Atrogrel

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATROGREL (Atrogrel)

Composition:

Active substance: clopidogrel;

1 tablet contains: clopidogrel as clopidogrel bisulfate (calculated as 100 % clopidogrel) − 75 mg;

Excipients: sodium croscarmellose, microcrystalline cellulose, lactose monohydrate, hydrogenated castor oil;

Film coating: hypromellose, lactose monohydrate, titanium dioxide (E 171), triacetin, carmine (E 120).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex film-coated tablets of pink color.

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, which inhibits platelet aggregation, clopidogrel must undergo biotransformation by cytochrome CYP450 enzymes. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its P2Y12 receptors on the platelet surface and subsequent ADP-induced activation of the glycoprotein IIb/IIIa complex, thereby inhibiting platelet aggregation. Since 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 the rate of 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.

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

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

Clinical efficacy and safety. The safety and efficacy of clopidogrel were evaluated in 7 double-blind studies involving over 100,000 patients: the CAPRIE study – comparing 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 (PAD). The CAPRIE study included 19,185 patients with atherothrombosis, manifested by recent myocardial infarction (< 35 days ago), recent ischemic stroke (from 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 then followed for 1 to 3 years. In the MI 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 combined 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 (which reached statistical significance 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 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 MI, the effect of clopidogrel was numerically smaller but statistically not significantly different from ASA (RRR = -4%; CI: -22.5–11.7 [p=0.639]). Furthermore, subgroup analysis by age suggests that the beneficial effect of clopidogrel in patients aged 75 years and older was lower than in patients ≤75 years.

Since the power of the CAPRIE study was insufficient to assess efficacy in individual subgroups, it remains unclear whether actual differences in relative risk reduction exist among patients with different conditions or whether the differences were due to chance.

Acute coronary syndrome. The CURE study 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 at least twice the upper limit of normal. Patients were randomized to receive clopidogrel (loading dose 300 mg, then 75 mg/day, n=6259) or placebo (n=6303), both in combination with ASA (75–325 mg once daily) and other standard therapy. Treatment duration was up to 1 year. In the CURE study, 823 (6.6%) patients also received concomitant therapy with a GPIIb/IIIa glycoprotein receptor antagonist. More than 90% of patients received heparins. This concomitant therapy did not statistically significantly affect the relative frequency of bleeding events with clopidogrel versus placebo.

The number of patients reaching the primary endpoint [cardiovascular death (CVD), myocardial infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel group and 719 (11.4%) in the placebo group. The relative risk reduction was 20% (95% CI 10%–28%; p=0.00009) for the clopidogrel group (17% with conservative treatment, 29% if patients underwent percutaneous transluminal coronary angioplasty with or without stent placement, and 10% if they underwent coronary artery bypass grafting). Prevention of new cardiovascular events (primary endpoint) occurred with a relative risk reduction of 22% (CI: 8.6–33.4), 32% (CI: 12.8–46.4), 4% (CI: -26.9–26.7), 6% (CI: -33.5–34.3), and 14% (CI: -31.6–44.2) during the periods 0–1, 1–3, 3–6, 6–9, and 9–12 months of the study, respectively. Thus, after more than 3 months of treatment, the beneficial effect observed in the clopidogrel + ASA group no longer increased, while the risk of bleeding remained (see section "Special precautions for use").

Use of clopidogrel during the CURE study 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 1035 (16.5%) in the clopidogrel group and 1187 (18.8%) in the placebo group. The relative risk reduction was 14% (95% CI: 6–21%, p=0.0005) in the clopidogrel group. This effect was primarily due to a statistically significant reduction in the incidence of MI [287 (4.6%) in the clopidogrel group and 363 (5.8%) in the placebo group]. No changes in the frequency of recurrent hospitalizations for unstable angina were observed.

