Thrombonet®-farmak

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TROMBONET®-FARMAK (TROMBONET-FARMAK)

Composition:

Active substance: clopidogrel bisulfate (clopidogrel hydrogen sulfate);

1 tablet contains 97.875 mg of clopidogrel bisulfate (clopidogrel hydrogen sulfate), equivalent to 75 mg of clopidogrel;

Excipients: mannitol (E 421), microcrystalline cellulose, low-substituted hydroxypropylcellulose, hydrogenated castor oil, polyethylene glycol, Opadry II 85F 240069 Pink (polyvinyl alcohol, titanium dioxide (E 171), talc, iron oxide red (E 172), iron oxide yellow (E 172), polyethylene glycol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex tablets, film-coated, ranging in color from pink to dark pink.

Pharmacotherapeutic group. Antiplatelet agents, excluding heparin.

ATC code B01A C04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Clopidogrel is a prodrug. One of the metabolites of clopidogrel is an inhibitor of platelet aggregation. To form the active metabolite that inhibits platelet aggregation, clopidogrel must be biotransformed 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 is restored at a rate corresponding to platelet turnover. Platelet aggregation induced by other agonists besides ADP is also inhibited due to the drug blocking platelet activation by released ADD.

Since the active metabolite is formed via cytochrome CYP450 enzymes, some of which are polymorphic or inhibited by other medicinal products, not all patients achieve sufficient inhibition of platelet aggregation.

Pharmacodynamic effects. With repeated daily doses of 75 mg, a significant reduction in ADP-induced platelet aggregation is observed from the first day of treatment. 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 seven 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 comparing clopidogrel with placebo, both in combination with ASA and other standard therapy.

Myocardial infarction (MI), recent stroke, or established peripheral arterial disease. The CAPRIE study included patients with atherothrombosis, manifested by recent MI (<35 days prior), recent ischemic stroke (7 days to 6 months prior), or established peripheral arterial disease (PAD). Patients were randomized to receive clopidogrel 75 mg/day or ASA 325 mg/day and were followed for 1 to 3 years. In the MI subgroup, most patients received ASA in the first few days following the event.

Clopidogrel significantly reduced the incidence of new ischemic events (composite endpoint consisting of MI, ischemic stroke, and cardiovascular death) compared to ASA. Analysis of overall mortality as a secondary endpoint showed no significant differences between clopidogrel therapy (5.8%) and ASA (6%).

Subgroup analysis by underlying disease (MI, ischemic stroke, and PAD) showed the greatest effect in patients with PAD, especially those with prior MI, and a smaller effect (not significantly different from ASA) in patients with stroke. In patients recently suffering MI included in the study, the effect of clopidogrel was numerically lower but not statistically different from ASA. Furthermore, subgroup analysis by age indicates that the beneficial effect of clopidogrel in patients aged 75 years and older was lower than in patients ≤75 years.

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

Acute coronary syndrome. The CURE study included patients with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave MI), who experienced chest pain or ischemic symptoms within the last 24 hours. Patients had ECG changes indicating new ischemia or elevated cardiac enzyme activity or troponin I or T at least twice the upper normal limit. Patients were randomized to receive clopidogrel (loading dose 300 mg, then 75 mg/day) or placebo, 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, 6.6% of patients also received concomitant therapy with a GPIIb/IIIa glycoprotein receptor antagonist. More than 90% of patients received heparins. This concomitant therapy did not significantly affect the relative frequency of bleeding events with clopidogrel versus placebo. The number of patients reaching the primary endpoint [cardiovascular death (CVD), MI, or stroke] was 9.3% in the clopidogrel group and 11.4% in the placebo group. Relative risk reduction was 20% 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 relative risk reductions of 22%, 32%, 4%, 6%, and 14% during months 0–1, 1–3, 3–6, 6–9, and 9–12 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 and GPIIb/IIIa glycoprotein receptor inhibitors.

