Clopidogrel

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CLOPIDOGREL (CLOPIDOGREL)

Composition:

Active substance: clopidogrel;

One film-coated tablet contains 75 mg of clopidogrel bisulfate, calculated as clopidogrel;

Excipients: microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, low-substituted hydroxypropylcellulose, magnesium stearate, talc, colloidal silicon dioxide, hydrogenated castor oil, film coating SOL Code IC-S-279 (Brown) (containing titanium dioxide (E 171) and iron oxide red (E 172)), isopropyl alcohol, dichloromethane.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, orange, round, biconvex.

Pharmacotherapeutic group. Antithrombotic agents. ATC code B01A C04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Clopidogrel is a prodrug. One of clopidogrel's metabolites is an inhibitor of platelet aggregation. To form the active metabolite that suppresses platelet aggregation, clopidogrel must undergo biotransformation by cytochrome CYP 450 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 suppressing platelet aggregation. Since binding is irreversible, platelets exposed to clopidogrel remain altered throughout their lifespan (approximately 7–10 days), and normal platelet function recovers at a rate corresponding to platelet turnover. Platelet aggregation induced by other agonists besides ADP is also inhibited, due to the drug's blockade of platelet activation by released ADP.

Because the active metabolite is formed via cytochrome CYP 450 enzymes, some of which are polymorphic or inhibited by other medicinal products, not all patients achieve sufficient platelet aggregation inhibition.

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 – comparing 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 therapy.

Recent myocardial infarction (MI), stroke, or established peripheral arterial disease. The CAPRIE trial included 19,185 patients with atherothrombosis, manifested as recent myocardial infarction (<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 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 consisting 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 overall 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 who had experienced myocardial infarction) (RRR = 23.7%; CI: 8.9–36.2), while a smaller effect (not significantly different from ASA) was observed in stroke patients (RRR = 7.3%; CI: -5.7–18.7 [p=0.258]). In patients included in the study based solely on recent myocardial infarction, 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 beneficial effect of clopidogrel in patients aged 75 years and older was lower than in those ≤75 years.

Since the power of the CAPRIE trial was insufficient to evaluate 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 normal limit. 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 therapy. Treatment duration was up to 1 year. In the CURE trial, 823 (6.6%) patients also received concomitant therapy with a GPIIb/IIIa glycoprotein receptor antagonist. Over 90% of patients received heparin. 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. Relative risk reduction was 20% (95% CI 10%–28%; p=0.00009) for the clopidogrel group (17% with conservative treatment, 29% if patients underwent percutaneous coronary intervention 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 the periods 0–1, 1–3, 3–6, 6–9, and 9–12 months of the study, respectively. Thus, beyond 3 months of treatment, the beneficial effect observed in the clopidogrel + ASA group no longer increased, while the risk of bleeding persisted (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 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. 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) were consistent with the primary analysis. Specifically, an additional analysis of 2172 patients (17% of the total CURE patient 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, results from the additional subgroup analysis align with the overall trial findings.

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 inhibitors, lipid-lowering agents, beta-blockers, and 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.

The safety and efficacy of clopidogrel in patients with acute MI with ST-segment elevation 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 MI with ST-segment elevation within the last 12 hours and for whom thrombolytic therapy was planned. 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. Patient follow-up continued for 30 days. The primary endpoint was occlusion of the infarct-related artery detected on angiography before discharge, fatal outcome, or recurrent MI before coronary angiography. For patients who did not undergo angiography, the primary endpoint was fatal outcome or recurrent MI before day 8 or discharge. The study population included 19.7% women, 29.2% patients ≥65 years. Overall, 99.7% of patients received fibrinolytics (fibrin-specific – 68.7%, non-fibrin-specific – 31.1%), 89.5% received 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, absolute reduction was 6.7%, with a 36% advantage favoring clopidogrel (95% CI: 24–47%; p < 0.001), primarily due to reduced incidence of occlusion of the infarct-related artery. 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 acute MI with ST-segment elevation undergoing percutaneous coronary intervention (PCI). Patients who received a 300 mg loading dose of clopidogrel (n=933) had a significantly lower incidence of CVD, MI, or stroke after PCI compared to those who received placebo (n=930) (3.6% vs. 6.2%, odds ratio [OR]: 0.54; 95% CI: 0.35–0.85; p=0.008). Patients who received a 300 mg loading dose of clopidogrel had a significantly lower incidence of CVD, MI, or stroke within 30 days after PCI compared to those who received placebo (7.5% vs. 12.0%, OR: 0.59; 95% CI: 0.43–0.81; p=0.001). However, this combined endpoint, evaluated in the overall CLARITY study population, was not statistically significant as a secondary endpoint. No significant difference in the frequency of major or minor hemorrhages was observed between the two treatment methods (2.0% with prior clopidogrel treatment vs. 1.9% with placebo, p>0.99). Results of this analysis confirm the efficacy of early use of a clopidogrel loading dose in patients with acute MI with ST-segment elevation and support the strategy of routine pre-treatment with clopidogrel in patients undergoing PCI.

The two-factor design of the COMMIT trial included 45,852 patients who within the last 24 hours developed symptoms suggestive of MI, 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 study 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 combination of recurrent MI, stroke, or death by 9% (p = 0.002), corresponding to absolute reductions of 0.5% and 0.9%, respectively. This effect was observed in patients of different ages and sexes, regardless of fibrinolytic use, and was evident within the first 24 hours.

Use of a 600 mg loading dose of clopidogrel in patients with acute coronary syndrome undergoing PCI.

CURRENT-OASIS-7 trial ("Optimal dose of clopidogrel and aspirin for reduction of recurrent events – Organization to Assess Strategies in Ischemic Syndromes-7")

This randomized factorial trial included 25,086 patients with acute coronary syndrome (ACS) requiring early percutaneous coronary intervention (PCI). Patients were randomly assigned to receive either double dose (600 mg on day 1, then 150 mg/day from day 2 to day 7, then 75 mg/day) or standard dose (300 mg on day 1, then 75 mg/day) of clopidogrel and either high-dose (300–325 mg/day) or low-dose (75–100 mg/day) ASA. 24,835 ACS patients underwent coronary angiography, and 17,263 underwent PCI. Among the 17,263 patients who underwent PCI, double-dose clopidogrel compared to standard dose reduced the incidence of the primary endpoint (3.9% vs. 4.5%; adjusted risk ratio [RR]: 0.86; 95% CI: 0.74–0.99, p=0.039) and significantly reduced stent thrombosis (1.6% vs. 2.3%, RR: 0.68; 95% CI: 0.55–0.85; p=0.001). Major bleeding was more frequent with double-dose compared to standard-dose clopidogrel (1.6% vs. 1.1%; RR: 1.41, 95% CI: 1.09–1.83, p=0.009). In this trial, a 600 mg loading dose of clopidogrel demonstrated consistent efficacy in patients both aged 75 years and older and younger than 75 years.

ARMYDA-6 MI ("Antiplatelet therapy to reduce myocardial damage during angioplasty and myocardial infarction")

This randomized, prospective, international, multicenter trial evaluated pretreatment with 600 mg versus 300 mg of clopidogrel as a loading dose in emergency PCI for patients with acute ST-elevation myocardial infarction.

Patients received clopidogrel 600 mg loading dose (n=103) or clopidogrel 300 mg loading dose (n=98) before PCI, then 75 mg/day from the next day after PCI to 1 year. Patients receiving a 600 mg loading dose of clopidogrel had significantly smaller infarct size compared to those receiving a 300 mg loading dose. With a 600 mg loading dose of clopidogrel, there was less frequent post-PCI thrombolysis in MI grade <3 (5.8% vs. 16.3%, p=0.031), improved LVEF at discharge (52.1 ±9.5% vs. 48.8 ±11.3%, p=0.026), and reduced major adverse cardiovascular events at 30 days (5.8% vs. 15%, p=0.049). No increase in bleeding or access site complications was observed (secondary endpoints at 30 days).

HORIZONS-AMI trial ("Harmonizing outcomes with revascularization and stenting in acute myocardial infarction")

This retrospective analysis trial was conducted to evaluate whether a 600 mg loading dose of clopidogrel provides faster and greater inhibition of platelet activation. Results showed significantly lower unadjusted 30-day mortality (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 a 600 mg loading dose of clopidogrel, without higher rates of hemorrhagic events. According to multivariate analysis, a 600 mg loading dose of clopidogrel was an independent predictor of lower incidence of major adverse cardiovascular events at 30 days (RR: 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 600 mg loading dose group and 9.4% in the 300 mg loading dose group (p=0.0005). The rate of minor bleeding was 11.3% in the 600 mg loading dose group and 13.8% in the 300 mg loading dose group (p=0.03).

Long-term (12 months) use of clopidogrel in patients with acute ST-elevation myocardial infarction after PCI.

CREDO trial ("Clopidogrel for Reduction of Events During Observation")

This randomized, double-blind, placebo-controlled trial was conducted in the United States and Canada to evaluate the benefits of long-term (12 months) clopidogrel treatment after PCI.

