INSTRUCTIONS

for medical use of the medicinal product

 

CLOPIDOGREL

 

 

Composition:

active substance: clopidogrel;

1 film-coated tablet contains clopidogrel bisulphate equivalent to clopidogrel 75 mg;

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

 

Pharmaceutical form. Film-coated tablets.

Basic physical and chemical properties: orange, round, biconvex film-coated tablets.

 

Pharmacotherapeutic group. Antithrombotic agents, ATC code: B01A C04.

 

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Clopidogrel is a prodrug. One of its metabolites acts as an inhibitor of platelet aggregation. In order to generate the active metabolite that inhibits platelet aggregation, clopidogrel must undergo biotransformation by cytochrome P450 (CYP450) enzymes. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its P2Y₁₂ receptors on the platelet surface and the subsequent ADP-mediated activation of the glycoprotein IIb/IIIa complex, thereby inhibiting platelet aggregation. Since the binding is irreversible, platelets that have interacted with clopidogrel remain affected for the remainder of their lifespan (approximately 7–10 days), and the recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet aggregation induced by other agonists besides ADP is also inhibited, as the drug prevents platelet activation by released ADP.

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

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

Clinical efficacy and safety.

The safety and efficacy of clopidogrel were evaluated in seven double-blind studies involving more than 100,000 patients: the CAPRIE study, which compared clopidogrel with acetylsalicylic acid (ASA), and the CURE, CLARITY, COMMIT, CHANCE, POINT, and ACTIVE-A studies, 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 study included 19,185 patients with atherosclerotic disease manifested as a recent myocardial infarction (<35 days), recent ischemic stroke (from 7 days to 6 months), or established peripheral arterial disease (PAD). Patients were randomized to receive clopidogrel 75 mg once daily or ASA 325 mg once daily and were followed for 1 to 3 years. In the myocardial infarction subgroup, most patients received ASA during the first few days after the event.

 

Compared with ASA, clopidogrel significantly reduced the incidence of new ischemic events (the composite endpoint consisting of myocardial infarction, ischemic stroke, and vascular death). In the analysis based on the treatment assigned at randomization, 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). This means that for every 1000 patients treated for two years, an additional 10 [95% CI: 0–20] patients avoided a new ischemic event. Analysis of overall mortality as a secondary endpoint revealed no significant difference between clopidogrel (5.8%) and ASA (6%) therapy.

Subgroup analysis according to baseline condition (myocardial infarction, ischemic stroke, and PAD) showed that the greatest benefit (statistically significant at p = 0.003) was observed in patients with PAD (particularly in those with a prior myocardial infarction) (RRR = 23.7% [95% CI: 8.9–36.2]), while a smaller, non-significant effect compared with ASA was observed in patients with stroke (RRR = 7.3% [95% CI: –5.7–18.7; p = 0.258]). Among patients enrolled based solely on recent myocardial infarction, the numerical effect of clopidogrel was smaller and not statistically different from that of ASA (RRR = –4% [95% CI: –22.5–11.7; p = 0.639]). Moreover, subgroup analysis by age indicated that the beneficial effect of clopidogrel in patients aged ≥75 years was lower than in those ≤75 years.

Since the CAPRIE study was not powered to assess efficacy within individual subgroups, it remains unclear whether the observed differences in relative risk reduction among patients with different conditions are genuine or occurred by chance.

Acute coronary syndrome

The CURE study included 12,562 patients with non–ST-segment elevation acute coronary syndrome (unstable angina or non–Q-wave myocardial infarction) who had experienced an episode of chest pain or ischemic symptoms within the previous 24 hours. Patients had either electrocardiographic changes indicative of new ischemia or elevated cardiac enzyme or troponin I or T levels at least twice the upper limit of normal. Patients were randomized to receive either clopidogrel (loading dose 300 mg followed by 75 mg once daily, n = 6259) or placebo (n = 6303), both in combination with ASA (75–325 mg once daily) and other standard therapy. Treatment duration was up to one year. In the CURE study, 823 (6.6%) patients also received concomitant glycoprotein IIb/IIIa receptor antagonist therapy. More than 90% of patients received heparins. Such concomitant therapy did not significantly affect the relative incidence of bleeding events between the clopidogrel and placebo groups.

The number of patients who reached the primary endpoint [cardiovascular death (CV death), myocardial infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel group and 719 (11.4%) in the placebo group. The relative risk reduction (RRR) was 20% (95% CI: 10%–28%; p = 0.00009) for clopidogrel (17% in patients receiving conservative treatment, 29% in those undergoing percutaneous transluminal coronary angioplasty with or without stenting, and 10% in those undergoing coronary artery bypass grafting).

Prevention of new cardiovascular events (primary endpoint) was associated with RRRs of 22% (CI: 8.6–33.4), 32% (CI: 12.8–46.4), 4% (CI: –26.9–26.7), 6% (CI: –33.5–34.3), and 14% (CI: –31.6–44.2) during the 0–1, 1–3, 3–6, 6–9, and 9–12 month periods of the study, respectively. Thus, after more than three months of treatment, the beneficial effect observed in the clopidogrel + ASA group did not further increase, while the risk of bleeding persisted (see section “Precautions for use”).

During the CURE study, clopidogrel use reduced the need for thrombolytic therapy (RRR = 43.3%; CI: 24.3–57.5%) and glycoprotein IIb/IIIa receptor inhibitors (RRR = 18.2%; CI: 6.5–28.3%).

The number of patients who reached the combined primary endpoint (CV death, MI, stroke, or refractory ischemia) was 1035 (16.5%) in the clopidogrel group and 1187 (18.8%) in the placebo group, corresponding to an RRR of 14% (95% CI: 6%–21%; p = 0.0005). This effect was mainly due to a statistically significant reduction in the incidence of MI [287 (4.6%) in the clopidogrel group vs. 363 (5.8%) in the placebo group]. No difference was observed in the rate of rehospitalisation for unstable angina.

Results obtained in patient subgroups with various characteristics (e.g., unstable angina or non–Q-wave MI, low to high risk, diabetes, need for revascularization, age, or sex) were consistent with those of the primary analysis. In particular, an additional analysis of 2172 patients (17% of the total CURE population) who underwent stent implantation (Stent-CURE) demonstrated a significant RRR (26.2%) in favour of clopidogrel in preventing the primary endpoint (CV death, MI, stroke), and a significant RRR (23.9%) for the second combined primary endpoint (CV death, MI, stroke, or refractory ischemia). Moreover, the safety profile of clopidogrel in this subgroup did not raise any particular concerns. Therefore, the subgroup analysis results were consistent with those of the overall study.

The beneficial effect of clopidogrel was demonstrated regardless of concomitant acute and long-term treatment with other cardiovascular agents (such as heparin/low molecular weight heparin, glycoprotein IIb/IIIa receptor inhibitors, lipid-lowering drugs, beta-blockers, and ACE inhibitors). The efficacy of clopidogrel was not dependent on the ASA dose (75–325 mg once daily).