Results obtained 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 results. In particular, a subgroup analysis of 2172 patients (17% of the total CURE group) who received a stent (Stent-CURE) showed that treatment with clopidogrel, compared to placebo, resulted in a significant RRR (26.2%), favoring clopidogrel in preventing the primary endpoint (CVD, MI, stroke), as well as a significant RRR (23.9%) for the second combined primary endpoint (CVD, MI, stroke, or refractory ischemia). Moreover, the safety profile of clopidogrel in this subgroup raised no particular concerns. Thus, the results of the subgroup analysis are consistent with the overall study results.

The beneficial effect of clopidogrel was demonstrated independently of the use of emergency and long-term 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).

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

The CLARITY study included 3491 patients who had experienced MI with ST-segment elevation within the previous 12 hours and were scheduled for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose, then 75 mg/day, n=1752) or placebo (n=1739), both in combination with ASA (loading dose 150–325 mg, then 75–162 mg/day), a fibrinolytic agent, and, if necessary, heparin. Patient follow-up lasted 30 days. The primary endpoint was occlusion of the infarct-related artery, as detected on angiogram before hospital 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 by day 8 or hospital 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, the absolute reduction was 6.7%, with a 36% advantage in favor of clopidogrel (95% CI: 24–47%; p < 0.001), primarily due to reduced incidence of occlusion of the infarct-related artery. This advantage was observed in all predefined patient subgroups, stratified by age, sex, infarct location, and type of fibrinolytic or heparin therapy received.

The two-by-two factorial design of the COMMIT study included 45,852 patients who, within the previous 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 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 in patients of all ages and sexes, regardless of fibrinolytic use, and was evident within the first 24 hours.

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

The clinical benefit provided by more potent P2Y12 receptor inhibitors, ticagrelor and prasugrel, in pivotal studies, is due to a statistically significant reduction in the frequency of 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 after treatment initiation. 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 following ACS. The TOPIC and TROPICAL-ACS studies were designed to investigate the possibility of reducing bleeding events while maintaining the efficacy of clopidogrel.

Study TOPIC (Timing of Platelet Inhibition After Acute Coronary Syndrome). This was a randomized open-label study including patients with ACS requiring percutaneous coronary intervention (PCI). Patients who were receiving 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 visits at 1 year were conducted in 316 patients (98.1%) in the de-escalation DAPT group and 318 patients (98.5%) in the unchanged DAPT group. Median follow-up for both groups was 359 days. Baseline characteristics of the study cohort were similar in the two groups.

The primary endpoint, a composite of cardiovascular death, stroke, emergency revascularization, and bleeding events ≥ grade 2 according to the 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; there was no reported difference in ischemic event endpoints (p = 0.36), while bleeding events ≥ grade 2 according to BARC criteria occurred less frequently in the de-escalation DAPT group (4.0%) compared to 14.9% in the unchanged DAPT group (p < 0.01). Bleeding events defined as all events according to BARC criteria were observed in 30 patients (9.3%) in the de-escalation DAPT group and 76 patients (23.5%) in the unchanged DAPT group (p < 0.01).

Study TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition and Patient Outcomes in Acute Coronary Syndromes). This was a randomized open-label study that included 2610 patients with ACS and positive biomarker results, in whom PCI was successfully performed. Patients were randomized into groups to receive either prasugrel 5 or 10 mg/day (days 0–14) (n = 1309), or prasugrel 5 or 10 mg/day (days 0–7), followed by de-escalation to clopidogrel 75 mg/day (days 8–14) (n = 1309), in combination with ASA (< 100 mg/day). Platelet function testing (PFT) was performed on day 14. Patients who remained on prasugrel continued prasugrel for 11.5 months.

In patients who underwent de-escalation, high on-treatment platelet reactivity (HPR) was assessed. If HPR was ≥ 46 units, patients were switched back to prasugrel 5 or 10 mg/day for 11.5 months; if HPR was < 46 units, patients continued clopidogrel 75 mg/day for 11.5 months. Thus, in the guided de-escalation group, patients received either prasugrel (40%) or clopidogrel (60%). All patients continued aspirin, and follow-up was conducted for one year.