The trial included 2116 patients randomized to receive clopidogrel 300 mg loading dose (n=1053) or placebo (n=1063) 3–24 hours before PCI. All patients also received 325 mg ASA. Afterward, 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 75 mg/day clopidogrel, while the control group received placebo. Both groups received ASA throughout the study (81–325 mg/day). At 1 year, there was a significant reduction in the combined risk of death, MI, or stroke with clopidogrel (26.9% relative reduction, 95% CI: 3.9%–44.4%; p=0.02; 3% absolute reduction) compared to placebo. At 1 year, there was no significant increase in major bleeding (8.8% in the clopidogrel group vs. 6.7% in the placebo group, p=0.07) or minor bleeding (5.3% in the clopidogrel group vs. 5.6% in the placebo group, p=0.84). The study authors concluded that continuing clopidogrel and ASA for at least 1 year leads to a statistically and clinically significant reduction in serious thrombotic events.

EXCELLENT trial ("Efficacy of Xience/Promus stents vs. Cypher stents for reducing late loss after stenting")

This prospective, open-label, randomized trial conducted in Korea evaluated whether 6-month dual antiplatelet therapy (DAPT) is non-inferior to 12-month DAPT after implantation of second-generation drug-eluting stents.

The trial included 1443 patients undergoing stent implantation, randomized to 6-month DAPT (ASA 100–200 mg/day and clopidogrel 75 mg/day for 6 months, then ASA alone until 12 months) or 12-month DAPT (ASA 100–200 mg/day and clopidogrel 75 mg/day for 12 months). There was no significant difference in target vessel failure (a composite of cardiac death, MI, or target vessel revascularization), the primary endpoint, between the 6-month and 12-month DAPT groups (RR: 1.14; 95% CI: 0.70–1.86; p=0.60). Additionally, the trial showed no significant difference in the safety endpoint (a combination of death, MI, stroke, stent thrombosis, or major bleeding by TIMI criteria) between the 6-month and 12-month DAPT groups (RR: 1.15; 95% CI: 0.64–2.06; p=0.64). The study authors concluded 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 ASA after the acute phase in patients with ACS was evaluated in two investigator-sponsored randomized trials – TOPIC and TROPICAL-ACS – with data on clinical outcomes.

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 efficacy with clopidogrel.

TOPIC trial ("Duration of platelet inhibition after acute coronary syndrome").

This randomized, open-label trial included patients with ACS requiring percutaneous coronary intervention (PCI). Patients who were taking aspirin and a more potent P2Y12 receptor blocker and had no 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).

Overall, data from 645 of 646 patients with STEMI (ST-elevation myocardial infarction) or NSTEMI (non-ST-elevation myocardial infarction), or unstable angina were analyzed (de-escalation DAPT (n = 322), unchanged DAPT (n = 323)). Follow-up visit at 1 year was 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 of the study cohort were similar in both groups.

The primary endpoint, a combination of cardiovascular death, stroke, emergency revascularization, and bleeding events ≥ grade 2 according to BARC (Bleeding Academic Research Consortium) criteria at 1 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 ≥ grade 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).

TROPICAL-ACS trial ("Testing platelet reactivity to guide long-term antiplatelet therapy in acute coronary syndromes")

This randomized, open-label trial included 2610 patients with ACS and positive biomarker testing, who successfully underwent PCI. Patients were randomized to 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 who continued prasugrel remained on 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 were followed for one year.

The primary endpoint (a composite of cardiovascular death, MI, stroke, and bleeding ≥ grade 2 by BARC criteria at 12 months) demonstrated 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 lead to increased combined ischemic risk (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—frequency of bleeding events ≥ grade 2 by BARC criteria (5% in the de-escalation group vs. 6% in the control group (p = 0.23)). The combined frequency of all bleeding events (grades 1–5 by BARC criteria) was 9% (114 events) in the guided 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 randomized trials—CHANCE and POINT—based on clinical safety and efficacy outcomes.

CHANCE (Clopidogrel for 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 (dose 75–300 mg at the treating physician's discretion). Patients randomly assigned to the clopidogrel-ASA group received clopidogrel 300 mg loading dose on day 1, then 75 mg/day from day 2 to day 90, plus 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 outcome 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% CI: 0.57–0.81; p < 0.001). 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 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 compared to 1.6% in the ASA group (RR 1.41; 95% CI: 0.95–2.10; p = 0.09).

POINT (Platelet inhibition to prevent TIA and minor ischemic stroke)

This randomized, double-blind, multicenter, placebo-controlled clinical trial included patients worldwide (4881 individuals) 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 (dose 50–325 mg, depending on the treating physician's prescription). Patients randomly assigned to the clopidogrel group received clopidogrel 600 mg loading dose 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 outcome was a combination of major ischemic events (stroke, MI, or death from ischemic vascular event) at day 90. These events occurred in 121 patients (5.0%) in the clopidogrel plus ASA 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 outcome was ischemic stroke. It occurred in 112 patients (4.6%) receiving clopidogrel plus 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 outcome was major bleeding. It occurred in 23 of 2,432 patients (0.9%) receiving clopidogrel plus 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 bleeding occurred in 40 patients (1.6%) receiving clopidogrel plus ASA and in 13 patients (0.5%) receiving ASA monotherapy (RR 3.12; 95% CI: 1.67–5.83; p = 0.001).

Analysis of CHANCE and POINT trial dynamics

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

Dynamics of serious ischemic events and major hemorrhages in treatment groups in the CHANCE and POINT trials

Number of cases
Results from CHANCE and POINT studies	Randomized to treatment group	Total	1st week	2nd week	3rd week
Major ischemic events	ASA (n = 5035)	458	330	36	21
	Clopidogrel + ASA (n = 5016)	328	217	30	14
	Difference	130	113	6	7
Major bleeding	ASA (n = 5035)	18	4	2	1
	Clopidogrel + ASA (n = 5016)	30	10	4	2
	Difference	-12	-6	-2	-1

Atrial fibrillation.

In the ACTIVE-W and ACTIVE-A studies, which were separate trials within the ACTIVE programme, patients with atrial fibrillation (AF) and 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 take 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, randomised, 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 75–100 mg daily. Patients were treated for up to 5 years.

Patients randomised 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 55–74 years, diabetes mellitus requiring medication, documented history of myocardial infarction (MI), documented ischaemic heart disease, prior treatment for systemic arterial hypertension, prior stroke, transient ischaemic attack (TIA), systemic embolism without CNS 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); requirement for clopidogrel or oral anticoagulants (OACs), or intolerance to either of these agents.

73% of patients included in the ACTIVE-A study could not receive VKA therapy due to physician judgment related to inability to monitor international normalised 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 refusal to take VKA therapy.

41.8% of patients were female. The mean age was 71 years, and 41.6% were aged ≥75 years. 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 reaching the primary endpoint (time to first occurrence of stroke, MI, systemic embolism without CNS involvement, or death) was 832 (22.1%) in the clopidogrel + ASA group 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 0.15 mg/kg in neonates only. At a dose of 0.2 mg/kg, the mean level of platelet aggregation inhibition was 49.3% (5 µM ADP-induced platelet aggregation), which was comparable to that observed in adults receiving clopidogrel 75 mg daily.

In a randomised, double-blind, parallel-group study (CLARINET), 906 children (neonates and infants) with cyanotic congenital heart disease undergoing palliative surgery with systemic-to-pulmonary arterial shunt creation were randomised to receive clopidogrel 0.2 mg/kg (n = 467) or placebo (n = 439), with concomitant background therapy until the second surgical stage. The mean time between palliative shunt surgery and first study drug administration was 20 days. Approximately 88% of patients also received ASA (1–23 mg/kg/day). No significant difference between groups was observed regarding the primary composite endpoint of death, shunt thrombosis, or cardiac surgery due to thrombotic events by day 120 (89 [19.1%] in the clopidogrel group vs. 90 [20.5%] in the placebo group) (see section "Posology and method of administration"). The most common adverse reaction in both the clopidogrel and placebo groups was bleeding, but no significant difference in bleeding frequency was observed between groups. During the subsequent long-term safety follow-up period, 26 patients with a functioning 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.

The reconstituted clopidogrel solution was used in the CLARINET and PICOLO studies. In a relative bioavailability study in adults, the reconstituted clopidogrel solution showed 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 repeated oral doses of 75 mg daily, clopidogrel is rapidly absorbed. Mean maximum 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%, as indicated by 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 unsaturated in vitro over a wide concentration range.