ST-segment elevation myocardial infarction

The safety and efficacy of clopidogrel in patients with acute ST-segment elevation myocardial infarction were evaluated in two randomized, placebo-controlled, double-blind CLARITY and COMMIT studies as well as in a prospective subgroup analysis of CLARITY (CLARITY-PCI).

In the CLARITY study, 3,491 patients who had experienced an ST-segment elevation myocardial infarction within the previous 12 hours and were scheduled to receive thrombolytic therapy were included. Patients received either clopidogrel (loading dose of 300 mg followed by 75 mg once daily, n = 1752) or placebo (n = 1739), both in combination with ASA (loading dose 150–325 mg, then 75–162 mg once daily), a fibrinolytic agent, and, if necessary, heparin. Patients were followed for 30 days.

The primary endpoint was the occurrence of infarct-related arterial occlusion detected on angiography before hospital discharge, death, or recurrent MI before coronary angiography. For patients who did not undergo angiography, the primary endpoint was death or recurrent MI by day 8 or hospital discharge. Among the study participants, 19.7% were women and 29.2% were aged ≥ 65 years. Overall, 99.7% of patients received fibrinolytics (fibrin-specific – 68.7%, non-fibrin-specific – 31.1%), 89.5% received heparin, 78.7% 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, corresponding to an absolute reduction of 6.7% and a 36% relative improvement in favour of clopidogrel (95% CI: 24–47%; p < 0.001), primarily due to a reduction in infarct-related arterial occlusion. This benefit was consistent across all prespecified subgroups classified by age, sex, infarct location, and type of fibrinolytic or heparin therapy received.

The CLARITY-PCI subgroup analysis included 1,863 patients with acute ST-segment elevation myocardial infarction who underwent percutaneous coronary intervention (PCI). Patients receiving a 300 mg loading dose of clopidogrel (n = 933) showed a significant reduction in the rate of cardiovascular death, MI, or stroke after PCI compared with 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). Similarly, during the 30 days following PCI, these patients had a significantly lower rate of cardiovascular death, MI, or stroke (7.5% vs 12.0%, OR: 0.59; 95% CI: 0.43–0.81; p = 0.001). However, this composite endpoint, assessed in the overall CLARITY population, was not statistically significant as a secondary endpoint. There was no significant difference in the incidence of major or minor bleeding between treatment groups (2.0% with clopidogrel pretreatment vs 1.9% with placebo; p > 0.99). These results confirm the efficacy of early clopidogrel loading in patients with acute ST-segment elevation myocardial infarction and support the strategy of routine clopidogrel pretreatment in patients undergoing PCI.

The COMMIT study had a factorial design and included 45,852 patients who presented within 24 hours of symptom onset suggestive of MI, confirmed by electrocardiographic abnormalities (e.g., ST-segment elevation or depression or left bundle branch block). Patients received clopidogrel (75 mg once daily, n = 22,961) or placebo (n = 22,891) in combination with ASA (162 mg once daily) for 28 days or until hospital discharge. The co-primary endpoints were death from any cause and the first occurrence of reinfarction, stroke, or death. Among participants, 27.8% were women, 58.4% were aged ≥ 60 years (26% ≥ 70 years), and 54.5% received fibrinolytic therapy.

Clopidogrel significantly reduced the relative risk of death from any cause by 7% (p = 0.029) and the relative risk of the composite endpoint (reinfarction, stroke, or death) by 9% (p = 0.002), corresponding to absolute reductions of 0.5% and 0.9%, respectively. This benefit was observed across age and sex subgroups, 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 study (“Clopidogrel and aspirin optimal dose usage to reduce recurrent events – Organization to assess strategies in ischemic syndromes-7”)

This randomized factorial study included 25,086 patients with acute coronary syndrome (ACS) who required early percutaneous coronary intervention (PCI). Patients were randomly assigned to receive either a double dose of clopidogrel (600 mg on Day 1, followed by 150 mg daily from Days 2 to 7, then 75 mg daily thereafter) or the standard dose (300 mg on Day 1, followed by 75 mg daily), as well as either a high dose (300–325 mg daily) or a low dose (75–100 mg daily) of acetylsalicylic acid (ASA).

A total of 24,835 ACS patients underwent coronary angiography, and 17,263 patients underwent PCI. Among the 17,263 patients who underwent PCI, compared to the standard dose, the double-dose clopidogrel regimen reduced the incidence of the primary endpoint (3.9% vs 4.5%, adjusted hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.74–0.99; p=0.039) and significantly reduced stent thrombosis (1.6% vs 2.3%, HR: 0.68; 95% CI: 0.55–0.85; p=0.001). Major bleeding occurred more frequently in the double-dose group than in the standard-dose group (1.6% vs 1.1%, HR: 1.41; 95% CI: 1.09–1.83; p=0.009). In this study, the 600 mg loading dose of clopidogrel demonstrated consistent efficacy in patients aged both ≥75 years and <75 years.

ARMYDA-6 MI study (“Antiplatelet therapy for reduction of myocardial damage during angioplasty and myocardial infarction”)

This randomized, prospective, international, multicenter study evaluated pretreatment with a 600 mg versus 300 mg loading dose of clopidogrel in the setting of primary PCI for patients with acute ST-segment elevation myocardial infarction.

Patients received a 600 mg loading dose of clopidogrel (n=103) or a 300 mg loading dose (n=98) before PCI, followed by 75 mg daily starting the day after PCI and continuing for one year.

Patients receiving the 600 mg loading dose had a significantly smaller infarct size compared with those receiving the 300 mg dose. The 600 mg loading dose of clopidogrel was associated with a lower incidence of post-PCI TIMI flow grade <3 (5.8% vs 16.3%, p=0.031), improved left ventricular ejection fraction (LVEF) at discharge (52.1 ±9.5% vs 48.8 ±11.3%, p=0.026), and a reduction in major adverse cardiovascular events at Day 30 (5.8% vs 15%, p=0.049). There was no increase in bleeding or access-site complications (secondary endpoints at Day 30).

HORIZONS-AMI Study (“Harmonizing outcomes with revascularization and stenting 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. The results demonstrated significantly lower unadjusted 30-day mortality rates (1.9% vs 3.1%, p=0.03), reinfarction rates (1.3% vs 2.3%, p=0.02), and definite or probable stent thrombosis (1.7% vs 2.8%, p=0.04) in patients receiving 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 a lower rate of major adverse cardiovascular events at 30 days (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.53–0.98; p=0.04). The incidence of major bleeding (not related to coronary artery bypass grafting) was 6.1% in the 600 mg group versus 9.4% in the 300 mg group (p=0.0005). Minor bleeding occurred in 11.3% of patients in the 600 mg group and in 13.8% in the 300 mg group (p=0.03).

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

CREDO Study (“Clopidogrel for the 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-month) treatment with clopidogrel after PCI.