The number of patients reaching the combined primary endpoint (CVD, MI, stroke, or refractory ischemia) was 16.5% in the clopidogrel group and 18.8% in the placebo group. Relative risk reduction was 14% in the clopidogrel group. This effect was primarily due to a statistically significant reduction in the incidence of MI (4.6% in the clopidogrel group and 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. Specifically, a subgroup analysis of patients (17% of the total CURE group) who received stents (PCI-CURE) showed that clopidogrel treatment, compared to placebo, resulted in a significant relative risk reduction (RRI) of 26.2%, favoring clopidogrel in preventing the primary endpoint (CVD, MI, stroke), as well as a significant RRI of 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 findings.

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

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 patients who had experienced MI with ST-segment elevation within the last 12 hours and were scheduled for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose, then 75 mg/day) or placebo, both in combination with ASA (loading dose 150–325 mg, then 75–162 mg/day), a fibrinolytic agent, and, if necessary, heparin. Follow-up lasted 30 days. The primary endpoint was occlusion of the infarct-related artery, as detected on angiography before discharge, death, or recurrent MI before coronary angiography. For patients not undergoing angiography, the primary endpoint was death or recurrent MI by day 8 or discharge. The patient group included 19.7% women, 29.2% patients ≥65 years. Overall, 99.7% of patients received fibrinolytics (fibrin-specific 68.7%, non-fibrin-specific 31.1%), 89.5% heparin, 78.7% beta-blockers, 54.7% ACE inhibitors, and 63% statins.

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

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

Clopidogrel significantly reduced the relative risk of all-cause mortality by 7% and the relative risk of the combination of recurrent MI, stroke, or death by 9%, with absolute reductions of 0.5% and 0.9%, respectively. This effect was observed in patients of different ages and sexes, regardless of fibrinolytic use, and occurred within the first 24 hours.

Atrial fibrillation. The ACTIVE-W and ACTIVE-A studies, separate studies within the ACTIVE program, included patients with atrial fibrillation (AF) who had at least one risk factor for vascular events. 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 receive this treatment.

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

The ACTIVE-A study was a multicenter, randomized, double-blind, placebo-controlled study comparing clopidogrel 75 mg daily + ASA with placebo + ASA. The recommended ASA dose was 75 to 100 mg daily. Patients were treated for up to 5 years.

Patients randomized in the ACTIVE program had documented AF, i.e., permanent AF or at least two episodes of paroxysmal AF within the last 6 months, and at least one of the following risk factors: age ≥75 years or age 55–74 years and/or diabetes requiring medication, documented prior MI, documented ischemic heart disease; previous 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).

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

73% of patients included in the ACTIVE-A study could not receive VKA 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; 26% of patients were excluded based on physician judgment due to patient unwillingness to receive VKA.

41.8% of patients were women. The mean age was 71 years, 41.6% of patients were aged ≥75 years. Overall, 23% of patients received antiarrhythmics, 52.1% beta-blockers, 54.6% angiotensin-converting enzyme inhibitors, and 25.4% statins.

The number of patients reaching the primary endpoint (time to first occurrence of stroke, MI, systemic embolism without CNS involvement, or death) was 22.1% in the clopidogrel + ASA group and 24.4% in the placebo + ASA group (relative risk reduction of 11.1%), primarily due to a significant reduction in stroke incidence. Strokes occurred in 7.8% of patients receiving clopidogrel + ASA and in 10.8% of patients receiving placebo + ASA (relative risk reduction of 28.4%).

Children. In a dose-escalation study involving newborns or infants up to 24 months of age at risk of thrombosis (PICOLO), clopidogrel was administered at sequential doses of 0.01, 0.1, and 0.2 mg/kg to newborns and infants, and at 0.15 mg/kg to newborns 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 in adults receiving clopidogrel 75 mg daily.