The primary endpoint (a composite endpoint of cardiovascular death, MI, stroke, and bleeding ≥ grade 2 according to BARC criteria at 12 months) demonstrated non-inferiority of clopidogrel. The primary 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 an increase in the combined risk of ischemic events (2.5% in the de-escalation group vs. 3.2% in the control group; p for non-inferiority = 0.0115), nor for the key secondary endpoint – frequency of bleeding events ≥ grade 2 according to BARC criteria (5% in the de-escalation group vs. 6% in the control group (p = 0.23)). The overall frequency of all bleeding events (grades 1–5 according to BARC) was 9% (114 events) in the guided de-escalation group compared to 11% (137 events) in the control group (p = 0.14).

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

Dual antiplatelet therapy with clopidogrel plus ASA for stroke prevention after minor acute stroke or high-risk TIA was evaluated in two investigator-sponsored randomized studies (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 5170 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 treating physician's discretion). Patients randomly assigned to the clopidogrel-ASA group received clopidogrel 300 mg loading dose on day 1, then 75 mg daily from day 2 to day 90, and ASA 75 mg daily 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 daily from day 2 to day 90.

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

This randomized, double-blind, multicenter, placebo-controlled clinical trial included patients worldwide (4881 patients) with acute TIA (ABCD2 score ≥ 4) or acute minor stroke (NIHSS score ≤ 3). All patients in both groups received open-label ASA from day 1 to day 90 (50–325 mg, depending on the treating physician's prescription). Patients randomly assigned to the clopidogrel group received clopidogrel 600 mg loading dose on day 1, then 75 mg daily from day 2 to day 90. Patients randomly assigned to the placebo group received placebo clopidogrel from day 1 to day 90.

The primary efficacy outcome was a composite of major ischemic events (stroke, MI, or death due to ischemic vascular event) by 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 the CHANCE and POINT study timelines

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

Timeline of serious ischemic events and major bleeding in treatment groups in the CHANCE and POINT studies

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

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

The ACTIVE-A study (n = 7554) was a multicenter, randomized, double-blind, placebo-controlled trial comparing clopidogrel 75 mg 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, i.e., either persistent AF or at least two episodes of paroxysmal AF within the preceding 6 months, and at least one of the following risk factors: age ≥75 years or age 55–74 years with diabetes mellitus requiring medication, documented prior 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 <50×10^9/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 VKAs due to physician judgment, 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 of 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 who reached the primary endpoint (time to first occurrence of stroke, MI, systemic embolism without CNS involvement, or death from any cause) 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), 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 congenital cyanotic 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), in addition to standard background therapy, until the second surgical stage. 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 before day 120 due to a thrombosis-related event—occurring in 89 [19.1%] in the clopidogrel group and 90 [20.5%] in the placebo group (see section "Dosage and administration"). The most common adverse reaction in both the clopidogrel and placebo groups was bleeding, but no significant differences in bleeding frequency were observed between groups. During the subsequent long-term safety follow-up period, 26 patients with a patent shunt at 1 year of age continued clopidogrel until 18 months of age. The safety profile of the drug did not change during this observation period.

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

Pharmacokinetics.

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

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

Metabolism. Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, two major metabolic pathways exist: one involving esterases leading to hydrolysis and formation of an inactive carboxylic acid derivative (accounting for 85% of circulating metabolites), 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 the formation of a thiol derivative—the active metabolite. This active metabolite is formed predominantly by 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 that observed after 4 days of 75 mg maintenance dosing. Cmax is reached approximately 30–60 minutes after administration.

Elimination. Within 120 hours after oral administration of radiolabeled \14\C-clopidogrel in humans, approximately 50% of the dose was excreted in urine and about 46% in feces. After a single 75 mg oral dose, the elimination half-life of clopidogrel is approximately 6 hours. The elimination half-life of the main circulating (inactive) 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 CYP2C19 genotype.