A total of 2,116 patients were randomized to receive either a 300 mg loading dose of clopidogrel (n=1,053) or placebo (n=1,063) 3–24 hours before PCI. All patients also received 325 mg of ASA. Subsequently, all patients in both groups received 75 mg of clopidogrel daily through Day 28. From Day 29 to 12 months, patients in the clopidogrel group continued 75 mg daily, while those in the control group received placebo. Both groups continued ASA throughout the study (81–325 mg/day). After 1 year, there was a significant reduction in the composite risk of death, myocardial infarction (MI), or stroke in the clopidogrel group (26.9% relative reduction; 95% CI: 3.9–44.4%; p=0.02; 3% absolute reduction) compared with placebo. After 1 year, there was no significant increase in the incidence of 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 study authors concluded that continuation of clopidogrel and ASA for at least one year leads to a statistically and clinically significant reduction in serious thrombotic events.

EXCELLENT Study (“Efficacy of Xience/Promus versus Cypher Stent to reduce late loss after stenting”)

This prospective, open-label, randomized study was conducted in Korea to assess whether 6-month dual antiplatelet therapy (DAPT) was non-inferior to 12-month DAPT following implantation of second-generation drug-eluting stents.

The study included 1,443 patients who underwent stent implantation and were randomized to receive either 6-month DAPT (ASA 100–200 mg/day and clopidogrel 75 mg/day for 6 months, followed by ASA alone up 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 the rate of target vessel failure (a composite of cardiac death, MI, or target vessel revascularization), which was the primary endpoint, between the 6-month and 12-month DAPT groups (HR: 1.14; 95% CI: 0.70–1.86; p=0.60). Moreover, no significant difference was observed in the safety endpoint (a composite of death, MI, stroke, stent thrombosis, or major bleeding per TIMI criteria) between the two groups (HR: 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 with respect to the risk of target vessel failure.

De-escalation of P2Y₁₂ receptor inhibitor therapy 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 studies (ISS), – the TOPIC and TROPICAL-ACS trials which provided clinical outcome data.

The clinical benefit of the more potent P2Y12 receptor inhibitors, ticagrelor and prasugrel, demonstrated in pivotal trials, was associated with a statistically significant reduction in recurrent ischemic events (including acute and subacute stent thrombosis, myocardial infarction, and urgent revascularization). Although the ischemic benefit was consistently observed during the first year, the reduction in recurrent ischemic events after ACS was greatest during the initial days of treatment. In contrast, post hoc analyses showed a statistically significant increase in the risk of bleeding with more potent P2Y₁₂ receptor inhibitors, occurring predominantly during the maintenance phase after the first month post-ACS. The TOPIC and TROPICAL-ACS studies were designed to evaluate the potential for reducing hemorrhagic events while maintaining the efficacy of clopidogrel.

TOPIC study (“Timing of platelet inhibition after acute coronary syndrome”)

This randomized, open-label trial included patients with ACS who required percutaneous coronary intervention (PCI). Patients receiving aspirin and a more potent P2Y12 receptor inhibitor who had no adverse events after one month were either switched to fixed-dose aspirin and clopidogrel (de-escalation dual antiplatelet therapy, DAPT) or continued on their prior regimen (unchanged DAPT).

A total of 645 out of 646 patients with STEMI (ST-segment elevation myocardial infarction), NSTEMI (non-ST-segment elevation myocardial infarction), or unstable angina were analysed (de-escalation DAPT, n=322; unchanged DAPT, n=323). At the 1-year follow-up, 316 patients (98.1%) in the de-escalation DAPT group and 318 patients (98.5%) in the unchanged DAPT group were evaluated. The median follow-up duration was 359 days in both groups. Baseline characteristics were similar between groups.

The primary endpoint, a composite of cardiovascular death, stroke, urgent revascularization, and bleeding events of ≥ Grade 2 according to the Bleeding Academic Research Consortium (BARC) criteria at 1 year post-ACS, occurred in 43 patients (13.4%) in the de-escalation DAPT group and in 85 patients (26.3%) in the unchanged DAPT group (p<0.01). This statistically significant difference was primarily driven by a lower number of bleeding events, with no difference in ischemic outcomes (p=0.36). Bleeding events of ≥ Grade 2 (BARC criteria) occurred less frequently in the de-escalation DAPT group (4.0%) compared with the unchanged DAPT group (14.9%) (p<0.01). Overall bleeding events (all BARC grades) were reported in 30 patients (9.3%) in the de-escalation DAPT group and in 76 patients (23.5%) in the unchanged DAPT group (p<0.01).

TROPICAL-ACS study (“Testing responsiveness to platelet inhibition on chronic antiplatelet treatment for acute coronary syndromes”)

This randomized, open-label trial enrolled 2,610 patients with biomarker-positive ACS who had undergone successful PCI. Patients were randomized to receive either prasugrel 5 or 10 mg/day for 14 days (n=1,306) or prasugrel 5 or 10 mg/day for 7 days followed by de-escalation to clopidogrel 75 mg/day for days 8–14 (n=1,304), both in combination with ASA (<100 mg/day). On Day 14, platelet function testing (PFT) was performed. Patients in the control group continued prasugrel for 11.5 months.

In the de-escalation group, 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 the remaining 11.5 months; if HPR was <46 units, they 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 up for one year.

The primary endpoint — a composite of cardiovascular death, myocardial infarction, stroke, or bleeding of ≥ Grade 2 according to BARC criteria at 12 months — was met, demonstrating at least non-inferior efficacy of clopidogrel. One of these events occurred in 95 patients (7%) in the guided de-escalation group and in 118 patients (9%) in the control group (p for non-inferiority = 0.0004). Guided de-escalation did not increase the combined risk of ischemic events (2.5% in the de-escalation group vs 3.2% in the control group; p for non-inferiority = 0.0115), nor the key secondary endpoint — bleeding events ≥ Grade 2 (5% vs 6%, p=0.23). The overall rate of all bleeding events (Grades 1–5, BARC criteria) was 9% (114 events) in the guided de-escalation group versus 11% (137 events) in the control group (p=0.14).

Dual antiplatelet therapy in acute minor ischemic stroke or high-/moderate-risk TIA

Dual antiplatelet therapy with a combination of clopidogrel and ASA for the prevention of stroke after acute minor ischemic stroke (IS) or high-/moderate-risk transient ischemic attack (TIA) was evaluated in two investigator-sponsored, randomized studies — CHANCE and POINT — with available data on clinical efficacy and safety.

CHANCE (Clopidogrel in high-risk patients with acute nondisabling cerebrovascular events)

This randomized, double-blind, multicenter, placebo-controlled clinical study included 5,170 Chinese patients with acute TIA (ABCD2 score ≥ 4) or acute minor ischemic stroke (NIHSS score ≤ 3). All patients received open-label ASA on Day 1 (75–300 mg, at the investigator’s discretion). Patients randomized to the clopidogrel + ASA group received a loading dose of clopidogrel 300 mg on Day 1, followed by clopidogrel 75 mg once daily from Days 2 to 90, plus ASA 75 mg once daily from Days 2 to 21. Patients randomized to the ASA monotherapy group received placebo clopidogrel from Days 1 to 90 and ASA 75 mg once daily from Days 2 to 90.