In a randomized, double-blind, parallel-group study (CLARINET) involving children (newborns and infants) with cyanotic congenital heart defects who underwent palliative surgery creating a systemic-to-pulmonary arterial shunt, patients were randomized to receive clopidogrel 0.2 mg/kg or placebo, along with concomitant background therapy, until the second surgical stage. The mean time between shunt creation surgery and first study drug administration was 20 days. Approximately 88% of patients simultaneously received ASA (1–23 mg/kg/day). No significant differences between groups were observed regarding achievement of the primary combined endpoint, consisting of death, shunt thrombosis, or surgical intervention due to thrombosis by day 120 of life, which was 19.1% in the clopidogrel group and 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 follow-up period for adverse events, 26 patients with a functioning shunt at age one year received clopidogrel until age 18 months. During this observation period, the safety profile of the drug did not change.

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

Pharmacokinetics.

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

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

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

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

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

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

The CYP2C19*1 allele corresponds to fully functional metabolism, while the CYP2C19*2 and CYP2C19*3 alleles correspond to non-functional metabolism. CYP2C19*2 and CYP2C19*3 alleles constitute the majority of alleles in Caucasian (85%) and Mongoloid (99%) populations with reduced metabolism. Other alleles associated with absent or reduced metabolism are less common and include CYP2C19*4, *5, *6, *7, and *8. A patient with reduced metabolism has two non-functional alleles as described above. According to published data, CYP2C19 genotypes corresponding to reduced metabolism occur in 2% of Caucasian populations, 4% of Negroid populations, and 14% of Chinese nationals. Tests are currently available to determine the CYP2C19 genotype.

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

Similarly, in a meta-analysis of 6 studies considering steady-state levels in patients receiving clopidogrel, blood concentration of the active metabolite decreased by 28% in individuals with intermediate metabolism and by 72% in those with reduced metabolism; platelet aggregation inhibition (5 μM ADP) also decreased, with PAI differences of 5.9% and 21.4%, respectively, compared to individuals with extensive metabolism.

The impact of CYP2C19 genotype on clinical outcomes in patients receiving clopidogrel has not been studied in prospective randomized controlled trials. However, several retrospective analyses have been conducted to assess this effect in patients receiving clopidogrel with available genotyping results: CURE, CLARITY-TIMI 28, TRITON-TIMI 38, and ACTIVE-A. Additionally, results from several published cohort studies are available.

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

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

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

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

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

Renal impairment. After regular 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 the same effect in healthy volunteers, and bleeding time was prolonged almost as much as in healthy volunteers receiving 75 mg clopidogrel daily. Clinical tolerability was good in all patients.

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

Racial origin. The prevalence of CYP2C19 alleles causing intermediate and poor metabolic activity of CYP2C19 varies by racial/ethnic origin (see section "Pharmacogenetics"). Limited data are available for Mongoloid populations to assess the clinical significance of genotyping this CYP.

Preclinical safety data. The most commonly observed adverse effects during preclinical animal studies were liver changes. These occurred with doses nearly 25 times higher than the therapeutic dose of 75 mg clopidogrel daily in humans and were due to the drug's effect on enzymes involved in hepatic metabolism. With therapeutic doses of clopidogrel in humans, no effect on enzymes involved in hepatic metabolism was observed.

Poor gastrointestinal tolerability of the drug (gastritis, erosive gastric lesions, and/or vomiting) was observed in animals given high doses of clopidogrel.

No evidence of carcinogenicity was obtained in mice treated with clopidogrel for 78 weeks and in rats for 104 weeks at doses up to 77 mg/kg daily (nearly 25 times the therapeutic dose of 75 mg clopidogrel daily in humans).

A series of genotoxicity studies of clopidogrel in vitro and in vivo were conducted, but no genotoxic effects were detected.

Clopidogrel did not affect reproductive function in male and female rats and had no teratogenic effects in rats or rabbits. Administration to lactating female rats resulted in slight developmental delay in offspring. Specific pharmacokinetic studies with radiolabeled clopidogrel demonstrated that the parent substance and its metabolites penetrate into breast milk. Therefore, both direct (slight toxic effect) and indirect (due to deterioration of milk taste) effects on offspring cannot be excluded.

