CYP2C19 metabolic phenotype: ultrarapid, extensive, intermediate, and poor), the pharmacokinetics and antiplatelet effects were evaluated after a 300 mg dose followed by 75 mg daily, and after a 600 mg dose followed by 150 mg daily. Each treatment regimen was administered for a total of 5 days (to reach steady state). No significant differences in plasma concentrations of the active metabolite or mean platelet aggregation inhibition (PAI) were observed between individuals with ultrarapid, extensive, and intermediate metabolism. In individuals with poor metabolism, plasma concentrations of the active metabolite were reduced by 63–71% compared to those with extensive metabolism. After administration of the 300 mg/75 mg regimen, antiplatelet effects in individuals with poor metabolism 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 individuals with extensive metabolism and 37% (24 hours) and 60% (day 5) in individuals with intermediate metabolism. When individuals with poor metabolism received the 600 mg/150 mg regimen, plasma concentrations of the active metabolite were higher than with the 300 mg/75 mg regimen. Furthermore, PAI values were 32% (24 hours) and 61% (day 5), which were higher than in poor metabolizers receiving 300 mg/75 mg and similar to values obtained in other CYP2C19 metabolic phenotype groups receiving the 300 mg/75 mg regimen. Based on clinical effect studies, the appropriate dosing regimen for this patient group has not been established.

Similarly, in a meta-analysis of 6 studies assessing steady-state data from 335 patients receiving clopidogrel, plasma concentrations of the active metabolite were reduced by 28% in intermediate metabolizers and by 72% in poor metabolizers; inhibition of platelet aggregation (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 evaluate this effect in patients receiving clopidogrel with available genotyping results: 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 published cohort studies are available.

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

In the analysis of CHARISMA and one cohort study (Simon), individuals with poor metabolism had a higher event rate compared to extensive metabolizers.

In the analyses of CURE, CLARITY, ACTIVE-A, and one cohort study (Trenk), the incidence of cardiovascular events did not significantly differ based on metabolic phenotype.

None of these analyses included a sufficient number of patients to 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 following special patient populations.

Renal impairment. After repeated administration of 75 mg clopidogrel daily in patients with severe renal impairment (creatinine clearance 5–15 mL/min), inhibition of ADP-induced platelet aggregation was less pronounced (25%) compared to healthy volunteers, while bleeding time was prolonged almost to the same 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, inhibition of ADP-induced platelet aggregation 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 weak metabolic activity varies by race/ethnicity (see section "Pharmacogenetics"). Limited data are available in Mongoloid patients to assess the clinical significance of genotyping for this CYP.

Preclinical safety data. The most commonly observed adverse effects in preclinical animal studies were liver changes. These occurred at doses leading to blood concentrations of clopidogrel nearly 25 times higher than those observed in humans receiving the clinical dose of 75 mg 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 gastrointestinal tolerance (gastritis, gastric erosive lesions, and/or vomiting) was observed in rats and baboons receiving high doses of clopidogrel.

No evidence of carcinogenicity was observed in mice treated for 78 weeks and rats treated for 104 weeks with doses up to 77 mg/kg daily (approximately 25 times the human exposure at the clinical dose of 75 mg daily).

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

Clopidogrel did not affect reproductive function in rats and had no teratogenic effects in rats or rabbits. In rats during lactation, clopidogrel caused minor developmental delay in offspring. Specific pharmacokinetic studies with radiolabelled clopidogrel demonstrated that the parent compound and its metabolites are excreted in breast milk. Therefore, both direct (minor toxic effect) and indirect effects (due to impaired milk palatability) on offspring cannot be excluded.

Clinical characteristics.

Indications.

Secondary prevention of atherothrombotic events in adult patients:

• who have had a 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 diagnosed peripheral arterial disease;
• with acute coronary syndrome:

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) (patients undergoing percutaneous coronary intervention, including those receiving stents, and patients receiving medical therapy eligible for thrombolytic/fibrinolytic therapy).

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

Clopidogrel in combination with ASA is indicated for adult patients with TIA of moderate or 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 of symptoms, and diagnosis of diabetes mellitus.

2 National Institutes of Health Stroke Scale.

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation. Clopidogrel in combination with ASA is indicated for 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. Acute 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 the potential additive effect, 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 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 their 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 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"). Despite this, clopidogrel and ASA have been used concomitantly for up to 1 year (see section "Pharmacological properties").