The primary efficacy endpoint was any new stroke event (ischemic or hemorrhagic) within the first 90 days after acute minor IS or high-risk TIA. Such events occurred in 212 patients (8.2%) in the clopidogrel + ASA group compared with 303 patients (11.7%) in the ASA group (Hazard Ratio [HR] 0.68; 95% Confidence Interval [CI] 0.57–0.81; p < 0.001). Ischemic stroke occurred in 204 patients (7.9%) in the clopidogrel + ASA group compared with 295 patients (11.4%) in the ASA group (HR 0.67; 95% CI 0.56–0.81; p < 0.001). Hemorrhagic stroke occurred in 8 patients (0.3%) in each group. Moderate or severe bleeding was observed in 7 patients (0.3%) in the clopidogrel + ASA group and 8 patients (0.3%) in the ASA group (p = 0.73). The overall rate of any bleeding event was 2.3% in the clopidogrel + ASA group versus 1.6% in the ASA group (HR 1.41; 95% CI 0.95–2.10; p = 0.09).

 

POINT (Platelet-oriented inhibition in new TIA and minor ischemic stroke)

This randomized, double-blind, multicenter, placebo-controlled clinical study included 4,881 patients worldwide with acute TIA (ABCD2 score ≥ 4) or acute minor ischemic stroke (NIHSS score ≤ 3). All patients received open-label ASA for 90 days (50–325 mg daily, at the investigator’s discretion). Patients randomized to the clopidogrel + ASA group received a clopidogrel loading dose of 600 mg on Day 1, followed by clopidogrel 75 mg once daily from Days 2 to 90. Patients randomized to the placebo group received placebo clopidogrel from Days 1 to 90. The primary efficacy endpoint was a composite of major ischemic events (ischemic stroke, myocardial infarction, or death due to ischemic vascular causes) at Day 90. These events occurred in 121 patients (5.0%) in the clopidogrel + ASA group versus 160 patients (6.5%) in the ASA monotherapy group (HR 0.75; 95% CI 0.59–0.95; p < 0.02). The secondary efficacy endpoint, ischemic stroke, occurred in 112 patients (4.6%) in the clopidogrel + ASA group compared with 155 patients (6.3%) in the ASA monotherapy group (HR 0.72; 95% CI 0.56–0.92; p = 0.01). The primary safety endpoint, major bleeding, was observed in 23 of 2,432 patients (0.9%) in the clopidogrel + ASA group and 10 of 2,449 patients (0.4%) in the ASA monotherapy group (HR 2.32; 95% CI 1.10–4.87; p = 0.02). Minor hemorrhages occurred in 40 patients (1.6%) in the clopidogrel + ASA group and 13 patients (0.5%) in the ASA monotherapy group (HR 3.12; 95% CI 1.67–5.83; p = 0.001).

Analysis of the dynamics in the CHANCE and POINT studies

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

 

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

 

Number of Cases
Results in CHANCE and POINT studies	Treatment group distribution	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
	Різниця	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

The ACTIVE-W and ACTIVE-A studies, which were separate investigations within the ACTIVE program, included patients with atrial fibrillation (AF) who had at least one risk factor for vascular events. 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). The ACTIVE-A study included patients who could not receive VKA therapy due to contraindications or unwillingness to take such treatment.

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

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

Patients randomized in the ACTIVE program had documented AF, defined as either permanent AF or at least two episodes of paroxysmal AF within the previous 6 months, and at least one of the following risk factors: age ≥ 75 years, or age 55–74 years with either diabetes mellitus requiring medication, documented prior myocardial infarction, or documented coronary artery disease; prior treatment for systemic arterial hypertension; previous stroke, transient ischemic attack (TIA), or systemic embolism without central nervous system involvement; left ventricular dysfunction with a left ventricular ejection fraction < 45%, or documented peripheral arterial 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 intracerebral hemorrhage; severe thrombocytopenia (platelet count < 50×10⁹/L); need for clopidogrel or oral anticoagulant (OAC) therapy; or intolerance to either of these two agents.

Among patients enrolled in ACTIVE-A, 73% were unable to receive VKA therapy based on the physician’s assessment due to inability to monitor the international normalized ratio (INR), risk of falls or head injury, or the presence of a specific bleeding risk factor; in 26% of patients, the physician’s decision was based on the patient’s unwillingness to receive VKA therapy.

Women accounted for 41.8% of the study population. The mean age was 71 years, with 41.6% of patients aged 75 years or older. Overall, 23% of patients received antiarrhythmic drugs, 52.1% beta-blockers, 54.6% angiotensin-converting enzyme inhibitors, and 25.4% statins.

The number of patients who reached the primary endpoint (time to first occurrence of stroke, myocardial infarction, non–central nervous system systemic embolism, 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 treated with clopidogrel + ASA and in 408 (10.8%) patients treated with placebo + ASA (relative risk reduction 28.4%; 95% CI: 16.8–38.3%; p = 0.00001).

Paediatric population

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

In a randomized, double-blind, parallel-group study (CLARINET), 906 paediatric patients (neonates and infants) with cyanotic congenital heart disease who had undergone a palliative systemic-to-pulmonary arterial shunt procedure were randomized to receive clopidogrel 0.2 mg/kg (n = 467) or placebo (n = 439), in addition to standard background therapy, until the time of the second-stage surgery. The median time between the palliative shunt procedure and the first administration of the study drug was 20 days. Approximately 88% of patients concomitantly received ASA (1–23 mg/kg/day). There were no statistically significant differences between groups in achieving the primary composite endpoint — death, shunt thrombosis, or need for a cardiac procedure before 120 days of life following a thrombosis-related event which occurred in 89 patients (19.1%) in the clopidogrel group and 90 patients (20.5%) in the placebo group (see section “Method of administration and dosage”). The most frequent adverse reaction in both treatment groups was bleeding, although there was no statistically significant difference in its incidence between groups. During the subsequent long-term follow-up for adverse events, 26 patients with a shunt still in place at one year of age continued to receive clopidogrel until reaching 18 months of age. Throughout this follow-up period, the safety profile of the medicinal product remained unchanged.

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

Pharmacokinetics.

Absorption

After oral administration of a single dose or repeated daily doses of 75 mg, clopidogrel is rapidly absorbed. Mean maximum plasma concentrations of unchanged clopidogrel (approximately 2.2–2.5 ng/mL after a single dose of 75 mg) were reached approximately 45 minutes after dosing. Absorption is at least 50%, as shown by urinary excretion of clopidogrel metabolites.

Distribution

Clopidogrel and the main circulating (inactive) metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). This binding is non-saturable in vitro over a wide range of concentrations.

Metabolism

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, there are two main metabolic pathways: one involves esterases and leads to hydrolysis forming an inactive carboxylic acid derivative (accounting for 85% of circulating plasma metabolites), and the other involves cytochrome P450 enzymes. Clopidogrel is first converted to the intermediate metabolite 2-oxo-clopidogrel. Further metabolism of 2-oxo-clopidogrel results in the formation of a thiol derivative — the active metabolite. This active metabolite is mainly formed by the CYP2C19 enzyme, with participation of several other CYP enzymes such as CYP1A2, CYP2B6, and CYP3A4. The active thiol metabolite of clopidogrel, which was isolated in vitro, binds rapidly and irreversibly to platelet receptors, thereby preventing platelet aggregation.