Clinical characteristics.

Indications.

Secondary prevention of atherothrombotic events in adults:

• patients who have had myocardial infarction (treatment initiation – within a few days, but no later than 35 days after onset), ischaemic stroke (treatment initiation – within 7 days, but no later than 6 months after onset), or diagnosed 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 ST-segment elevation myocardial infarction, in combination with acetylsalicylic acid (in patients receiving standard medical therapy and for whom thrombolytic therapy is indicated).

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

Clopidogrel in combination with ASA is indicated for adult patients with TIA of moderate or high risk (ABCD2 score ≥ 4) or minor ischaemic 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 for 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 component of the medicinal product. Severe hepatic impairment. Active bleeding (e.g. peptic ulcer or intracranial haemorrhage).

Interaction with other medicinal products and other forms of interaction.

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

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

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

ACETYLSALICYLIC ACID (ASA). Acetylsalicylic acid does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but clopidogrel enhances the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg ASA twice daily for one day did not cause a significant increase in bleeding time prolonged by clopidogrel. Since a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid with an increased risk of bleeding is possible, concomitant use of these agents requires caution (see section "Special precautions for use"). Despite this, clopidogrel and ASA have been used concomitantly for up to 1 year (see section "Pharmacological properties").

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

THROMBOLYTIC AGENTS. The safety of concomitant use of clopidogrel with fibrin-specific or non-fibrin-specific thrombolytic agents and heparins was evaluated in patients with acute MI. 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 clinical study involving healthy volunteers, concomitant use of clopidogrel and naproxen increased the number of occult gastrointestinal bleeding episodes. However, due to the lack of interaction studies with other NSAIDs, it is not yet established whether the risk of gastrointestinal bleeding increases with all NSAIDs. Therefore, caution is required when using NSAIDs, particularly COX-2 inhibitors, concomitantly with clopidogrel (see section "Special precautions for use").

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs). Concomitant use of SSRIs with clopidogrel should be done with caution due to the effect of SSRIs on platelet activation and increased risk of bleeding.

CONCOMITANT USE OF OTHER MEDICINAL PRODUCTS.

INDUCERS OF CYP2C19

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

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

INHIBITORS OF CYP2C19

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

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

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

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

A less pronounced reduction in metabolite plasma concentration was observed with pantoprazole or lansoprazole.

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

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

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

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

COMBINATION WITH OTHER MEDICINAL PRODUCTS. A number of clinical studies have been conducted with clopidogrel and other medicinal products to investigate potential pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interaction was observed when clopidogrel was used concomitantly with atenolol, nifedipine, or both. In addition, the pharmacodynamic activity of clopidogrel remained virtually unchanged when used concomitantly with phenobarbital and estrogen.

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

ANTACIDS did not affect the absorption of clopidogrel.

Data from human liver microsome studies indicate that the carboxylic acid metabolites of clopidogrel may inhibit the activity of cytochrome P450 2C9. This could potentially increase plasma levels of medicinal products such as phenytoin and tolbutamide, and NSAIDs, which are metabolized by cytochrome P450 2C9. Despite this, results from the CAPRIE study indicate that phenytoin and tolbutamide can be safely used concomitantly with clopidogrel.

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

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

As with other oral P2Y12 inhibitors, concomitant use of opioid agonists may potentially delay and reduce the absorption of clopidogrel, likely due to delayed 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. After administration of clopidogrel 300 mg, exposure to rosuvastatin was found to increase two-fold (AUC) and 1.3-fold (Cmax). After repeated administration of clopidogrel 75 mg, exposure to rosuvastatin increased 1.4-fold (AUC) without affecting Cmax.

Special precautions for use.