HEPARIN. Clinical study data in healthy volunteers indicate that clopidogrel does not require dose adjustment of heparin and does not alter heparin's effect on coagulation. Concomitant administration of heparin does not alter the inhibitory effect of clopidogrel on platelet aggregation. However, 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 with fibrin-specific or non-fibrin-specific thrombolytic agents and heparins 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 in healthy volunteers, concomitant use 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). Concomitant use of SSRIs with clopidogrel should be done cautiously, as SSRIs affect platelet activation and increase the risk of bleeding.

CONCOMITANT USE OF OTHER MEDICINAL PRODUCTS.

INDUCERS OF CYP2C19

Since clopidogrel is metabolized to its active metabolite partially via CYP2C19, the use 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 precautionary measure, concomitant use of strong CYP2C19 inducers should be avoided (see section "Special precautions for use").

INHIBITORS OF CYP2C19.

Since clopidogrel is converted to its active metabolite partially via CYP2C19, the use 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 precautionary measure, 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 by 40% (maintenance dose). This reduction was associated with a decrease in platelet aggregation inhibition by 39% (loading dose) and by 21% (maintenance dose). A similar interaction with clopidogrel is expected with esomeprazole.

Observational and clinical studies have yielded conflicting data regarding the clinical consequences of these pharmacokinetic and pharmacodynamic interactions in terms of the occurrence of major cardiovascular events. As a precautionary measure, 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 by 14% (maintenance dose). This reduction was associated with a decrease in the 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-receptor antagonists 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 revascularization or thrombotic events despite high-dose clopidogrel therapy. Concomitant use of clopidogrel and ritonavir may lead to 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 used concomitantly with atenolol, nifedipine, or both. Furthermore, the pharmacodynamic activity of clopidogrel remained essentially unchanged when used concomitantly with phenobarbital and estrogen.

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

ANTACIDS did not affect the absorption of clopidogrel.

Results from the CAPRIE study indicate that phenytoin and tolbutamide, which are metabolized via the CYP2C9 enzyme, can be safely used concomitantly with clopidogrel.

MEDICINAL PRODUCTS THAT ARE SUBSTRATES OF THE CYP2C8 ENZYME. Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies demonstrated that this increased repaglinide exposure 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 and medicinal products primarily eliminated via metabolism mediated by the CYP2C8 enzyme (such as repaglinide, paclitaxel) requires caution (see section "Special precautions for use").

Except for the information on interactions with specific medicinal products mentioned above, studies on interactions between clopidogrel and medicinal products commonly prescribed for atherothrombosis have not been conducted. However, patients participating in clinical trials of clopidogrel used other medicinal products concomitantly, 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 signs of clinically significant adverse effects.

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

ROSUVASTATIN. It has been found that after administration of clopidogrel 300 mg, rosuvastatin exposure in patients increased 2-fold (AUC) and 1.3-fold (Cmax), and after repeated administration of clopidogrel 75 mg, rosuvastatin exposure increased 1.4-fold (AUC) without affecting Cmax.

Special precautions for use.

Hemorrhage and hematological disorders. Due to the risk of bleeding and hematological adverse reactions, a complete blood count and/or other appropriate tests should be performed immediately if symptoms suggesting 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, nonsteroidal anti-inflammatory drugs (including COX-2 inhibitors), selective serotonin reuptake inhibitors (SSRIs), potent CYP2C19 inducers, or other medicinal products associated with an increased risk of hemorrhagic events (see section "Interaction with other medicinal products and other forms of interaction"). Due to the increased risk of bleeding, triple antiplatelet therapy (clopidogrel + ASA + dipyridamole) is not recommended for secondary stroke prevention in patients with acute non-cardioembolic ischemic stroke or transient ischemic attack (TIA) (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 following invasive cardiac procedures and surgery. Concomitant use of clopidogrel with oral anticoagulants is not recommended, as it 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 a new medicinal product. Clopidogrel prolongs bleeding time; therefore, it should be used with caution in patients with an increased risk of bleeding (particularly gastrointestinal and intraocular).

Patients should be advised that when taking clopidogrel (alone or in combination with ASA), bleeding may take longer than usual to stop, and they should report any unusual bleeding (in location or duration) to their physician.

A loading dose of 600 mg clopidogrel is not recommended in patients with non-ST-segment elevation acute coronary syndrome aged ≥75 years due to an increased risk of bleeding in this group.

Due to limited clinical data in patients aged ≥75 years with ST-segment elevation acute coronary syndrome (STEMI) undergoing PCI and at increased risk of bleeding, administration of a 600 mg loading dose of clopidogrel should be considered only 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 with neurological symptoms, renal dysfunction, or fever. TTP is a potentially life-threatening condition that may lead to death and requires immediate treatment, including plasma exchange.