The C_max value for the active metabolite is twice as high after administration of a single 300 mg loading dose of clopidogrel compared with that observed after four days of maintenance dosing at 75 mg. C_max is reached approximately 30–60 minutes after administration.

Elimination

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

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

The CYP2C191 allele corresponds to fully functional metabolism, whereas the CYP2C192 and CYP2C193 alleles correspond to non-functional metabolism. The CYP2C192 and CYP2C193 alleles account for the majority of reduced-function alleles in Caucasian (85%) and Asian (99%) populations with reduced metabolism. Other alleles associated with absent or reduced metabolism occur much less frequently. These include CYP2C194, *5, *6, *7, and *8. A poor metabolizer is a patient carrying two non-functional alleles, as listed above. According to published data, CYP2C19 genotypes associated with reduced metabolism occur in approximately 2% of Caucasians, 4% of African-Americans, and 14% of Chinese. Tests are now available to identify the CYP2C19 genotype.

In a crossover study involving 40 healthy volunteers—10 in each of the four groups corresponding to specific CYP2C19 metabolic phenotypes (ultrarapid, extensive, intermediate, and poor metabolizers)—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 regimen was administered for a total of five days (until steady state was reached). No significant differences in plasma concentrations of the active metabolite or in mean platelet aggregation inhibition (PAI) were observed among ultrarapid, extensive, and intermediate metabolizers. In poor metabolizers, the plasma concentration of the active metabolite was reduced by 63–71% compared with extensive metabolizers. Following the 300 mg/75 mg dosing regimen, antiplatelet effects in poor metabolizers were less pronounced, with mean PAI values (5 μM ADP-induced platelet aggregation) of 24% (at 24 hours) and 37% (on day 5), compared with 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 dosing regimen, plasma concentrations of the active metabolite were higher than those observed with the 300 mg/75 mg regimen. Moreover, PAI values were 32% (at 24 hours) and 61% (on day 5), which were greater than in poor metabolizers receiving 300 mg/75 mg, and comparable to those observed in other CYP2C19 metabolic phenotype groups receiving 300 mg/75 mg. Based on clinical outcomes, an appropriate dosing regimen for this group of patients has not been established.

Similarly, in a meta-analysis of six studies involving steady-state data from 335 patients treated with clopidogrel, plasma concentrations of the active metabolite were reduced by 28% in intermediate metabolizers and by 72% in poor metabolizers. Platelet aggregation inhibition (5 μM ADP) was also reduced, with differences in PAI of 5.9% and 21.4%, respectively, compared with extensive metabolizers.

The influence of CYP2C19 genotype on clinical outcomes in patients receiving clopidogrel has not been evaluated in prospective randomized controlled trials. However, several retrospective analyses have been conducted to assess this effect in genotyped patients who received clopidogrel: CURE (n = 2721), CHARISMA (n = 2428), CLARITY-TIMI 28 (n = 227), TRITON-TIMI 38 (n = 1477), and ACTIVE-A (n = 601). In addition, results from several published cohort studies are available.

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

In analyses from CHARISMA and one cohort study (Simon), poor metabolizers showed a higher incidence of events compared with extensive metabolizers.

In analyses from CURE, CLARITY, ACTIVE-A, and one cohort study (Trenk), the incidence of cardiovascular events was not significantly related to metabolic status.

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

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

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

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

Ethnicity. The prevalence of CYP2C19 alleles resulting in intermediate and poor metabolism of CYP2C19 varies among ethnic/racial groups (see section “Pharmacogenetics”). There are limited data for Asian patients available to evaluate the clinical significance of CYP genotyping in terms of clinical outcomes.

Preclinical data.

The most frequently observed adverse effects in animal studies were liver changes. These occurred at doses resulting in clopidogrel blood concentrations approximately 25 times higher than those observed in humans following clinical administration of a 75 mg daily dose of clopidogrel, and were a consequence of the drug’s effect on enzymes involved in hepatic metabolism. At therapeutic doses in humans, no effect on hepatic metabolic enzymes was observed.

At high doses in rats and baboons, clopidogrel caused poor gastric tolerability (gastritis, erosive gastric lesions, and/or vomiting).

Administration of clopidogrel to mice for 78 weeks and to rats for 104 weeks at doses up to 77 mg/kg per day (approximately 25 times higher than the concentrations observed in humans at the clinical dose of 75 mg/day) provided no evidence of carcinogenicity.

A range of in vitro and in vivo genotoxicity studies with clopidogrel showed no evidence of genotoxic potential.

Clopidogrel had no effect on the reproductive function of rats and showed no teratogenic effects in rats or rabbits. When administered to lactating rats, clopidogrel caused a slight delay in offspring development. Specific pharmacokinetic studies with radiolabelled clopidogrel demonstrated that the parent compound and its metabolites are excreted in breast milk. Therefore, both a direct effect on the offspring (slight toxic effect) and an indirect effect (due to changes in the taste of milk) cannot be excluded.

 

Clinical particulars.

Indications.

Prevention of atherothrombotic events in adults:

• in patients who have experienced myocardial infarction (treatment initiation – a few days after the event but no later than 35 days after its occurrence), ischemic stroke (treatment initiation – 7 days after the event but no later than 6 months after its occurrence), or in patients diagnosed with peripheral arterial disease (arterial lesions and atherothrombosis of the lower limb vessels);
• in patients with acute coronary syndrome:

– with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), including patients undergoing stent placement during percutaneous coronary intervention, in combination with acetylsalicylic acid;

– with acute ST-segment elevation myocardial infarction in combination with ASA is indicated for patients undergoing percutaneous coronary intervention (PCI), including those receiving stents, or for patients receiving standard medical therapy who are candidates for thrombolytic/fibrinolytic therapy.

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

Clopidogrel in combination with ASA is indicated for

• adult patients with TIA of moderate to high risk score (ABCD2¹ ≥ 4), or minor ischemic stroke (NIHSS² score ≤ 3) within 24 hours of the TIA or ischemic stroke event.

¹ Age, blood pressure, clinical features, duration of symptoms, and history of diabetes.

² National Institutes of Health Stroke Scale.

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation

Clopidogrel in combination with acetylsalicylic acid is indicated in adult patients with atrial fibrillation who have at least one risk factor for vascular events, who have contraindications to treatment with vitamin K antagonists, and who have a low risk of bleeding, for the prevention of atherothrombotic and thromboembolic events, including stroke.

For further information, see section "Pharmacological properties".

 

Contraindications.

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

Severe hepatic impairment.

Active bleeding (e.g., peptic ulcer or intracranial hemorrhage).

 

Interaction with other medicinal products and other forms of interaction.

Medicinal products associated with increased risk of bleeding. Due to a potential additive effect, there is an increased risk of hemorrhagic complications; therefore, concomitant use of such medicinal products with clopidogrel requires caution (see section "Precautions for use").