The CYP2C19*1 allele corresponds to fully functional metabolism, while the CYP2C19*2 and CYP2C19*3 alleles correspond to non-functional metabolism. CYP2C19*2 and CYP2C19*3 alleles constitute the majority of non-functional alleles in Caucasian (85%) and Mongoloid (99%) populations with reduced metabolism. Other alleles associated with absent or diminished metabolism are less common and include CYP2C19*4, *5, *6, *7, and *8. A patient with reduced metabolism has two non-functional alleles as defined above. According to published data, CYP2C19 genotypes associated with reduced metabolism occur in 2% of Caucasians, 4% of African Americans, 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), 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 plasma concentrations of the active metabolite or mean platelet aggregation inhibition (PAI) were observed between ultrarapid, extensive, and intermediate metabolizers. In poor metabolizers, plasma concentrations of the active metabolite were reduced by 63–71% compared to extensive metabolizers. After administration of the 300 mg/75 mg regimen, antiplatelet effects in poor metabolizers were less pronounced, with mean PAI (5 µM ADP) of 24% (24 hours) and 37% (day 5), compared to 39% (24 hours) and 58% (day 5) in extensive metabolizers and 37% (24 hours) and 60% (day 5) in intermediate metabolizers. When poor metabolizers received the 600 mg/150 mg regimen, plasma concentrations of the active metabolite were higher than with the 300 mg/75 mg regimen. Furthermore, PAI values were 32% (24 hours) and 61% (day 5), which were higher than in poor metabolizers receiving 300 mg/75 mg and similar to values observed in other metabolizer groups receiving the 300 mg/75 mg regimen. Based on clinical effect studies, the appropriate dosing regimen for this patient group has not been established.

Consistent with the above findings, in a meta-analysis of 6 steady-state studies involving 335 patients receiving 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 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 who had genotyping results available: 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, myocardial infarction, stroke) or stent thrombosis compared to extensive metabolizers.

In the CHARISMA analysis and one cohort study (Simon), poor metabolizers showed an increased event rate compared to extensive metabolizers.

In analyses of CURE, CLARITY, ACTIVE-A, and one cohort study (Trenk), the incidence of cardiovascular events did not significantly differ by metabolizer 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 special patient populations listed below.

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

Hepatic impairment. After repeated administration of 75 mg clopidogrel daily for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was 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 race patients to assess the clinical significance of genotyping for this CYP.

Preclinical safety data. The most commonly observed adverse effects in preclinical animal studies were liver-related changes. These occurred at doses leading to blood clopidogrel 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/day (approximately 25 times the human exposure at the clinical dose of 75 mg daily).

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

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

Clinical characteristics.

Indications.

Secondary prevention of atherothrombotic events in adults:

• patients who have experienced myocardial infarction (treatment initiation – within a few days, but no later than 35 days after onset), ischemic stroke (treatment initiation – within 7 days, but no later than 6 months after onset), or who have been diagnosed with peripheral arterial disease;
• patients with acute coronary syndrome:
  • acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), including patients who have undergone percutaneous coronary intervention with stent placement, in combination with acetylsalicylic acid (ASA);
  • acute myocardial infarction with ST-segment elevation, in combination with ASA (in patients receiving standard medical therapy and for whom thrombolytic therapy is indicated).

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

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

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

2 National Institutes of Health Stroke Scale.

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation.

Clopidogrel in combination with ASA is indicated in adult patients with atrial fibrillation who have at least one risk factor for vascular events, for 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 bleeding (including peptic ulcer or intracranial hemorrhage).

Interaction with other medicinal products and other forms of interaction.

Medicinal products associated with bleeding risk: there is an increased risk of bleeding due to a potential additive effect. Concomitant use of medicinal products associated with bleeding risk should be performed with caution (see section "Special warnings and precautions for use").

Oral anticoagulants: concomitant use of clopidogrel with oral anticoagulants, including warfarin, 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 at a dose of 75 mg/day does not alter the pharmacokinetics of S-warfarin or the international normalized ratio (INR), concomitant use of clopidogrel and warfarin in patients on long-term warfarin therapy increases the risk of bleeding due to independent effects on hemostasis.

Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients at increased risk of bleeding due to trauma, surgery, or other pathological conditions when glycoprotein IIb/IIIa inhibitors are used concomitantly (see section "Special warnings and precautions for use").