Acquired hemophilia. Cases of acquired hemophilia have been reported following clopidogrel use. In case of isolated prolonged 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 managed by a specialist and receive appropriate treatment; clopidogrel should be discontinued in such patients.

Recent ischemic stroke.

Initiation of treatment

• In patients with acute minor ischemic stroke or moderate- to high-risk TIA, dual antiplatelet therapy (clopidogrel and ASA) should be initiated within 24 hours of symptom onset.
• 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.
• In patients with non-minor ischemic stroke, clopidogrel monotherapy 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 receiving interventional procedures.

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

Cytochrome P450 2C19 (CYP2C19). Pharmacogenetics: Patients with genetically reduced CYP2C19 function have lower plasma concentrations of the active metabolite of clopidogrel and a less pronounced antiplatelet effect when standard doses of clopidogrel are administered. Genetic tests are currently available to identify the CYP2C19 genotype of a patient.

Since clopidogrel is partially metabolized to its active metabolite via CYP2C19, concomitant use of medicinal products that reduce the activity of this enzyme will likely result in decreased plasma concentrations of the active metabolite of clopidogrel. However, the clinical significance of this interaction is not fully established. As a precautionary measure, 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 precautionary measure, 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-sensitivity of thienopyridines. Patients should be evaluated for history of hypersensitivity to other thienopyridines (such as clopidogrel, ticlopidine, prasugrel), as cross-hypersensitivity among thienopyridines has been reported (see section "Adverse reactions"). Use of thienopyridines may lead to allergic reactions ranging from mild to severe, such as rash, Quincke's edema, 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 different reactions to another thienopyridine. Monitoring for signs of hypersensitivity is recommended in patients with known allergy to thienopyridines.

Renal 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 impairment. Experience with the use of clopidogrel in patients with moderate liver disease and potential for hemorrhagic diathesis is limited; therefore, clopidogrel should be used with caution in these patients (see section "Dosage and administration").

Excipients. One Plavix® tablet contains 3 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.

One Plavix® tablet contains 3.3 mg of hydrogenated castor oil, which may cause gastrointestinal disturbances and diarrhea.

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

Use during pregnancy or breastfeeding.

Pregnancy. Due to lack of clinical data on clopidogrel use during pregnancy, administration of the drug to pregnant women is not recommended (precautionary measure).

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

Breastfeeding. 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. No adverse effects of clopidogrel on fertility were observed in animal studies.

Ability to influence the speed of reactions when driving or operating machinery.

Clopidogrel has no effect or a negligible effect on the ability to drive or operate machinery.

Dosage and Administration

Adults and elderly patients. Plavix® should be taken at a dose of 75 mg once daily, independently of food intake.

In patients with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), treatment with clopidogrel should be initiated with a single loading dose of 300 mg or 600 mg. A loading dose of 600 mg may be used in patients under 75 years of age when percutaneous coronary intervention (PCI) is planned (see section "Special Instructions"). Treatment with clopidogrel should be continued at a dose of 75 mg once daily (in combination with acetylsalicylic acid (ASA) at a dose of 75–325 mg daily). Since higher doses of ASA increase the risk of bleeding, it is recommended not to exceed an ASA 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 benefit observed after 3 months of therapy (see section "Pharmacological Properties").

Patients with acute ST-segment elevation myocardial infarction, who are receiving medical therapy and for whom thrombolytic/fibrinolytic therapy is indicated, should receive clopidogrel 75 mg once daily, initiated with a single 300 mg loading dose in combination with ASA, with or without thrombolytic agents. In patients aged 75 years and older, treatment should be initiated without a loading dose of clopidogrel. Combination therapy should be started as early as possible after symptom onset and continued for at least 4 weeks. The benefit of using clopidogrel in combination with ASA beyond 4 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 treatment 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 loading dose of clopidogrel should be administered.

Clopidogrel treatment should be continued at a dose of 75 mg once daily in combination with ASA. In clinical practice, the maintenance dose of ASA ranges from 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. Combination 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 300 mg loading dose of clopidogrel, followed by maintenance therapy with 75 mg clopidogrel once daily and ASA 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.

Patients with atrial fibrillation should receive clopidogrel at a single daily dose of 75 mg. ASA (75–100 mg daily) should be initiated and continued concomitantly with clopidogrel (see section "Pharmacological Properties").

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) due to lack of data on efficacy in this patient population (see section "Pharmacodynamics").

Overdose. Overdose with clopidogrel may result in prolonged bleeding time with subsequent complications. In case of bleeding, 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 transfusion of platelet concentrates.