Metabolism

Clopidogrel is extensively metabolised in the liver. In vitro and in vivo, two main metabolic pathways exist: one involving esterases leading to hydrolysis and formation of an inactive carboxylic acid derivative (accounting for 85% of circulating metabolites in plasma), and another involving cytochrome P450 enzymes. Initially, clopidogrel is converted to the intermediate metabolite 2-oxo-clopidogrel. Further metabolism of 2-oxo-clopidogrel leads to 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 label was excreted in urine and about 46% in faeces. After a single oral 75 mg dose, the elimination half-life of clopidogrel is about 6 hours. The half-life of the main (inactive) circulating metabolite is 8 hours after both single and repeated 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 according to 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 account for the majority of loss-of-function alleles in Caucasian (85%) and Asian (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. According to published data, CYP2C19 genotypes associated with reduced metabolism occur in 2% of Caucasian patients, 4% of Black 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 metaboliser 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 ultrarapid, extensive, and intermediate metabolisers. In poor metabolisers, active metabolite plasma concentrations were reduced by 63–71% compared to extensive metabolisers. After the 300 mg/75 mg dosing regimen, antiplatelet effects in poor metabolisers 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 metabolisers and 37% (24 hours) and 60% (day 5) in intermediate metabolisers. When poor metabolisers received the 600 mg/150 mg regimen, active metabolite plasma concentrations were higher than with the 300 mg/75 mg regimen. Additionally, PAI values were 32% (24 hours) and 61% (day 5), which were higher than in poor metabolisers receiving 300 mg/75 mg and similar to values observed in other metaboliser groups receiving 300 mg/75 mg. Based on clinical effect studies, the appropriate dosing regimen for this patient group has not been established.

Consistent with the above results, in a meta-analysis of 6 steady-state studies involving 335 patients receiving clopidogrel, active metabolite plasma concentrations were reduced by 28% in intermediate metabolisers and by 72% in poor metabolisers; platelet aggregation inhibition (5 µM ADP) was also reduced, with PAI differences of 5.9% and 21.4%, respectively, compared to extensive metabolisers.

The impact of CYP2C19 genotype on clinical outcomes in patients receiving clopidogrel has not been studied in prospective randomised 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 published cohort studies are available.

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

In the CHARISMA analysis and one cohort study (Simon), poor metabolisers had a higher event rate compared to extensive metabolisers.

In the CURE, CLARITY, ACTIVE-A, and one cohort study (Trenk) analyses, 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 in poor metabolisers.

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, patients with severe renal impairment (creatinine clearance 5–15 mL/min) showed less pronounced inhibition of ADP-induced platelet aggregation (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, patients with severe hepatic impairment showed similar inhibition of ADP-induced platelet aggregation as healthy volunteers. Mean prolongation of bleeding time was also similar in both groups.

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

Preclinical data.

The most commonly observed adverse effects in preclinical animal studies were liver changes. These occurred at doses leading to clopidogrel blood concentrations approximately 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 has been observed in humans receiving therapeutic doses of clopidogrel.

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

No evidence of carcinogenic potential 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 higher than human plasma concentrations at the clinical dose of 75 mg daily).

A number 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 either rats or rabbits. Administration to lactating rats resulted in 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

Clopidogrel is indicated:

• in adult patients who have suffered myocardial infarction (treatment initiation – within a few days, but no later than 35 days after onset), ischaemic stroke (treatment initiation – within 7 days, but no later than 6 months after onset), or who have been diagnosed with peripheral arterial disease;
• in adult patients 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 in patients undergoing percutaneous coronary intervention (including patients receiving stents), or in patients receiving standard medical therapy and who are candidates for thrombolytic/fibrinolytic therapy.

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

Clopidogrel in combination with ASA is indicated:

• in adult patients with TIA of moderate to high risk (ABCD21 ≥ 4) or minor ischaemic stroke (NIHSS2 ≤ 3) within 24 hours after 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 of the excipients.

Severe hepatic impairment.

Acute pathological bleeding (e.g., peptic ulcer or intracranial haemorrhage).

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 haemorrhagic complications; therefore, concomitant use of such medicinal products with clopidogrel requires caution (see section "Special warnings and precautions for use").

ORAL ANTICOAGULANTS. Concomitant use of clopidogrel with oral anticoagulants is not recommended, as this combination may increase the risk and severity of bleeding (see section "Special warnings and precautions for use"). Although administration of clopidogrel 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 haemostasis.

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

ACETYLSALICYLIC ACID (ASA). Acetylsalicylic acid does not affect the inhibitory action of clopidogrel on ADP-induced platelet aggregation, but clopidogrel enhances the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, concomitant administration of 500 mg ASA twice daily for one day did not significantly increase the 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 warnings and precautions for use"). Nevertheless, clopidogrel and ASA have been co-administered 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 did 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 warnings and precautions for use").

THROMBOLYTIC AGENTS. The safety of concomitant use of clopidogrel with fibrin-specific or non-fibrin-specific thrombolytic agents and heparins has been 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 "Undesirable effects").

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 bleeding episodes. However, due to the lack of interaction studies with other NSAIDs, it is not known 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 warnings and precautions for use").

OTHER ANTIPLATELET AGENTS. Concomitant use of antithrombotic medicinal products increases the risk of bleeding due to an additive effect. If a patient is being treated concomitantly with other antiplatelet agents, any signs or symptoms of bleeding require immediate evaluation (see section "Special warnings and precautions for use").

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs). Concomitant use of SSRIs with clopidogrel should be done with caution, as SSRIs affect platelet activation and increase the risk of bleeding.

Concomitant use with other medicinal products.

CYP2C19 INDUCERS

Since clopidogrel is partially converted to its active metabolite by CYP2C19, the use of medicinal products that increase the activity of this enzyme will most likely lead to increased plasma concentrations of the active metabolite of clopidogrel. Rifampicin strongly induces CYP2C19, resulting in both increased levels of the active metabolite of clopidogrel and enhanced platelet inhibition, which may, in particular, increase the risk of bleeding. As a precaution, concomitant use of strong CYP2C19 inducers should be avoided (see sections "Special warnings and precautions for use").

CYP2C19 INHIBITORS

Since clopidogrel is partially converted to its active metabolite by 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 precaution, concomitant use of strong and moderate CYP2C19 inhibitors should be avoided (see sections "Special warnings and 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 administered within 12 hours of each other, reduced the plasma concentration of the active metabolite by 45% (loading dose) and 40% (maintenance dose). This reduction was associated with a 39% decrease in platelet aggregation inhibition (loading dose) and 21% (maintenance dose). A similar interaction with clopidogrel is expected with esomeprazole.

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

A less pronounced reduction in metabolite concentration 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 15% and 11% decrease in mean platelet aggregation inhibition, 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.

BOOSTER 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 ritonavir-boosted ART who experienced recurrent occlusive events after revascularization or thrombotic events despite high-dose clopidogrel therapy. 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 used concomitantly with atenolol, nifedipine, or both. In addition, the pharmacodynamic activity of clopidogrel remained almost unchanged when used concomitantly with phenobarbital and estrogen.

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

ANTACIDS did not affect the absorption of clopidogrel.

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

MEDICINAL PRODUCTS THAT ARE SUBSTRATES OF THE CYP2C8 ENZYME. It has been shown that clopidogrel increases repaglinide exposure in healthy volunteers. In vitro studies have 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 that are primarily eliminated via CYP2C8-mediated metabolism (e.g., repaglinide, paclitaxel) requires caution (see section "Special warnings and 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 concomitantly 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 clopidogrel absorption, likely due to delayed gastric emptying. The clinical significance of this is unknown. Parenteral antiplatelet agents should be considered 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 2-fold (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.

Bleeding and hematological disorders.

Due to the risk of bleeding and hematological adverse reactions, a full 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, surgery, or other pathological conditions, and also when patients are receiving acetylsalicylic acid (ASA), heparin, glycoprotein IIb/IIIa inhibitors, or nonsteroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors, serotonin reuptake inhibitors (SSRIs), potent inducers of CYP2C19, 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, especially 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").

In case of planned surgical intervention, when the antiplatelet effect is temporarily undesirable, treatment with clopidogrel should be discontinued 7 days prior to surgery. Patients must inform their physician (including dentist) that they are taking clopidogrel before being prescribed any surgery 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 bleeding).

Patients should be warned that when being treated with clopidogrel (alone or in combination with ASA), bleeding may take longer to stop than usual, and they should report any episodes of unusual bleeding (in site or duration) to their physician.

The use of 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 increased risk of bleeding in this group.

The use of a 600 mg loading dose of clopidogrel should only be considered after individual assessment by the physician of the risk of bleeding in patients, due to limited clinical data in patients aged ≥75 years with ST-segment elevation myocardial infarction and increased risk of bleeding.

Thrombotic thrombocytopenic purpura (TTP).

Very rare cases of TTP have been observed after clopidogrel use, sometimes even after short-term treatment. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia, neurological symptoms, renal dysfunction, or fever. TTP is a potentially life-threatening condition that may lead to death and therefore requires immediate treatment, including plasma exchange.

Acquired hemophilia.

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

Recent ischemic stroke.

• Initiation of treatment:
  • Dual antiplatelet therapy (clopidogrel and ASA) should be initiated within 24 hours of symptom onset 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, who are scheduled for or have undergone interventional procedures:

There are no data confirming the benefit of dual antiplatelet therapy in patients scheduled for carotid endarterectomy or endovascular thrombectomy, or in patients planned 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. Currently, tests are available to identify the CYP2C19 genotype of a patient.

Since clopidogrel is partially converted to its active metabolite via 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 established. Therefore, as a precaution, concomitant use of strong and moderate inhibitors of CYP2C19 should be avoided (see section "Interaction with other medicinal products and other forms of interaction" for a list of CYP2C19 inhibitors; also see section "Pharmacokinetics").