Acetylsalicylic acid (ASA): ASA does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but clopidogrel enhances the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg ASA twice daily for one day did not significantly increase bleeding time prolonged by clopidogrel. Since pharmacodynamic interaction between clopidogrel and ASA may increase the risk of bleeding, concomitant use of these agents requires caution (see section "Special warnings and precautions for use"). However, there is experience with concomitant use of clopidogrel and ASA for up to one year (see section "Pharmacological properties").

Heparin: in a study of clopidogrel in healthy volunteers, administration of clopidogrel did not require dose adjustment of heparin and did not alter the effect of heparin 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 increased bleeding risk 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, fibrin-specific or non-fibrin-specific thrombolytic agents, and heparin was evaluated in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed with concomitant use of thrombolytic agents and heparin with ASA (see section "Adverse reactions").

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

Selective serotonin reuptake inhibitors (SSRIs): since SSRIs affect platelet activation and increase the risk of bleeding, caution is required when SSRIs are used concomitantly with clopidogrel.

Other concomitant therapies.

Inducers of CYP2C19: since clopidogrel is metabolized to its active metabolite partly via CYP2C19, it is expected that use of medicinal products inducing the activity of this enzyme will lead to increased plasma levels of the active metabolite of clopidogrel.

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

Inhibitors of CYP2C19: since clopidogrel is metabolized to its active metabolite partly via CYP2C19, it is expected that use of medicinal products inhibiting the activity of this enzyme will lead to decreased plasma concentrations of the active metabolite of clopidogrel. The clinical significance of this interaction is not established. As a precaution, concomitant use of strong or moderate CYP2C19 inhibitors should be avoided (see sections "Special warnings and precautions for use" and "Pharmacokinetics").

Examples of strong or moderate CYP2C19 inhibitors include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, efavirenz.

Proton pump inhibitors (PPIs): omeprazole at a dose of 80 mg once daily, when used concomitantly with clopidogrel or within 12 hours between doses of these two drugs, reduced the plasma concentration of the active metabolite by 45% (loading dose) and 40% (maintenance dose). This reduction was accompanied by a decrease in platelet aggregation inhibition by 39% (loading dose) and 21% (maintenance dose). The interaction between esomeprazole and clopidogrel is expected to be similar.

Observational and clinical studies have provided conflicting data regarding the clinical consequences of these pharmacokinetic (PK) and pharmacodynamic (PD) interactions in terms of the risk of serious 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 concentrations was observed with pantoprazole or lansoprazole.

With concomitant use of pantoprazole 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 mean platelet aggregation inhibition by 15% and 11%, respectively. These results suggest that concomitant use of clopidogrel and pantoprazole is possible.

There is no evidence that other acid-reducing agents, such as H2-receptor antagonists or antacids, affect the antiplatelet activity of clopidogrel.

Boosted antiretroviral therapy.

HIV-infected patients receiving boosted antiretroviral therapy (ART) have a high risk of vascular events. In HIV patients receiving ritonavir- or cobicistat-boosted ART, a significant reduction in the effect of the active metabolite of clopidogrel and a significant reduction in platelet aggregation inhibition were observed. Although the clinical significance of these findings is not established, spontaneous reports have been received of recurrent occlusive or thrombotic events in HIV-infected patients receiving ritonavir-boosted ART after revascularization procedures during clopidogrel loading. The effect of clopidogrel and mean platelet aggregation inhibition may be reduced when used concomitantly with ritonavir. Therefore, concomitant use of clopidogrel with boosted ART should be avoided.

Combination with other medicinal products: several studies have been conducted with clopidogrel and other drugs to investigate potential pharmacodynamic and pharmacokinetic interactions. When clopidogrel was used concomitantly with:

• atenolol, nifedipine, or both drugs simultaneously, no clinically significant pharmacodynamic interaction was observed;
• phenobarbital, cimetidine, and estrogens, no significant effect on the pharmacodynamics of clopidogrel was observed;
• digoxin or theophylline: pharmacokinetic parameters were not altered;
• antacid agents: no effect on clopidogrel absorption was observed;
• phenytoin, tolbutamide: results from the CAPRIE study indicate that phenytoin and tolbutamide, which are metabolized via the CYP2C9 enzyme, can be safely used concomitantly with clopidogrel;

Substrates of CYP2C8: clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies showed that 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 metabolism (e.g., repaglinide, paclitaxel) should be performed with caution (see section "Special warnings and precautions for use").