Oral anticoagulants. Concomitant use of Clopidogrel with oral anticoagulants is not recommended, as this combination may increase bleeding intensity. Although clopidogrel 75 mg daily does not alter the pharmacokinetics of S-warfarin or the international normalized ratio (INR) in patients receiving long-term warfarin therapy, the concomitant administration of clopidogrel and warfarin increases the risk of bleeding due to independent effects on hemostasis.

Glycoprotein IIb/IIIa receptor inhibitors. Clopidogrel should be used with caution in patients receiving glycoprotein IIb/IIIa receptor inhibitors (see section "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, the concomitant use of 500 mg acetylsalicylic acid twice daily for one day did not significantly prolong bleeding time already prolonged by clopidogrel. Since a possible pharmacodynamic interaction between clopidogrel and acetylsalicylic acid may increase the risk of bleeding, concomitant use requires caution (see section "Precautions for use"). Nevertheless, clopidogrel and acetylsalicylic acid were co-administered for up to 1 year (see section "Pharmacological properties").

Heparin. In a clinical study involving healthy volunteers, clopidogrel did not require dose adjustment of heparin and did not alter the effect of heparin on coagulation. Concomitant administration of heparin did not change clopidogrel’s inhibition of platelet aggregation. Since a pharmacodynamic interaction between clopidogrel and heparin may increase the risk of bleeding, concomitant use requires caution (see section "Precautions for use").

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

Non-steroidal anti-inflammatory drugs (NSAIDs). In a clinical study involving healthy volunteers, concomitant administration of clopidogrel and naproxen increased the incidence of occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs, it is currently unclear whether gastrointestinal bleeding risk increases with all NSAIDs. Therefore, caution is advised when NSAIDs, particularly COX-2 inhibitors, are used together with clopidogrel (see section "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 being treated concurrently with other antiplatelet agents, any signs or symptoms of bleeding must be promptly evaluated (see section "Precautions for use").

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

Concomitant use of other drugs.

CYP2C19 inducers

Since clopidogrel is partially converted to its active metabolite via CYP2C19, the use of drugs that decrease the activity of this enzyme is likely to reduce the plasma concentration of clopidogrel’s active metabolite.

Rifampicin is a strong inducer of CYP2C19, which leads to both increased levels of clopidogrel’s active metabolite and enhanced platelet inhibition, potentially increasing the risk of bleeding. As a precautionary measure, co-administration of strong CYP2C19 inhibitors should be avoided (see sections “Precautions for use”).

CYP2C19 inducers

Since clopidogrel is partially metabolized into its active metabolite by CYP2C19, use of drugs that inhibit this enzyme may lead to a decrease in plasma levels of the active clopidogrel metabolite. The clinical significance of this interaction is unclear. As a precaution, concomitant use of strong and moderate CYP2C19 inhibitors should be avoided (see sections "Precautions for use" and "Pharmacokinetics").

Drugs that inhibit CYP2C19 activity include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, and efavirenz.

Proton pump inhibitors (PPIs). Omeprazole at a dose of 80 mg once daily, when co-administered with clopidogrel or taken within 12 hours of clopidogrel, reduced plasma levels of the active metabolite by 45% (loading dose) and 40% (maintenance dose). This reduction was accompanied by a 39% decrease in platelet aggregation inhibition (loading dose) and 21% (maintenance dose). Esomeprazole is expected to have a similar interaction with clopidogrel.

Results from observational and clinical studies have produced conflicting data regarding the clinical consequences of these pharmacokinetic and pharmacodynamic interactions in terms of major cardiovascular events. As a precaution, concomitant use of omeprazole or esomeprazole with clopidogrel should be avoided (see section "Precautions for use").

A lesser decrease in metabolite concentration was observed with pantoprazole or lansoprazole.

When pantoprazole was co-administered at 80 mg once daily, plasma concentrations of the active metabolite decreased by 20% (loading dose) and 14% (maintenance dose). This reduction was accompanied by a decrease in the mean platelet aggregation inhibition rate by 15% and 11%, respectively. The findings suggest that clopidogrel and pantoprazole can be used concomitantly.

There is no evidence that other drugs that reduce stomach acid production, such as H₂-receptor antagonists or antacids, affect the antiplatelet activity of clopidogrel.

Boosted antiretroviral therapy

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

Significantly reduced platelet inhibition has been observed in HIV-infected patients receiving ART boosted with ritonavir or cobicistat. Although the clinical significance of these findings has not been established, spontaneous reports describe HIV-infected patients on ritonavir-boosted ART who experienced recurrent occlusive events after deobstruction or thrombotic events while receiving high-dose clopidogrel therapy. Co-administration of clopidogrel with ritonavir may result in reduced average platelet inhibition. Therefore, concomitant use of clopidogrel with boosted ART should be avoided.

Combination with other medicinal products

A number of clinical studies were conducted with clopidogrel in combination with other drugs to investigate potential pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both. Furthermore, the pharmacodynamic activity of clopidogrel remained essentially unchanged when co-administered with phenobarbital and estrogen.

The pharmacokinetics of digoxin or theophylline was not altered by co-administration 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 CYP2C9, can be safely co-administered with clopidogrel.

Drugs that are CYP2C8 substrates

Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies demonstrated that this increase is due to inhibition of CYP2C8 by clopidogrel’s glucuronide metabolite. Due to the risk of increased plasma levels, concomitant use of clopidogrel with drugs primarily eliminated by CYP2C8 metabolism (e.g., repaglinide, paclitaxel) requires caution (see section "Precautions for use").

With the exception of the drug interactions described above, no interaction studies of clopidogrel with drugs commonly used in patients with atherothrombosis have been conducted. However, patients in clopidogrel clinical trials commonly received other medications, including diuretics, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, lipid-lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, and GPIIb/IIIa antagonists, without evidence of clinically significant adverse interactions.

As with other oral P2Y12 inhibitors, co-administration of opioid agonists may potentially delay and reduce the absorption of clopidogrel, likely due to slowed gastric emptying. The clinical significance of this is unknown. Parenteral antiplatelet therapy should be considered for patients with acute coronary syndrome who require concomitant administration of morphine or other opioid agonists.

Rosuvastatin

It has been observed that after a single 300 mg dose of clopidogrel, exposure to rosuvastatin increased 2-fold (AUC) and 1.3-fold (C_max), while after repeated administration of clopidogrel 75 mg, rosuvastatin exposure increased 1.4-fold (AUC) without affecting C_max.

 

Precautions for use.

Bleeding and hematological disorders

Due to the risk of bleeding and hematological adverse reactions, a complete blood count and/or other appropriate tests should be performed immediately if symptoms suggestive of bleeding occur during treatment (see section “Adverse reactions”). As with other antiplatelet agents, clopidogrel should be used with caution in patients at increased risk of bleeding due to trauma, surgery, or other pathological conditions, as well as in patients receiving ASA, heparin, glycoprotein IIb/IIIa inhibitors, NSAIDs including COX-2 inhibitors, selective serotonin reuptake inhibitors (SSRIs), potent CYP2C19 inducers, or other drugs 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”). Due to the increased risk of bleeding, triple antiplatelet therapy (clopidogrel + ASA + dipyridamole) is not recommended for secondary prevention of stroke in patients with acute non-cardioembolic ischemic stroke or TIA (see sections “Interaction with other medicinal products and other forms of interaction” and “Adverse reactions”).