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

Substrates of the 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 ticlopidine, prasugrel), as cross-reactivity 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 reactions such as thrombocytopenia and neutropenia. Patients who have previously experienced allergic and/or hematological reactions to one thienopyridine may have an increased risk of such 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 administered with caution in such patients (see section "Dosage and administration").

Hepatic function impairment.

Experience with clopidogrel use 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.

Clopidogrel contains lactose; therefore, patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Clopidogrel contains hydrogenated castor oil, which may cause gastrointestinal discomfort and diarrhea.

Special precautions for disposal of unused medicinal product 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 the use of clopidogrel during pregnancy, the drug should not be administered to pregnant women (precautionary measure).

Animal studies have not shown any direct or indirect adverse effects of clopidogrel on pregnancy, embryonal/fetal development, delivery, or postnatal development (see section "Preclinical data").

Breastfeeding. It is not known whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion of clopidogrel in milk; therefore, breastfeeding should be discontinued during treatment with this medicinal product.

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

Ability to drive and use machines.

Clopidogrel has no effect or has a negligible effect on the ability to drive and use machines.

Method of Administration and Dosage

Dosage

Adults, including elderly patients.

Clopidogrel should be administered at a dose of 75 mg once daily, regardless of food intake.

Patients with acute coronary syndrome:

• 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 600-mg loading dose may be considered in patients under 75 years of age when percutaneous coronary intervention (PCI) is required (see section "Special Instructions"). Treatment with clopidogrel should be continued at a dose of 75 mg once daily (in combination with acetylsalicylic acid at a dose of 75–325 mg daily). Since higher doses of ASA increase the risk of bleeding, the dose of acetylsalicylic acid should not exceed 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").
• In patients with acute myocardial infarction with ST-segment elevation:
  • For patients undergoing medical therapy and indicated for thrombolytic/fibrinolytic therapy, clopidogrel should be administered at 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 combining clopidogrel with ASA beyond 4 weeks in this condition has not been studied (see section "Pharmacological Properties").
  • Patients undergoing percutaneous coronary intervention (PCI):
    • Patients undergoing primary PCI, as well as those undergoing PCI more than 24 hours after fibrinolytic therapy, should receive a 600-mg loading dose of clopidogrel. In patients aged ≥75 years, a 600-mg loading dose of clopidogrel should be administered with caution (see section "Special Instructions").
    • Patients undergoing PCI within 24 hours after fibrinolytic therapy should receive a 300-mg loading dose of clopidogrel.

Clopidogrel treatment should be continued at 75 mg once daily in combination with acetylsalicylic acid at 75–100 mg daily. Combination therapy should be initiated as early as possible after symptom onset and continued for up to 12 months (see section "Pharmacodynamics").

Adult patients with moderate to high-risk TIA or minor ischemic stroke (IS):

Adult patients with moderate to high-risk TIA (ABCD2 score ≥ 4) or minor IS (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.

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 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.

Special patient populations

Elderly patients.

• Acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction): A 600-mg loading dose of clopidogrel may be considered in patients under 75 years of age when percutaneous coronary intervention is required (see section "Special Instructions").
• Acute myocardial infarction with ST-segment elevation: In patients aged ≥75 years undergoing medical therapy and indicated for thrombolytic/fibrinolytic therapy, clopidogrel treatment should be initiated without a loading dose.
• In patients aged ≥75 years undergoing primary PCI, as well as those undergoing PCI more than 24 hours after fibrinolytic therapy, a 600-mg loading dose of clopidogrel should be administered with caution (see section "Special Instructions").

Renal impairment.

Therapeutic experience with clopidogrel in patients with renal impairment is limited (see section "Special Instructions").

Hepatic impairment.

Therapeutic experience with clopidogrel in patients with moderate liver disease and potential for hemorrhagic diathesis is limited (see section "Special Instructions").

Method of administration

For oral use. The drug may be taken with or without food.

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.

Prolongation of bleeding time with subsequent complications may occur in case of clopidogrel overdose. Symptomatic treatment is recommended if bleeding occurs.

There is no known antidote to 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 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). The clinically significant adverse effects observed in the CAPRIE study showed that the overall effect 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 data from the CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE-A clinical trials, spontaneous reports of adverse reactions during post-marketing use of the drug in clinical practice were also considered.

Bleeding was the most commonly observed adverse reaction both in clinical trials and during post-marketing surveillance, with the majority of cases 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 frequency of severe bleeding events was similar between clopidogrel and ASA.

In the CURE study, no increase in the incidence of major bleeding was observed with the combination of clopidogrel + ASA during 7 days following coronary artery bypass graft (CABG) surgery in patients who discontinued treatment more than 5 days before the surgical procedure. In patients who continued treatment until less than 5 days before CABG surgery, the incidence of this event 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 group receiving clopidogrel + ASA compared to the placebo + ASA group. The rate of major bleeding was similar in both groups. This finding remained consistent across subgroups of patients differing by baseline characteristics and type of fibrinolytic 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 group receiving clopidogrel + ASA 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 the placebo + ASA group (1.4% vs. 0.8%, respectively). There was no statistically significant difference between the groups in the incidence of fatal bleeding (1.1% in the clopidogrel + ASA group vs. 0.7% in the placebo + ASA group) 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) had higher rates of excessive and severe bleeding compared to monotherapy with clopidogrel or dual therapy with ASA and dipyridamole (adjusted overall RR 2.54, 95% CI 2.05–3.16, p<0.0001).

List of adverse reactions

Adverse effects observed during clinical trials or in clinical practice based on spontaneous reporting are listed below.

Adverse reactions are categorized by system organ class, and their frequency is defined as follows: common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from available data). Within each organ system class, adverse effects are listed in order of decreasing severity.

Blood and lymphatic system disorders: uncommon – thrombocytopenia, leukopenia, eosinophilia; rare – neutropenia, including severe neutropenia; very rare, frequency not known* – TTP (see section "Special precautions"), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired hemophilia A, granulocytopenia, anemia.

Cardiac disorders: very rare, frequency not known* – Kounis syndrome (allergic angina/vasospastic myocardial infarction) as a result of hypersensitivity reaction to clopidogrel*.

Immune system disorders: very rare, frequency not known* – serum sickness, anaphylactoid reactions, cross-sensitivity among thienopyridines (e.g., ticlopidine, prasugrel) (see section "Special precautions")*, autoimmune insulin syndrome potentially leading to severe hypoglycemia, especially in patients with HLA DRA4 subtype (more commonly found among Japanese ethnicity)*.

Psychiatric disorders: very rare, frequency not known* – hallucinations, confusion.

Nervous system disorders: uncommon – intracranial hemorrhage (in some cases fatal), headache, paresthesia, dizziness; very rare, frequency not known* – taste disturbance, ageusia.

Eye disorders: uncommon – ocular hemorrhage (conjunctival, ocular, retinal).

Ear and labyrinth disorders: rare – vertigo.

Vascular disorders: common – hematoma; very rare, frequency not known* – severe hemorrhage, surgical wound bleeding, vasculitis, arterial hypotension.

Respiratory, thoracic and mediastinal disorders: common – epistaxis; very rare, frequency not known* – respiratory tract hemorrhage (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.

Gastrointestinal disorders: common – gastrointestinal hemorrhage, diarrhea, abdominal pain, dyspepsia; uncommon – gastric and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence; rare – retroperitoneal hemorrhage; very rare, frequency not known* – fatal gastrointestinal and retroperitoneal hemorrhage, pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis.

Hepatobiliary disorders: very rare, frequency not known* – acute liver failure, hepatitis, abnormal liver function tests.

Skin and subcutaneous tissue disorders: common – subcutaneous hemorrhage; uncommon – rash, pruritus, petechiae (purpura); very rare, frequency not known* – bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, acute generalized exanthematous pustulosis (AGEP)), angioedema, 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: rare – gynecomastia.

Musculoskeletal and connective tissue disorders: very rare, frequency not known* – musculoskeletal hemorrhage (hemarthrosis), arthritis, arthralgia, myalgia.

Renal and urinary disorders: uncommon – hematuria; very rare, frequency not known* – glomerulonephritis, increased blood creatinine levels.

General disorders and administration site conditions: common – injection site bleeding; very rare, frequency not known* – fever.

Investigations: uncommon – prolonged bleeding time, decreased neutrophil and platelet counts.

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

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continued 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 efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in a dry, light-protected place, out of reach of children, at temperatures not exceeding 30 °C.

Packaging. 10 tablets per blister; 1, 3, or 10 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Ananta Medicare Limited.

Manufacturer's address and location.

Chak 17 ML, Agro Food Park Road, RIICO Industrial Area, Udaipurwati, Sri Ganganagar-335002 (Rajasthan), India.

Marketing authorization holder. Ananta Medicare Ltd.