Except for studies on interactions with specific medicinal products mentioned above, no interaction studies have been conducted between clopidogrel and drugs commonly prescribed to patients with atherothrombosis. However, patients in clinical trials with clopidogrel used various concomitant medications, including diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, calcium antagonists, cholesterol-lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic drugs, hormone replacement therapy, and GPIIb/IIIa antagonists, without evidence of clinically significant interactions.

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

Rosuvastatin: it has been shown that in patients, administration of clopidogrel 300 mg increases rosuvastatin exposure by 2-fold (AUC) and 1.3-fold (Cmax), and after repeated administration of 75 mg clopidogrel, by 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 complete blood count and/or other appropriate tests should be performed immediately whenever symptoms suggesting possible bleeding occur during treatment with the drug (see section "Adverse reactions"). As with other antiplatelet agents, clopidogrel should be used with caution in patients with an increased risk of bleeding due to trauma, surgical procedures, or other pathological conditions, and in patients receiving treatment with aspirin (ASA), heparin, glycoprotein IIb/IIIa inhibitors, NSAIDs including COX-2 inhibitors, SSRIs, or potent inducers of CYP2C19, or other drugs associated with a risk of bleeding such as pentoxifylline (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 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 any signs of bleeding, including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiovascular procedures or surgical interventions. 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").

If surgery is planned and the antithrombotic effect is temporarily undesirable, clopidogrel treatment should be discontinued 7 days prior to the operation. Patients should inform physicians and dentists that they are taking clopidogrel before being prescribed any surgery or any new medication.

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 last longer than usual, and they should report any episodes of 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 acute coronary syndrome without ST-segment elevation and aged ≥ 75 years due to an increased risk of bleeding in this population.

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

Thrombotic thrombocytopenic purpura (TTP).

Very rare cases of TTP have been reported after clopidogrel use, sometimes even after short-term administration. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia, neurological symptoms, renal dysfunction, or fever. TTP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

Acquired hemophilia.

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

Recent ischemic stroke.

• Initiation of therapy.
  • 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 symptom onset.
  • There are no data on the benefit-risk ratio of short-term dual antiplatelet therapy in patients with acute minor ischemic stroke or moderate- to high-risk TIA who have a history of (non-traumatic) intracranial hemorrhage.
  • In patients with non-minor ischemic stroke, monotherapy with clopidogrel should be initiated only 7 days after the event.
• Patients with non-minor ischemic stroke (NIHSS > 4).

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

• Recent minor ischemic stroke or moderate- to high-risk TIA in patients for whom intervention is indicated or planned.

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

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. Furthermore, they experience significantly more cardiovascular complications after myocardial infarction compared to patients with normal CYP2C19 function. CYP2C19 genotyping tests are currently available.

Since clopidogrel is partially metabolized to its active metabolite via CYP2C19, concomitant use of drugs that reduce the activity of this enzyme will most likely result in decreased plasma concentrations of the active metabolite of clopidogrel. The clinical significance of this interaction has not been fully established; therefore, concomitant use of potent or moderate inhibitors of CYP2C19 should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

It is expected that drugs inducing CYP2C19 activity will increase plasma levels 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").

CYP2C8 substrates.

Caution should be exercised when administering clopidogrel concomitantly with medicinal products that are substrates of CYP2C8 (see section "Interaction with other medicinal products and other forms of interaction").

Cross-reactivity among thienopyridines.