Patients should be closely 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 it may increase the severity of bleeding (see section “Interaction with other medicinal products and other forms of interaction”).

For planned surgery, when the antiplatelet effect is temporarily undesirable, clopidogrel treatment should be discontinued 7 days before the procedure. Patients must inform their physician (including dentists) that they are taking clopidogrel before any surgery or before starting any new medication. Clopidogrel prolongs bleeding time, so it should be used with caution in patients at increased risk of bleeding, particularly gastrointestinal and intraocular bleeding.

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

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

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

Thrombotic thrombocytopenic purpura (TTP)

Cases of TTP have been reported very rarely following clopidogrel administration, sometimes after a short course of treatment. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological symptoms, renal dysfunction, or fever. TTP is a potentially life-threatening condition that requires urgent treatment, including plasma exchange.

Acquired haemophilia

Cases of acquired hemophilia have been reported following clopidogrel use. In patients with confirmed isolated prolongation of activated partial thromboplastin time (aPTT), with or without bleeding, acquired hemophilia should be considered. Patients with confirmed acquired hemophilia should be managed by specialists and treated appropriately; clopidogrel should be discontinued.

Recent ischemic stroke

• - Initiation of therapy
• o In patients with acute minor ischemic stroke or moderate- to high-risk TIA, dual antiplatelet therapy (clopidogrel and ASA) should be initiated no later than 24 hours after the onset of the event.
• o There are no data on the risk-benefit 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.
• o In patients with non-minor ischemic stroke, clopidogrel monotherapy should be initiated only 7 days after the event.
• - Patients with non-minor ischemic stroke (NIHSS score > 4):

Due to lack of data, dual antiplatelet therapy is not recommended (see section “Indications”).

• - Patients with recent minor ischemic stroke or moderate- to high-risk TIA scheduled for or having undergone interventional procedures:

There are no data confirming the advisability of dual antiplatelet therapy in patients who are indicated for carotid endarterectomy or intravascular thromboectomy, or in patients who are scheduled for thrombolysis or anticoagulant therapy. Dual antiplatelet therapy is not recommended in these situations.

Cytochrome P450 2C19 (CYP2C19)

Pharmacogenetics: In patients with genetically reduced CYP2C19 function, lower plasma concentrations of the active clopidogrel metabolite and reduced antiplatelet effects are observed when using the recommended doses of clopidogrel. Tests are now available to identify the CYP2C19 genotype in patients.

Since clopidogrel is partly converted into its active metabolite by CYP2C19, use of drugs that inhibit this enzyme may lead to reduced plasma levels of the active metabolite. However, the clinical significance of this interaction is unclear. Therefore, as a precaution, concomitant use of strong and moderate CYP2C19 inhibitors should be avoided (see section “Interactions with other medicinal products and other forms of interactions” with a list of CYP2C19 inhibitors; see also section “Pharmacokinetics”).

The use of drugs that induce CYP2C19 activity is expected to increase the levels of clopidogrel’s active metabolite and may enhance the risk of bleeding. As a precaution, co-administration of strong CYP2C19 inducers should be avoided (see section “Interaction with other medicinal products and other forms of interaction”).

CYP2C8 substrates

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

Cross-reactivity among thienopyridines

Patients should be assessed for a history of hypersensitivity to other thienopyridines (such as ticlopidine or prasugrel), as reports of cross-reactivity among thienopyridines have been received (see section “Adverse reactions”). Use of thienopyridines may lead to mild to severe allergic reactions, such as rash or angioedema, as well as hematologic reactions, including thrombocytopenia and neutropenia. Patients with a previous history of allergic and/or hematologic reactions to one thienopyridine may have an increased risk of developing similar reactions to another thienopyridine. Monitoring for signs of hypersensitivity is recommended in patients with known thienopyridine allergies.

Renal impairment

Therapeutic experience with clopidogrel in patients with renal insufficiency is limited; therefore, clopidogrel should be used with caution in these patients (see section Posology and method of administration).

Hepatic impairment

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

Excipients

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

Clopidogrel also contains hydrogenated castor oil, which may cause stomach upset and diarrhea.

Special precautions for disposal of remnants and waste

Any unused product or waste material should be disposed of in accordance with local requirements.

 

Pregnancy and lactation.

Pregnancy

Due to the lack of clinical data on the use of clopidogrel during pregnancy, the drug should not be prescribed to pregnant women as a precautionary measure.

Animal studies have not shown any direct or indirect harmful effects of clopidogrel on pregnancy, embryonic/foetal development, parturition, or postnatal development (see section “Preclinical data”).

Breastfeeding

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

Fertility

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

 

Effects on ability to drive and use machines.

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

 

Method of administration and dosage.

Posology

Adults, including elderly patients
Clopidogrel should be administered at 75 mg once daily, regardless of food intake.

Patients with acute coronary syndrome:

Acute coronary syndrome without ST-segment elevation (unstable angina or non–Q-wave myocardial infarction) treatment with clopidogrel is 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 “Precautions for use”).
Maintenance therapy is continued at 75 mg once daily, in combination with acetylsalicylic acid (ASA) 75–325 mg once daily. As higher ASA doses increase the risk of bleeding, exceeding 100 mg ASA daily is not recommended. The optimal duration of treatment has not been formally established. Clinical trial results support treatment up to 12 months, with the maximum effect observed after 3 months (see section “Pharmacological properties”). Acute myocardial infarction with ST-segment elevation:

• - For patients receiving medical treatment and indicated for thrombolytic/fibrinolytic therapy, clopidogrel is given at 75 mg once daily, starting with a single 300 mg loading dose in combination with ASA, with or without thrombolytic therapy. Patients ≥75 years should start therapy without a loading dose. 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 has not been studied in this condition (see section “Pharmacological properties”).
• - Patients undergoing PCI:
  • Patients undergoing primary PCI or PCI >24 hours after fibrinolytic therapy should receive a 600 mg loading dose. In patients ≥75 years, the 600 mg loading dose should be used with caution (see section “Precautions for use”).
  • Patients undergoing PCI within 24 hours after fibrinolytic therapy should receive a 300 mg loading dose.
    Maintenance therapy is continued at 75 mg once daily, together with ASA 75–100 mg once daily. Combined therapy should be started as early as possible after symptom onset and continued up to 12 months (see section “Pharmacodynamics”).

Adults with moderate- to high-risk TIA or minor ischemic stroke (IS):
Adults 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 75 mg once daily together with ASA 75–100 mg once daily. Therapy with clopidogrel and ASA should be started within 24 hours of the event and continued for 21 days, followed by antiplatelet monotherapy.

Patients with atrial fibrillation:
Clopidogrel should be given at 75 mg once daily, together with ASA 75–100 mg once daily (see section “Pharmacological properties”).