Address of marketing authorization holder.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

INSTRUCTIONS

for medical use of the medicinal product

CLOPIDOGREL

(CLOPIDOGREL)

Composition:

Active substance: clopidogrel;

One film-coated tablet contains 75 mg of clopidogrel (calculated as clopidogrel hydrogen sulfate);

Excipients: microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, low-substituted hydroxypropylcellulose, magnesium stearate, talc, colloidal silicon dioxide, hydrogenated castor oil, film coating SOL Code IC-S-279 (Brown) (containing titanium dioxide (E 171) and red iron oxide (E 172)), isopropyl alcohol, dichloromethane.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, orange-colored, round, biconvex.

Pharmacotherapeutic group. Antithrombotic agents. ATC code B01AC04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Clopidogrel is a prodrug. One of clopidogrel's metabolites is an inhibitor of platelet aggregation. To form the active metabolite, which suppresses platelet aggregation, clopidogrel must undergo biotransformation by cytochrome CYP 450 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-mediated activation of the glycoprotein IIb/IIIa complex, thus inhibiting platelet aggregation. Since binding is irreversible, platelets exposed to clopidogrel remain altered throughout their lifespan (approximately 7–10 days), and normal platelet function recovers at a rate consistent with platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited, due to the drug's blockade of platelet activation by released ADP.

Since the active metabolite is formed under the influence of cytochrome CYP 450 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 75 mg dosing of the drug. This effect progressively intensifies and stabilizes between days 3 and 7. At steady state, the average level of inhibition 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 – comparing 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 therapy.

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 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 during the first few days after MI onset.

Compared to ASA, clopidogrel significantly reduced the incidence of new ischemic events (a composite endpoint consisting of myocardial infarction, ischemic stroke, and vascular death). In the intention-to-treat analysis, there were 939 events in the clopidogrel group and 1,020 events in the ASA group (relative risk reduction (RRR) 8.7%, [95% CI: 0.2–16.4]; p = 0.045). Thus, over 2 years of treatment, an additional 10 [CI: 0–20] patients per 1,000 avoided a new ischemic event. Analysis of total mortality as a secondary endpoint revealed 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 due to recent MI alone, the effect of clopidogrel was numerically smaller but not statistically 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 is lower in patients aged ≥75 years compared to those ≤75 years.

Since the CAPRIE trial was not sufficiently powered 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 at least a twofold increase in cardiac enzyme activity or troponin I or T compared to the upper limit of normal. Patients were randomized to receive clopidogrel (loading dose 300 mg, then 75 mg/day, n=6,259) or placebo (n=6,303), both in combination with ASA (75–325 mg once daily) and other standard therapy. Treatment duration was up to 1 year. In the CURE trial, 823 (6.6%) patients also received concomitant therapy with a GPIIb/IIIa glycoprotein receptor antagonist. More than 90% of patients received heparin. 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. 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 coronary intervention with or without stenting, and 10% if they underwent coronary artery bypass grafting). Prevention of new cardiovascular events (primary endpoint) occurred with relative risk reductions 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, beyond 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").

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

The number of patients reaching the combined primary endpoint (CVD, MI, stroke, or refractory ischemia) was 1,035 (16.5%) in the clopidogrel group and 1,187 (18.8%) in the placebo group. 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 MI incidence [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 in patient subgroups 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. Specifically, an additional analysis of 2,172 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, results from this subgroup analysis align with those of the overall trial.

The beneficial effect of clopidogrel was demonstrated independently of concomitant 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 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.

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

The CLARITY trial included 3,491 patients who had experienced MI with ST-segment elevation within the previous 12 hours and for whom thrombolytic therapy was planned. Patients received clopidogrel (300 mg loading dose, then 75 mg/day, n=1,752) or placebo (n=1,739), both in combination with ASA (loading dose 150–325 mg, then 75–162 mg/day), a fibrinolytic agent, and, if necessary, heparin. Patient follow-up lasted 30 days. The primary endpoint was occlusion of the infarct-related artery detected on angiogram before 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 discharge. The study population included 19.7% women, 29.2% patients ≥65 years. Overall, 99.7% of patients received fibrinolytics (fibrin-specific 68.7%, non-fibrin-specific 31.1%), 89.5% heparin, 78.7% beta-blockers, 54.7% ACE inhibitors, and 63% statins.

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

The CLARITY PCI subgroup analysis included 1,863 patients with acute MI with ST-segment elevation undergoing percutaneous coronary intervention (PCI). Patients receiving a 300 mg loading dose of clopidogrel (n=933) had significantly lower rates of CVD, MI, or stroke after PCI compared to those receiving placebo (n=930) (3.6% vs. 6.2%, odds ratio [OR]: 0.54; 95% CI: 0.35–0.85; p=0.008). Patients receiving a 300 mg loading dose of clopidogrel had significantly lower rates of CVD, MI, or stroke within 30 days after PCI compared to those receiving placebo (7.5% vs. 12.0%, OR: 0.59; 95% CI: 0.43–0.81; p=0.001). However, this combined endpoint, evaluated in the overall CLARITY population, was not statistically significant as a secondary endpoint. No significant difference in the frequency of major or minor hemorrhages was observed between the two treatment approaches (2.0% with prior clopidogrel vs. 1.9% with placebo, p>0.99). Results of this analysis confirm the efficacy of early use of a 300 mg loading dose of clopidogrel in patients with acute MI with ST-segment elevation and support the strategy of routine pre-treatment with clopidogrel in patients undergoing PCI.

The two-by-two factorial design of the COMMIT trial included 45,852 patients who had 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. Combined primary endpoints were all-cause mortality and the first recurrence of MI, stroke, or death. The study 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 of recurrent MI, stroke, or death by 9% (p = 0.002), corresponding to absolute reductions of 0.5% and 0.9%, respectively. This effect was observed across age and sex groups, regardless of fibrinolytic use, and was evident within the first 24 hours.

Use of a 600 mg loading dose of clopidogrel in patients with acute coronary syndrome undergoing PCI.

CURRENT-OASIS-7 trial ("Optimal dose of Clopidogrel and Aspirin for Reducing Events – Organization to Assess Strategies in Ischemic Syndromes-7")

This randomized factorial trial included 25,086 patients with acute coronary syndrome (ACS) requiring early percutaneous coronary intervention (PCI). Patients were randomly assigned to receive either double-dose (600 mg on day 1, then 150 mg/day from day 2 to day 7, then 75 mg/day) or standard-dose (300 mg on day 1, then 75 mg/day) clopidogrel, and either high-dose (300–325 mg/day) or low-dose (75–100 mg/day) ASA. 24,835 ACS patients underwent coronary angiography, and 17,263 underwent PCI. Among the 17,263 patients who underwent PCI, double-dose clopidogrel reduced the incidence of the primary endpoint compared to standard dose (3.9% vs. 4.5%; adjusted risk ratio [RR]: 0.86; 95% CI: 0.74–0.99, p=0.039) and significantly reduced stent thrombosis (1.6% vs. 2.3%, RR: 0.68; 95% CI: 0.55–0.85; p=0.001). Major bleeding occurred more frequently with double-dose than with standard-dose clopidogrel (1.6% vs. 1.1%; RR: 1.41, 95% CI: 1.09–1.83, p=0.009). In this trial, a 600 mg loading dose of clopidogrel demonstrated consistent efficacy in patients both ≥75 and <75 years of age.

ARMYDA-6 MI ("Antiplatelet Therapy to Reduce Myocardial Damage during Angioplasty and Myocardial Infarction")

This randomized, prospective, international, multicenter trial evaluated pretreatment with 600 mg vs. 300 mg clopidogrel loading dose in the setting of emergency PCI in patients with acute MI with ST-segment elevation.

Patients received clopidogrel 600 mg loading dose (n=103) or 300 mg loading dose (n=98) before PCI, then 75 mg/day from the day after PCI to 1 year. Patients receiving the 600 mg loading dose had significantly smaller infarct size compared to those receiving the 300 mg loading dose. With the 600 mg loading dose, there was less frequent thrombolysis in myocardial infarction (TIMI) grade <3 flow after PCI (5.8% vs. 16.3%, p=0.031), improved LVEF at discharge (52.1 ±9.5% vs. 48.8 ±11.3%, p=0.026), and reduced major adverse cardiovascular events at 30 days (5.8% vs. 15%, p=0.049). No increase in bleeding or access site complications was observed (secondary endpoints at 30 days).

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

This retrospective analysis was conducted to evaluate whether a 600 mg loading dose of clopidogrel provides faster and greater inhibition of platelet activation. Results showed significantly lower unadjusted 30-day mortality (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 the 600 mg loading dose, without higher rates of hemorrhagic events. According to multivariate analysis, a 600 mg loading dose of clopidogrel was an independent predictor of lower 30-day major adverse cardiovascular events (RR: 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 600 mg loading dose group and 9.4% in the 300 mg loading dose group (p=0.0005). The rate of minor bleeding was 11.3% in the 600 mg loading dose group and 13.8% in the 300 mg loading dose group (p=0.03).

Long-term (12 months) use of clopidogrel in patients with acute MI with ST-segment elevation after PCI.

CREDO trial ("Clopidogrel for Reduction of Events During Observation")

This randomized, double-blind, placebo-controlled trial conducted in the United States and Canada evaluated the benefits of long-term (12 months) clopidogrel treatment after PCI.