Adverse Reactions

Short description of safety profile

The safety of clopidogrel has been evaluated in more than 44,000 patients who participated in clinical trials (including over 12,000 patients treated for 1 year or longer). In the CAPRIE trial, the overall clinical adverse effects observed with clopidogrel 75 mg once daily were generally comparable to those with 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 post-marketing use of the drug in clinical practice were also considered.

Bleeding was the most commonly reported adverse reaction observed both in clinical trials and during post-marketing experience, with the majority of bleeding events occurring during the first month of treatment.

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

In the CURE study, no increase in the incidence of major bleeding was observed with clopidogrel + ASA combination therapy during the 7 days following 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 surgery, the incidence of major bleeding was 9.6% in the clopidogrel + ASA group versus 6.3% in the placebo + ASA group.

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

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

In the ACTIVE-A study, 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, major bleeding events were predominantly extracranial (5.3% in the clopidogrel + ASA group vs. 3.5% in the placebo + ASA group), mainly 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 the 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 study, patients with recent ischemic stroke receiving intensive triple antiplatelet therapy (ASA + clopidogrel + dipyridamole) experienced higher rates of any bleeding and major bleeding compared to those receiving monotherapy with clopidogrel or dual therapy with ASA + dipyridamole (adjusted odds ratio 2.54, 95% CI 2.05–3.16, p < 0.0001).

List of adverse reactions in table format

The adverse effects observed during clinical trials or during clinical use of the medicinal product based on spontaneous reporting are listed in the table below. Adverse reactions are categorized by system organ class, and their 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 system organ class, adverse effects are listed in order of decreasing severity.

System Organ Class	Common	Uncommon	Rare	Very rare, frequency unknown*
Blood and lymphatic system disorders		Thrombocytopenia, leukopenia, eosinophilia	Neutropenia, including severe neutropenia	Thrombotic thrombocytopenic purpura (TTP) (see section "Special precautions for use"), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired hemophilia A, granulocytopenia, anemia
Cardiac disorders				Kounis syndrome (vasospastic allergic angina / allergic myocardial infarction) as a result of hypersensitivity reaction to clopidogrel*
Immune system disorders				Serum sickness, anaphylactoid reactions, cross-sensitivity of thienopyridines (such as ticlopidine, prasugrel) (see section "Special precautions for use")*, autoimmune insulin syndrome, which may lead to severe hypoglycemia, especially in patients with HLA DRA4 subtype
Psychiatric disorders				Hallucinations, confusion
Nervous system disorders		Intracranial hemorrhage (in some cases fatal), headache, paresthesia, dizziness		Change in taste perception, ageusia
Eye disorders		Eye hemorrhage (conjunctival, ocular, retinal)
Ear and labyrinth disorders			Vertigo
Vascular disorders	Hema- toma			Severe hemorrhage, bleeding from surgical wound, vasculitis, arterial hypotension
Respiratory, thoracic and mediastinal disorders	Nose- bleed			Respiratory tract bleeding (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonia, eosinophilic pneumonia
Gastrointestinal disorders	Gastro- intestinal bleeding, diarrhea, abdo- minal pain, dyspepsia	Ulcer of stomach and duodenum, gastritis, vomiting, nausea, constipation, flatulence	Retroperi- toneal hemorrhage	Gastrointestinal and retroperitoneal hemorrhages with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic), stomatitis
Hepatobiliary disorders				Acute liver failure, hepatitis, abnormal liver function test results
Skin and subcutaneous tissue disorders	Sub- cuta- neous hemor- rhage	Rash, pruritus, intradermal hemorrhages (purpura)		Bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, acute generalized exanthematous pustulosis (AGEP), angioneurotic edema, drug hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), erythematous or exfoliative rash, urticaria, eczema, lichen planus
Reproductive system and breast disorders			Gynecomastia
Musculoskeletal and connective tissue disorders				Soft tissue hemorrhage (hemarthrosis), arthritis, arthralgia, myalgia
Renal and urinary disorders		Hematuria		Glomerulonephritis, increased blood creatinine levels
General disorders and administration site conditions	Ble- eding at injection site			Fever
Investigations		Increased bleeding time, decreased neutrophil and platelet counts

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

Reporting of suspected adverse reactions.

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

Shelf life. 3 years.

Storage conditions. Keep out of reach of children. Store in the original packaging.

Packaging. No. 28 (14x2): 14 tablets in a blister, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. SANOFI WINTHROP INDUSTRIE.

Manufacturer's location and address of the place of business. 1, rue de la Virgule et Lagrave, 33565 – CARBON BLANC Cedex, France.