Patients should be questioned about a history of hypersensitivity to thienopyridines (such as clopidogrel, ticlopidine, prasugrel), as reports of cross-allergy between thienopyridines have been documented (see section "Adverse reactions"). Use of thienopyridines may lead to allergic reactions ranging from mild to severe, such as rash, angioedema, and/or hematological reactions such as thrombocytopenia and neutropenia. Patients with a history of allergic and/or hematological reactions to one thienopyridine have an increased risk of developing similar or other reactions to other thienopyridines. Monitoring for signs of hypersensitivity is recommended in patients with known allergy to thienopyridines.

Renal function impairment.

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

Hepatic function impairment.

Experience with the use of the drug in patients with moderate liver disease, which may be associated with a hemorrhagic diathesis, is limited. Therefore, clopidogrel should be used with caution in such patients (see section "Posology and method of administration").

Excipients.

The medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

The product contains hydrogenated castor oil, which may cause gastrointestinal upset and diarrhea.

If a patient misses a dose of the drug and less than 12 hours have passed since the scheduled dose, the missed dose should be taken as soon as possible, and the next dose should be taken at the usual time. If more than 12 hours have passed, the missed dose should be skipped and the next dose taken at the usual time. Double dosing is not allowed.

Alcohol should not be consumed during treatment with the drug due to an increased risk of gastrointestinal bleeding.

Special precautions for disposal of unused medicine and 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 the 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 adverse effects on pregnancy, embryonic/fetal development, delivery, or postnatal development.

Breastfeeding. It is unknown whether clopidogrel is excreted in human breast milk; therefore, breastfeeding should be discontinued during treatment with this drug.

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

Ability to influence reaction speed when driving or operating machinery.

The medicinal product has no effect or has a negligible effect on the ability to drive or operate machinery (see section "Adverse reactions").

Method of Administration and Dosage

Adults and elderly patients. The drug should be administered at a dose of 1 tablet (75 mg) once daily, independently of food intake.

For patients with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), clopidogrel therapy should be initiated with a single loading dose of 300 mg or 600 mg. A loading dose of 600 mg may be used in patients under 75 years of age when percutaneous coronary intervention is required (see section "Special Warnings and Precautions for Use"). Clopidogrel treatment should then continue at a dose of 75 mg once daily (in combination with acetylsalicylic acid (ASA) at a dose of 75–325 mg daily). Since higher doses of ASA increase the risk of bleeding, it is recommended not to exceed an ASA dose of 100 mg. The optimal duration of treatment has not been formally established. Study results support treatment for up to 12 months, with maximum benefit observed after 3 months of therapy (see section "Pharmacological Properties").

For patients with acute ST-segment elevation myocardial infarction, clopidogrel should be administered at 75 mg once daily, starting with a single 300 mg loading dose, in combination with ASA, with or without thrombolytic agents. In patients aged 75 years and older, clopidogrel therapy should be initiated without a loading dose. Combination therapy should be started as early as possible after symptom onset and continued for at least 4 weeks. The benefit of using clopidogrel in combination with ASA beyond 4 weeks in this condition has not been studied (see section "Pharmacological Properties").

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

Adult patients with moderate to high-risk TIA (ABCD2 score ≥ 4) or minor ischemic stroke (NIHSS score ≤ 3) should receive a clopidogrel loading dose of 300 mg, followed by continuation of 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.

For patients with atrial fibrillation, clopidogrel should be administered at a daily dose of 75 mg. ASA (75–100 mg daily) should be initiated together with clopidogrel and continued.

In case of a missed dose:

• If less than 12 hours have passed since the scheduled dose time, the patient should take the missed dose immediately, and the next dose should be taken at the usual time;
• If more than 12 hours have passed, the patient should take the next dose at the usual time and should not double the dose to compensate for the missed dose.

Pharmacogenetics. The prevalence of CYP2C19 alleles associated with intermediate and reduced CYP2C19 metabolic activity varies depending on race/ethnicity. The optimal dosing regimen in individuals with reduced CYP2C19 metabolism has not yet been established.

Renal impairment. Therapeutic experience with the use of the drug in patients with renal impairment is limited (see section "Special Warnings and Precautions for Use").

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

Children.

Safety and efficacy of clopidogrel in children (under 18 years of age) have not been established; therefore, the drug should not be used in pediatric patients (see section "Pharmacological Properties").