The trial included 2,116 patients randomized to receive clopidogrel 300 mg loading dose (n=1,053) or placebo (n=1,063) 3–24 hours before PCI. All patients also received 325 mg ASA. Subsequently, 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 75 mg/day clopidogrel, while the control group received placebo. Both groups received ASA throughout the trial (81–325 mg/day). At 1 year, there was a significant reduction in the combined risk of death, MI, or stroke with clopidogrel (26.9% relative reduction, 95% CI: 3.9%–44.4%; p=0.02; 3% absolute reduction) compared to placebo. At 1 year, there was no significant increase in major bleeding (8.8% in the clopidogrel group vs. 6.7% in the placebo group, p=0.07) or minor bleeding (5.3% vs. 5.6%, p=0.84). The trial authors concluded that continuing clopidogrel and ASA for at least 1 year leads to a statistically and clinically significant reduction in serious thrombotic events.

EXCELLENT trial ("Efficacy of Xience/Promus stents vs. Cypher stents for reducing late loss after stenting")

This prospective, open-label, randomized trial conducted in Korea evaluated whether 6-month dual antiplatelet therapy (DAPT) is non-inferior to 12-month DAPT after implantation of second-generation drug-eluting stents.

The trial included 1,443 patients undergoing stent implantation, randomized to 6-month DAPT (ASA 100–200 mg/day and clopidogrel 75 mg/day for 6 months, then ASA alone to 12 months) or 12-month DAPT (ASA 100–200 mg/day and clopidogrel 75 mg/day for 12 months). There was no significant difference in target vessel failure (composite of cardiac death, MI, or target vessel revascularization), the primary endpoint, between the 6-month and 12-month DAPT groups (RR: 1.14; 95% CI: 0.70–1.86; p=0.60). Additionally, the trial showed no significant difference in the safety endpoint (composite of death, MI, stroke, stent thrombosis, or major TIMI bleeding) between the 6-month and 12-month DAPT groups (RR: 1.15; 95% CI: 0.64–2.06; p=0.64). The authors concluded 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 ASA after the acute phase in patients with ACS was evaluated in two investigator-sponsored randomized trials (ISS), the TOPIC and TROPICAL-ACS trials, with clinical outcome data.

The clinical benefit provided by more potent P2Y12 receptor inhibitors, ticagrelor and prasugrel, in pivotal trials was driven by statistically significant reductions in recurrent ischemic events (including acute and subacute stent thrombosis, myocardial infarction, and urgent 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 efficacy with clopidogrel.

TOPIC trial ("Duration of Platelet Inhibition After Acute Coronary Syndrome")

This randomized, open-label trial included patients with ACS requiring percutaneous coronary intervention (PCI). Patients treated with aspirin and a more potent P2Y12 receptor blocker who had no 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).

Overall, data from 645 of 646 patients with STEMI (ST-elevation myocardial infarction) or NSTEMI (non-ST-elevation myocardial infarction), or unstable angina (de-escalation DAPT [n = 322], unchanged DAPT [n = 323]) were analyzed. Follow-up visits at 1 year were completed by 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 between the two groups.

The primary endpoint, a composite of cardiovascular death, stroke, urgent 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 endpoints (p = 0.36), while bleeding events ≥ grade 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 BARC criteria events 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).

TROPICAL-ACS trial ("Testing Response to Platelet Inhibition During Long-term Antiplatelet Treatment of Acute Coronary Syndromes")

This randomized, open-label trial included 2,610 patients with ACS and positive biomarker testing, who had successfully undergone PCI. Patients were randomized to either prasugrel 5 or 10 mg/day (days 0–14) (n = 1,306), or prasugrel 5 or 10 mg/day (days 0–7), followed by de-escalation to clopidogrel 75 mg/day (days 8–14) (n = 1,304), both in combination with ASA (< 100 mg/day). Platelet function testing (PFT) was performed on day 14. Patients continuing prasugrel remained on 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 were followed for one year.

The primary endpoint (composite of cardiovascular death, MI, stroke, and bleeding ≥ grade 2 by BARC criteria at 12 months) was reached, demonstrating at least non-inferior efficacy of clopidogrel. The endpoint 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 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—rate of bleeding events ≥ grade 2 by BARC criteria (5% in the de-escalation group vs. 6% in the control group (p = 0.23)). The overall rate of all bleeding events (grades 1–5 by BARC criteria) was 9% (114 events) in the managed 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 and 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—based on clinical safety and efficacy outcomes.

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

This randomized, double-blind, multicenter, placebo-controlled clinical trial included 5,170 patients from China with acute TIA (ABCD2 score ≥ 4) or acute minor stroke (NIHSS score ≤ 3). Patients in both groups received open-label ASA on day 1 (75–300 mg at the physician's discretion). Patients randomly assigned to the clopidogrel-ASA group received clopidogrel 300 mg loading dose on day 1, then 75 mg/day from day 2 to day 90, plus ASA 75 mg/day from day 2 to day 21. Patients randomly assigned to the ASA group received placebo clopidogrel from day 1 to day 90 and ASA 75 mg/day from day 2 to day 90.

The primary efficacy outcome 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 vs. 303 patients (11.7%) in the ASA group (risk ratio [RR] 0.68; 95% 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 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 rate 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 in New TIA and Minor Ischemic Stroke)

This randomized, double-blind, multicenter, placebo-controlled clinical trial included patients worldwide (4,881 patients) with acute TIA (ABCD2 score ≥ 4) or acute minor stroke (NIHSS score ≤ 3). All patients in both groups received open-label ASA from day 1 to day 90 (50–325 mg, per physician's discretion). Patients randomly assigned to the clopidogrel group received clopidogrel 600 mg loading dose on day 1, then 75 mg/day from day 2 to day 90. Patients randomly assigned to the placebo group received placebo clopidogrel from day 1 to day 90.

The primary efficacy outcome was a composite of major ischemic events (stroke, MI, or death from ischemic vascular event) at 90 days. These events occurred in 121 patients (5.0%) in the clopidogrel plus ASA group vs. 160 patients (6.5%) in the ASA monotherapy group (RR 0.75; 95% CI: 0.59–0.95; p < 0.02). The secondary efficacy outcome 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 outcome was major bleeding. It occurred in 23 of 2,432 patients (0.9%) receiving clopidogrel plus ASA and 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 and 13 patients (0.5%) receiving ASA monotherapy (RR 3.12; 95% CI: 1.67–5.83; p = 0.001).

Analysis of event dynamics in CHANCE and POINT trials

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

Dynamics of serious ischemic events and major hemorrhages in treatment groups in the CHANCE and POINT trials

Number of cases
Results from the CHANCE and POINT studies	Randomized treatment group	Total	Week 1	Week 2	Week 3
Major ischemic events	ASA (n = 5035)	458	330	36	21
	Clopidogrel + ASA (n = 5016)	328	217	30	14
	Difference	130	113	6	7
Major bleeding	ASA (n = 5035)	18	4	2	1
	Clopidogrel + ASA (n = 5016)	30	10	4	2
	Difference	-12	-6	-2	-1

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). Patients who could not receive VKA therapy due to contraindications or unwillingness to undergo such 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 multicenter, 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 75–100 mg daily. Patients were treated for up to 5 years.

Patients randomized in the ACTIVE program had documented AF, either persistent 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, diabetes mellitus requiring medication, documented history of myocardial infarction (MI), documented ischemic heart disease, prior treatment for systemic arterial hypertension, prior stroke, transient ischemic attack (TIA), systemic embolism without CNS 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), need for clopidogrel or oral anticoagulants (OACs), or intolerance to either agent.

73% of patients included in the ACTIVE-A study could not receive VKA therapy based on physician judgment due to 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 refusal to take VKA therapy.

41.8% of patients were women. The mean age was 71 years, and 41.6% were aged ≥75 years. 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 involvement, or death) was 832 (22.1%) in the clopidogrel + ASA group 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 to neonates and infants, and at 0.15 mg/kg to 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 clopidogrel 75 mg daily.