Missed dose:

• - If less than 12 hours have passed since the scheduled dose, the missed dose should be taken immediately, and the next dose taken at the usual time.
• - If more than 12 hours have passed, the next dose should be taken at the usual time, without doubling the dose.

Special populations

Elderly patients

• - Acute coronary syndrome without ST-segment elevation (unstable angina or non–Q-wave myocardial infarction): the use of a 600 mg loading dose of clopidogrel may be considered in patients younger than 75 years when percutaneous coronary intervention is required (see section “Precautions for use”).
• - Acute ST-segment elevation myocardial infarction: in patients aged ≥ 75 years undergoing medical treatment and eligible 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 in patients undergoing PCI more than 24 hours after fibrinolytic therapy, the 600 mg loading dose of clopidogrel should be used with caution (see section “Precautions for use”).

Renal impairment
Therapeutic experience in patients with renal insufficiency is limited (see section “Precautions for use”).

Hepatic impairment
Therapeutic experience in patients with moderate liver disease and risk of hemorrhagic diathesis is limited (see section “Precautions for use”).

Method of administration
For oral use. Clopidogrel may be taken with or without food.

 

Children
Clopidogrel should not be used in children under 18 years, as there is no data on efficacy in this age group (see section “Pharmacodynamics”).

  

Overdose.

In case of clopidogrel overdose, prolongation of bleeding time with subsequent complications may occur. In the event of bleeding, symptomatic treatment is recommended.

An antidote to the pharmacological activity of clopidogrel is not known. If immediate correction of prolonged bleeding time is necessary, the effect of clopidogrel can be reversed by platelet transfusion.

 

Adverse reactions.

Brief overview of the safety profile

The safety of clopidogrel has been investigated in more than 44,000 patients who participated in clinical trials (of whom more than 12,000 received treatment for 1 year or longer). Clinically significant adverse events observed in the CAPRIE study—clopidogrel 75 mg once daily—were generally comparable to those observed with ASA 325 mg once daily, regardless of patients’ age, sex, or race.

In addition to data from the CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE-A clinical trials, spontaneous reports of adverse reactions during routine clinical use were considered.

Bleeding was the most frequently reported adverse reaction, observed both in clinical trials and post-marketing experience, most often occurring during the first month of treatment.

In the CAPRIE study, the overall incidence of bleeding in patients treated with clopidogrel or ASA was 9.3%. The incidence of major bleeding events was similar for clopidogrel and ASA.

In the CURE study, there was no increase in the incidence of major bleeding with the combination of clopidogrel + ASA during the 7 days following coronary artery bypass graft (CABG) surgery in patients who discontinued therapy more than 5 days before surgery. In patients who continued therapy up to 5 days before CABG, the incidence of major bleeding was 9.6% in the clopidogrel + ASA group and 6.3% in the placebo + ASA group.

In the CLARITY study, an overall increase in the incidence of bleeding was observed in the clopidogrel + ASA group compared with the placebo + ASA group. The incidence of major bleeding was similar in both groups. This finding was consistent across patient subgroups differing in 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 groups.

In the ACTIVE-A study, the incidence of major bleeding was higher in the clopidogrel + ASA group compared with the placebo + ASA group (6.7% vs. 4.3%). In both groups, major bleeding was predominantly of extracranial origin (5.3% in the clopidogrel + ASA group, 3.5% in the placebo + ASA group), mainly gastrointestinal bleeding (3.5% vs. 1.8%). There was an increase in the number of intracranial bleeding events in the clopidogrel + ASA group compared with the placebo + ASA group (1.4% vs. 0.8%, respectively). No statistically significant difference was observed between these 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) experienced excessive bleeding and severe bleeding compared with clopidogrel monotherapy or ASA + dipyridamole combination therapy (adjusted overall HR 2.54, 95% CI 2.05–3.16, p<0.0001).

List of adverse reactions

The adverse effects observed during clinical trials or reported during the use of the medicinal product in clinical practice through spontaneous reporting are listed below.

Adverse reactions are classified by organ system, and their frequency is defined as follows: common (> 1/100 to <1/10), uncommon (> 1/1,000 to  <1/100), rare (> 1/10,000 to  <1/1,000), very rare (< 1/10,000), frequency unknown. 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 unknown* – thrombotic thrombocytopenic purpura (TTP) (see section “Precautions for use”), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired hemophilia A, granulocytopenia, anemia.

Cardiac disorders: very rare, frequency unknown* – Kounis syndrome (vasospastic allergic angina/allergic myocardial infarction) as a result of hypersensitivity reaction to clopidogrel*.

Immune system disorders: very rare, frequency unknown* – serum sickness, anaphylactoid reactions, cross-hypersensitivity among thienopyridines (e.g., ticlopidine, prasugrel) (see section “Precautions for use”), autoimmune insulin syndrome, which may lead to severe hypoglycemia, especially in patients with HLA DRA4 subtype (more common among Japanese patients).

Psychiatric disorders: very rare, frequency unknown* – hallucinations, confusion.

Nervous system disorders: uncommon – intracranial bleeding (in some cases fatal), headache, paresthesia, dizziness; very rare, frequency unknown* – taste disturbance, ageusia.

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

Ear and labyrinth disorders: rare – vertigo.

Vascular disorders: common – hematoma; very rare, frequency unknown* – severe hemorrhage, surgical site bleeding, vasculitis, arterial hypotension.

Respiratory, thoracic, and mediastinal disorders: common – epistaxis; very rare, frequency unknown* – respiratory tract bleeding (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.

Gastrointestinal disorders: common – gastrointestinal bleeding, diarrhea, abdominal pain, dyspepsia;

uncommon – gastric and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence;

rare – retroperitoneal hemorrhage; very rare, frequency unknown* – fatal gastrointestinal and retroperitoneal hemorrhage, pancreatitis, colitis (including ulcerative or lymphocytic), stomatitis.

Hepatobiliary disorders: very rare, frequency unknown* – acute hepatic failure, hepatitis, abnormal liver function tests.

Skin and subcutaneous tissue disorders: common – subcutaneous hemorrhage; uncommon – rash, pruritus, intradermal hemorrhage (purpura); very rare, frequency unknown* – bullous dermatitis (toxic epidermal necrolysis, Stevens–Johnson syndrome, erythema multiforme, acute generalized exanthematous pustulosis [AGEP]), angioedema, drug hypersensitivity syndrome, drug rash 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 unknown* – musculoskeletal hemorrhages (hemarthrosis), arthritis, arthralgia, myalgia.

Renal and urinary disorders: uncommon – hematuria; very rare, frequency unknown* – glomerulonephritis, increased blood creatinine.

General disorders and administration site conditions: common – bleeding at the injection site; very rare, frequency unknown* – fever.

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

* Information on clopidogrel with “frequency unknown.”

 

Reporting suspected adverse reactions

Reporting suspected adverse reactions after the authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals, pharmacists, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product 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 place protected from light at a temperature not exceeding 30 °C. Keep out of reach of children,

 

Packaging: 10 tablets in a blister; 1, 3 or 10 blister in a box.

 

Terms of dispensing. On prescription.

 

Date of last update.

19.05.2025