Overdose.

Symptoms: prolonged bleeding time with subsequent hemorrhagic complications.

Treatment: symptomatic. There is no specific antidote. If immediate correction of prolonged bleeding time is required, the effects of clopidogrel can be reversed by transfusion of platelet concentrate.

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 trial showed that the safety profile of clopidogrel 75 mg once daily was generally comparable to that of acetylsalicylic acid (ASA) 325 mg once daily, regardless of patient age, gender, or race.

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

Bleeding was the most commonly reported adverse reaction observed both in clinical trials and in the post-marketing period, 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, there was no increase in the frequency of major bleeding events with clopidogrel + ASA combination therapy during the 7 days following coronary artery bypass graft (CABG) surgery in patients who discontinued treatment more than 5 days prior to surgery. In patients who continued treatment up to 5 days before CABG surgery, the incidence of this event was 9.6% in the clopidogrel + ASA group and 6.3% in the placebo + ASA group.

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

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

In the ACTIVE-A study, the incidence of major bleeding was higher in the clopidogrel + ASA group compared to the placebo + ASA group (6.7% vs. 4.3%). In both groups, major bleeding events were predominantly extracranial (5.3% in the clopidogrel + ASA group, 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%). 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) 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).

Adverse reactions observed during clinical trials or during clinical use of the drug based on spontaneous reporting are listed in the table below. Adverse reactions are categorized by System Organ Class, and their frequency is defined as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), 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: thrombotic thrombocytopenic purpura (TTP) (see section "Special warnings and precautions for use"), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anemia, acquired hemophilia A.

Cardiac disorders.

Frequency not known: Kounis syndrome (vasospastic allergic angina/allergic myocardial infarction) in the context of hypersensitivity reaction to clopidogrel.

Immune system disorders.

Very rare: serum sickness-like reactions, anaphylactoid/anaphylactic reactions.

Frequency not known: cross-sensitivity between thienopyridines (e.g., ticlopidine, prasugrel) (see section "Special warnings and precautions for use"); insulin autoimmune syndrome that may lead to severe hypoglycemia, particularly in patients with HLA DRB4 subtype (more common in Japanese population).

Psychiatric disorders.

Very rare: hallucinations, confusion.

Nervous system disorders.

Uncommon: intracranial hemorrhage (in some cases fatal), headache, paresthesia, dizziness.

Very rare: taste disturbance, ageusia.

Eye disorders.

Uncommon: ocular bleeding (conjunctival, ocular, retinal).

Ear and labyrinth disorders.

Rare: vertigo.

Vascular disorders.

Common: hematoma.

Very rare: severe bleeding, surgical wound bleeding, vasculitis, arterial hypotension.

Respiratory, thoracic and mediastinal disorders.

Common: epistaxis.

Very rare: bleeding of respiratory tract (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonia, 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: gastrointestinal and retroperitoneal hemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis.

Hepatobiliary disorders.

Very rare: acute liver failure, hepatitis, abnormal liver function test results.

Skin and subcutaneous tissue disorders.

Common: subcutaneous hemorrhage.

Uncommon: rash, pruritus, purpura.

Very rare: bullous dermatoses (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, acute generalized exanthematous pustulosis (AGEP)), angioedema, erythematous or exfoliative rash, urticaria, drug hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), eczema, lichen planus.

Reproductive system and breast disorders.

Rare: gynecomastia.

Musculoskeletal and connective tissue disorders.

Very rare: musculoskeletal hemorrhage (hemarthrosis), arthritis, arthralgia, myalgia.

Renal and urinary disorders.

Uncommon: hematuria.

Very rare: glomerulonephritis, increased blood creatinine levels.

General disorders.

Common: puncture site bleeding.

Very rare: fever.

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 pharmacists, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

10 tablets per blister; 1, 3 or 6 blisters per carton.

Prescription category. Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Borshchahivskiy Chemical and Pharmaceutical Plant".

Manufacturer's address and place of business.

17 Myru Street, Kyiv, 03134, Ukraine.