In a randomized, double-blind, parallel-group study (CLARINET), 906 children (neonates and infants) with cyanotic congenital heart disease undergoing palliative surgery with systemic-to-pulmonary arterial shunt creation were randomized to receive clopidogrel 0.2 mg/kg (n = 467) or placebo (n = 439), with concomitant 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—death, shunt thrombosis, or cardiac surgery due to thrombotic event by day 120—occurring in 89 [19.1%] in the clopidogrel group and 90 [20.5%] in the placebo group (see section "Posology and method of administration"). The most common adverse reaction in both the clopidogrel and placebo groups was bleeding, but no statistically significant difference in bleeding frequency was observed between groups. During the subsequent long-term safety follow-up period, 26 patients with a patent shunt at 1 year of age received 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 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 repeated oral doses of 75 mg daily, clopidogrel is rapidly absorbed. The mean 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%, as indicated by 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 unsaturated 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 circulating metabolites in plasma), and the other involves cytochrome P450 enzymes. Initially, clopidogrel is converted to an intermediate metabolite, 2-oxo-clopidogrel. Further metabolism of 2-oxo-clopidogrel leads to a thiol derivative—the active metabolite. This active metabolite is formed predominantly via the CYP2C19 enzyme, 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 as high after a single 300 mg loading dose of clopidogrel compared to after 4 days of maintenance therapy at 75 mg. 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 label was excreted in urine and about 46% in feces. After a single oral dose of 75 mg, 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 multiple 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, 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. CYP2C19*2 and CYP2C19*3 account for the majority of loss-of-function alleles in Caucasian (85%) and Mongoloid (99%) patients with reduced metabolism. Other alleles associated with absent or reduced metabolism are much 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 metabolizer groups: ultrarapid, extensive, intermediate, and poor), pharmacokinetics and antiplatelet effects were evaluated after administration of a 300 mg dose followed by 75 mg daily, and 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 active metabolite plasma concentrations or mean platelet aggregation inhibition (PAI) were observed between individuals with ultrarapid, extensive, or intermediate metabolism. In poor metabolizers, active metabolite plasma concentrations were reduced by 63–71% compared to extensive metabolizers. After the 300 mg/75 mg dosing 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 poor metabolizers received the 600 mg/150 mg regimen, active metabolite plasma concentrations were higher than with the 300 mg/75 mg regimen. Additionally, 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 in other CYP2C19 metabolizer groups receiving 300 mg/75 mg. Based on clinical effect studies, an optimal dosing regimen for this patient group has not been established.

Similarly, in a meta-analysis of 6 steady-state studies involving 335 patients receiving clopidogrel, 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 published cohort studies are available.

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

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

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

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

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, patients with severe renal impairment (creatinine clearance 5–15 mL/min) showed less pronounced inhibition of ADP-induced platelet aggregation (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, patients with severe hepatic impairment showed inhibition of ADP-induced platelet aggregation similar to that in healthy volunteers. Mean prolongation of bleeding time was also similar in both groups.

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

Preclinical data.

The most commonly observed adverse effects in preclinical animal studies were liver 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 daily and were due to the drug's effect on enzymes involved in hepatic metabolism. No effect on enzymes involved in hepatic metabolism has been observed in humans receiving therapeutic doses of clopidogrel.

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

Administration of clopidogrel to mice for 78 weeks and to rats for 104 weeks 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) provided no evidence of carcinogenic potential.

A series of genotoxicity studies of clopidogrel in vitro and in vivo showed no genotoxic effects.

Clopidogrel did not affect reproductive function in rats and had 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 (minor toxic effect) and indirect effects (due to impaired milk taste) on offspring cannot be excluded.

Clinical characteristics.

Indications.

Secondary prevention of atherothrombotic events

Clopidogrel is indicated:

• in adult patients who have suffered myocardial infarction (treatment initiation – within a few days, but no later than 35 days after onset), ischaemic stroke (treatment initiation – within 7 days, but no later than 6 months after onset), or who have been diagnosed with peripheral arterial disease;
• in adult patients 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 in patients undergoing percutaneous coronary intervention (including patients receiving stents), or in patients receiving standard medical therapy who are candidates for thrombolytic/fibrinolytic therapy.

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

Clopidogrel in combination with ASA is indicated:

• in adult patients with moderate- to high-risk TIA (ABCD2* ≥ 4) or minor ischaemic stroke (NIHSS** ≤ 3) within 24 hours of the TIA or IS event.

[*] Age, Blood pressure, Clinical features, Duration of symptoms, Diabetes mellitus.

[**] 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 of the excipients.

Severe hepatic impairment.

Acute pathological bleeding (e.g., peptic ulcer or intracranial haemorrhage).

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 haemorrhagic complications; therefore, concomitant use of such medicinal products with clopidogrel requires caution (see section "Special warnings and precautions for use").

Oral anticoagulants. Concomitant use of clopidogrel with oral anticoagulants is not recommended, as this combination may increase the risk and severity of bleeding (see section "Special warnings and precautions for use"). Although 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 on long-term warfarin therapy, concomitant use of clopidogrel and warfarin increases the risk of bleeding due to their independent effects on haemostasis.

Glycoprotein IIb/IIIa inhibitors. Clopidogrel should be used with caution in patients receiving glycoprotein IIb/IIIa inhibitors (see section "Special warnings and 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 acetylsalicylic acid on collagen-induced platelet aggregation. However, concomitant administration of 500 mg ASA twice daily for one day did not significantly increase bleeding time prolonged by clopidogrel. Since a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, increasing the risk of bleeding, concomitant use of these agents requires caution (see section "Special warnings and precautions for use"). Nevertheless, clopidogrel and ASA have been used concomitantly for up to 1 year (see section "Pharmacological properties").

Heparin. Clinical data from a study 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 affect the inhibitory effect of clopidogrel on platelet aggregation. Since a pharmacodynamic interaction between clopidogrel and heparin is possible, increasing the risk of bleeding, concomitant use of these agents requires caution (see section "Special warnings and precautions for use").

Thrombolytic agents. The safety of concomitant use of clopidogrel, 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 "Undesirable effects").

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 bleeding episodes. 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 warnings and precautions for use").

Other antiplatelet agents. Concomitant use of antiplatelet medicinal products increases the risk of bleeding due to an additive effect. If a patient is receiving concomitant therapy with other antiplatelet agents, any signs or symptoms of bleeding require immediate evaluation (see section "Special warnings and precautions for use").

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

Concomitant use of other medicinal products.

CYP2C19 inducers

Since clopidogrel is partially converted to its active metabolite by CYP2C19, the use of medicinal products that increase the activity of this enzyme is likely to result in increased plasma concentrations 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, in particular, increase the risk of bleeding. As a precaution, concomitant use of strong CYP2C19 inducers should be avoided (see sections "Special warnings and precautions for use").

CYP2C19 inhibitors

Since clopidogrel is partially converted to its active metabolite by CYP2C19, the use of medicinal products that reduce the activity of this enzyme is likely to result in 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 warnings and 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 of each other, reduced the plasma concentration of the active metabolite by 45% (loading dose) and 40% (maintenance dose). This reduction was associated with a 39% decrease in platelet aggregation inhibition (loading dose) and 21% (maintenance dose). A similar interaction with clopidogrel is expected with esomeprazole.

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

A less pronounced reduction in metabolite concentration 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 15% and 11% reduction in mean platelet aggregation inhibition, 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.

Booster 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 ritonavir-boosted ART who experienced recurrent occlusive events after revascularization or thrombotic events despite high-dose clopidogrel therapy. 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 used concomitantly with atenolol, nifedipine, or both. In addition, the pharmacodynamic activity of clopidogrel remained almost unchanged when used concomitantly with phenobarbital and estrogen.

The pharmacokinetic properties of digoxin or theophylline were not altered when used 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 the CYP2C9 enzyme, can be safely used concomitantly with clopidogrel.

MEDICINAL PRODUCTS THAT ARE SUBSTRATES OF THE CYP2C8 ENZYME. It has been shown that clopidogrel increases repaglinide exposure in healthy volunteers. In vitro studies have 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 with medicinal products primarily eliminated via CYP2C8-mediated metabolism (e.g., repaglinide, paclitaxel) requires caution (see section "Special warnings and 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 used concomitant medications, 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 absorption of clopidogrel, likely due to delayed gastric emptying. The clinical significance of this is unknown. Parenteral antiplatelet therapy should be considered in patients with acute coronary syndrome who require concomitant administration of morphine or other opioid agonists.

Rosuvastatin. Following a 300 mg dose of clopidogrel, rosuvastatin exposure was found to increase by 2-fold (AUC) and 1.3-fold (Cmax). After repeated administration of clopidogrel 75 mg, rosuvastatin exposure increased by 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 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, surgery, or other pathological conditions, and also when patients are receiving acetylsalicylic acid (ASA), heparin, glycoprotein IIb/IIIa inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors, serotonin reuptake inhibitors (SSRIs), potent CYP2C19 inducers, or other medicinal products associated with an increased risk of hemorrhagic events, such as pentoxifylline (see section "Interaction with other medicinal products and other forms of interaction"). Triple antiplatelet therapy (clopidogrel + ASA + dipyridamole) is not recommended due to an increased risk of bleeding for secondary prevention of stroke 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, especially during the first weeks of treatment and/or after cardiac invasive procedures and surgery. Concomitant use of clopidogrel with oral anticoagulants is not recommended, as this may increase the risk and 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 bleeding).

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

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

A loading dose of 600 mg clopidogrel should be considered only after individual assessment by the physician of the risk of bleeding in patients, due to limited clinical data in patients aged ≥75 years with ST-elevation myocardial infarction and an increased risk of bleeding.

Thrombotic thrombocytopenic purpura (TTP).

Very rare cases of TTP have been observed after 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 therefore requires immediate treatment, including plasma exchange.

Acquired hemophilia.

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

Recent ischemic stroke.

• Initiation of treatment:
  • Dual antiplatelet therapy (clopidogrel and ASA) should be initiated within 24 hours of symptom onset 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 undergoing 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 receiving standard doses of clopidogrel. Tests are currently available to identify the CYP2C19 genotype of a patient.