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

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

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

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

Thrombotic thrombocytopenic purpura (TTP). TTP has been reported very rarely following clopidogrel use, sometimes even after short-term 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 may be fatal and requires immediate treatment, including plasma exchange.

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

Recent ischemic stroke.

Initiation of treatment

• In patients with acute minor ischemic stroke or moderate- to high-risk TIA, dual antiplatelet therapy (clopidogrel and ASA) should be initiated 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 score > 4).

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

Patients with recent minor ischemic stroke or moderate- to high-risk TIA who are scheduled for or have undergone interventional procedures.

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

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

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

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

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

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

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

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

One tablet of Trombonet®-Farmak contains 3.3 mg of hydrogenated castor oil, which may cause gastrointestinal discomfort and diarrhea.

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

Use during pregnancy or breastfeeding.

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

Animal studies did not reveal any direct or indirect adverse effects on pregnancy, embryonic/fetal development, parturition, or postnatal development (see subsection "Preclinical safety data").

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

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Adults, including elderly patients. Take Thrombocyte®-Pharmak 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 treatment should be initiated with a single loading dose of 300 mg or 600 mg. A 600 mg loading dose may be used in patients under 75 years of age when percutaneous coronary intervention is required (see section "Special Instructions"). Clopidogrel treatment should be continued at a dose of 75 mg once daily (in combination with acetylsalicylic acid (ASA) at a dose of 75–325 mg daily). Since higher ASA doses increase the risk of bleeding, it is recommended not to exceed an acetylsalicylic acid dose of 100 mg. The optimal duration of treatment has not been formally established. Clinical trial data support treatment duration up to 12 months, with maximum effect observed after 3 months of therapy (see section "Pharmacological Properties").

Patients with acute myocardial infarction with ST-segment elevation should receive clopidogrel 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. Combined 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 300 mg loading dose of clopidogrel, followed by continuation of therapy with 75 mg clopidogrel once daily and ASA 75–100 mg once daily. Clopidogrel and ASA therapy should be initiated within 24 hours of the event and continued for 21 days, followed by antiplatelet monotherapy.

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

In case of a missed dose:

• If less than 12 hours have passed since the scheduled dose was due: 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 scheduled dose at the usual time and should not double the dose to compensate for the missed dose.

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

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

Children.

Clopidogrel should not be used in children, as there are no data on efficacy in this patient age group (see section "Pharmacodynamics").

Overdose.

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

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

Adverse reactions.

Short description of safety profile.

The safety of clopidogrel has been evaluated in more than 44,000 patients who participated in clinical studies (including over 12,000 patients with treatment duration of 1 year or longer). Clinically significant adverse effects observed in the CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE-A studies are described below. In the CAPRIE study, the effect of clopidogrel at a dose of 75 mg once daily was generally comparable to that of acetylsalicylic acid (ASA) at a dose of 325 mg once daily, regardless of patient age, gender, or race.

In addition to data from clinical trials, adverse reactions reported during post-marketing use of the drug were also considered.

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

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

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

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

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

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

In the TARDIS study, patients with recent ischemic stroke receiving intensive triple antiplatelet therapy (ASA + clopidogrel + dipyridamole) had higher rates of any bleeding and major bleeding compared to those receiving monotherapy with clopidogrel or dual therapy with ASA + dipyridamole (adjusted hazard ratio 2.54, 95% CI 2.05–3.16, p<0.0001).

List of adverse reactions in table format.

Adverse effects observed during clinical studies or during clinical use of the medicinal product are listed in the table below. Adverse reactions are categorized by system organ class, and their frequency is defined as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and frequency not known. Within each organ system class, adverse effects are listed in order of decreasing severity.

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

Reporting of suspected adverse reactions.

Reporting of adverse reactions after marketing authorization of a medicinal product is of great importance. This enables continuous monitoring of the benefit/risk balance of the use of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

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

Keep out of reach and sight of children.

Packaging. 10 tablets per blister. 1, 3, 6, or 8 blisters per carton.

Prescription category. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.