Since clopidogrel is partially metabolized to its active metabolite by CYP2C19, concomitant use of medicinal products that reduce the activity of this enzyme will likely result in reduced plasma concentrations of the active metabolite of clopidogrel. However, the clinical significance of this interaction has not been 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" for a list of CYP2C19 inhibitors; also see section "Pharmacokinetics").

The use of medicinal products that induce CYP2C19 activity is expected to increase the 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 the 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 a history of hypersensitivity to other thienopyridines (e.g., ticlopidine, prasugrel), as cross-reactivity 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 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 such 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 "Posology and method of administration").

Hepatic impairment.

Experience with clopidogrel use in patients with moderate liver disease and potential for hemorrhagic diathesis is limited; therefore, clopidogrel should be used with caution in such patients (see section "Posology and method of administration").

Excipients.

Clopidogrel contains lactose; therefore, patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Clopidogrel contains 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.

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

Animal studies have not shown direct or indirect harmful effects of clopidogrel on pregnancy, embryonal/fetal development, parturition, or postnatal development (see section "Preclinical data").

Breastfeeding. It is not known whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion of clopidogrel into breast milk; therefore, breastfeeding should be discontinued during treatment with this medicinal product.

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Dosage

Adults, including elderly patients

Clopidogrel should be administered at a dose of 75 mg once daily, independently of food intake.

Patients with acute coronary syndrome:

• 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 considered in patients under 75 years of age when percutaneous coronary intervention (PCI) is required (see section "Special Instructions"). Treatment with clopidogrel should be continued at a dose of 75 mg once daily (in combination with acetylsalicylic acid at a dose of 75–325 mg daily). Since higher doses of ASA increase the risk of bleeding, the dose of acetylsalicylic acid should not exceed 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").
• In patients with acute myocardial infarction with ST-segment elevation:
  • For patients undergoing medical treatment and indicated for thrombolytic/fibrinolytic therapy, clopidogrel should be administered at 75 mg once daily, initiated with a single loading dose of 300 mg 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. Combined therapy should be initiated as early as possible after symptom onset and continued for at least 4 weeks. The benefit of combining clopidogrel with ASA beyond 4 weeks in this condition has not been studied (see section "Pharmacological Properties").
  • Patients undergoing percutaneous coronary intervention (PCI):
    • Patients who have undergone primary PCI, as well as those undergoing PCI more than 24 hours after fibrinolytic therapy, should receive a 600 mg loading dose of clopidogrel. In patients aged ≥ 75 years, a 600 mg loading dose of clopidogrel should be administered with caution (see section "Special Instructions").
    • Patients undergoing PCI within 24 hours after fibrinolytic therapy should receive a 300 mg loading dose of clopidogrel.

Clopidogrel treatment should be continued at 75 mg once daily in combination with acetylsalicylic acid at a dose of 75–100 mg daily. Combined therapy should be initiated as early as possible after symptom onset and continued for up to 12 months (see section "Pharmacodynamics").

Adult patients with moderate to high-risk TIA or minor ischemic stroke (IS):

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 continuation of treatment 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.

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 missed dose:

• If less than 12 hours have passed since the scheduled dose, 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.

Special patient populations

Elderly patients

• Acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction): A 600 mg loading dose of clopidogrel may be considered in patients under 75 years of age when percutaneous coronary intervention (PCI) is required (see section "Special Instructions").
• Acute myocardial infarction with ST-segment elevation: In patients aged ≥ 75 years undergoing medical treatment and indicated for thrombolytic/fibrinolytic therapy, clopidogrel treatment should be initiated without a loading dose.
• In patients aged ≥ 75 years who have undergone primary PCI, as well as those undergoing PCI more than 24 hours after fibrinolytic therapy, a 600 mg loading dose of clopidogrel should be administered with caution (see section "Special Instructions").

Renal impairment

Therapeutic experience with clopidogrel in patients with renal impairment is limited (see section "Special Instructions").

Hepatic impairment

Therapeutic experience with clopidogrel in patients with moderate liver disease and potential for hemorrhagic diathesis is limited (see section "Special Instructions").

Method of administration

For oral use. The drug may be taken with or without food.

Children

Clopidogrel should not be used in children (under 18 years of age) due to lack of efficacy data in this patient population (see section "Pharmacodynamics").

Overdose

Prolonged bleeding time with subsequent complications may occur in case of clopidogrel overdose. Symptomatic treatment is recommended if bleeding occurs.

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 concentrate.

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 12,000 patients treated for 1 year or longer). The clinically significant adverse effects observed in the CAPRIE study showed that the overall effect 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 data from the CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE-A clinical trials, spontaneous reports of adverse reactions during clinical use of the drug have been considered.

Bleeding was the most commonly reported adverse reaction observed both in clinical trials and in the post-marketing period, with the highest incidence occurring during the first month of treatment.

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

In the CURE study, no increase in the frequency of major bleeding was observed with the combination of clopidogrel + ASA 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 until less than 5 days before CABG surgery, the frequency of this event was 9.6% in the clopidogrel + ASA group and 6.3% in the placebo + ASA group.

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

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

In the ACTIVE-A study, the frequency 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, 3.5% in the placebo + ASA group), mainly gastrointestinal bleeding (3.5% vs. 1.8%). An increased incidence of intracranial bleeding was observed in the clopidogrel + ASA group compared to the placebo + ASA group (1.4% vs. 0.8%, respectively). There was no statistically significant difference between the groups in the frequency of fatal bleeding (1.1% in the clopidogrel + ASA group vs. 0.7% in the placebo + ASA group) 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 excessive and severe bleeding compared to monotherapy with clopidogrel or combination therapy with ASA and dipyridamole (adjusted overall RR 2.54, 95% CI 2.05–3.16, p<0.0001).

List of adverse reactions

Adverse effects observed during clinical trials or from spontaneous post-marketing reports are listed below.

Adverse reactions are categorized by system organ class, and frequency is defined as follows: common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data). Within each system organ class, adverse effects are listed in order of decreasing severity.

Blood and lymphatic system disorders: uncommon – thrombocytopenia, leukopenia, eosinophilia; rare – neutropenia, including severe neutropenia; very rare, frequency not known* – TTP (see section "Special precautions for use"), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired hemophilia A, granulocytopenia, anemia.

Cardiac disorders: very rare, frequency not known* – Kounis syndrome (allergic angina/vasospastic angina or allergic myocardial infarction) as a result of hypersensitivity reaction to clopidogrel*.

Immune system disorders: very rare, frequency not known* – serum sickness, anaphylactoid reactions, cross-sensitivity among thienopyridines (e.g., ticlopidine, prasugrel) (see section "Special precautions for use")*, autoimmune insulin syndrome potentially leading to severe hypoglycemia, particularly in patients with HLA DRA4 subtype (more commonly found in Japanese population)*.

Psychiatric disorders: very rare, frequency not known* – hallucinations, confusion.

Nervous system disorders: uncommon – intracranial hemorrhage (in some cases fatal), headache, paresthesia, dizziness; very rare, frequency not known* – altered taste perception, ageusia.

Eye disorders: uncommon – ocular hemorrhage (conjunctival, ocular, retinal).

Ear and labyrinth disorders: rare – vertigo.

Vascular disorders: common – hematoma; very rare, frequency not known* – severe hemorrhage, surgical wound bleeding, vasculitis, arterial hypotension.

Respiratory, thoracic and mediastinal disorders: common – epistaxis; very rare, frequency not known* – respiratory tract hemorrhage (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonia, eosinophilic pneumonia.

Gastrointestinal disorders: common – gastrointestinal hemorrhage, diarrhea, abdominal pain, dyspepsia; uncommon – gastric and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence; rare – retroperitoneal hemorrhage; very rare, frequency not known* – fatal gastrointestinal and retroperitoneal hemorrhage, pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis.

Hepatobiliary disorders: very rare, frequency not known* – acute liver failure, hepatitis, abnormal liver function test results.

Skin and subcutaneous tissue disorders: common – subcutaneous hemorrhage; uncommon – rash, pruritus, intradermal hemorrhages (purpura); very rare, frequency not known* – 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: rare – gynecomastia.

Musculoskeletal and connective tissue disorders: very rare, frequency not known* – musculoskeletal hemorrhage (hemarthrosis), arthritis, arthralgia, myalgia.

Renal and urinary disorders: uncommon – hematuria; very rare, frequency not known* – glomerulonephritis, increased blood creatinine levels.

General disorders and administration site conditions: common – injection site bleeding; very rare, frequency not known* – pyrexia.

Investigations: uncommon – prolonged bleeding time, decreased neutrophil and platelet counts.

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

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in a dry, light-protected place, out of reach of children, at a temperature not exceeding 30 °C.

Packaging. 10 tablets per blister; 1, 3, or 10 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Arthura Pharmaceuticals Pvt. Ltd.

Manufacturer's address and location of operations.

1505 Portia Road, Sri City SEZ, Sedyavedu Mandal, Chittoor District – 517 588, Andhra Pradesh, India.

Marketing Authorization Holder. Ananta Medikare Ltd.

Address of the Marketing Authorization Holder.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.