ONECLAPZ

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ONECLAPZ (ONECLAPZ)

Composition:

Active substance: clopidogrel;

1 tablet contains clopidogrel bisulfate 97.875 mg (equivalent to clopidogrel) – 75 mg;

Excipients: microcrystalline cellulose, mannite (E 421), low-substituted hydroxypropylcellulose, crospovidone, polyethylene glycol 6000, hydrogenated castor oil, lactose monohydrate, hypromellose 15 cP, titanium dioxide (E 171), triacetin/glycerol triacetate, iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: pink-colored, round, biconvex film-coated tablets with beveled edges, embossed with "E" on one side and "34" on the other.

Pharmacotherapeutic group.
Antiplatelet agents, excluding heparin. ATC code B01AC04.

Pharmacological Properties

Pharmacodynamics.

Mechanism of action. Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its receptor on the platelet surface and the subsequent ADP-mediated activation of the GPIIb/IIIa complex, thereby suppressing platelet aggregation. A biotransformation of clopidogrel is required for the generation of active inhibition of platelet aggregation. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the amplification of platelet activation caused by released ADP. Clopidogrel irreversibly modifies ADP receptors on platelets. Therefore, platelets exposed to clopidogrel are affected for the remainder of their lifespan. Normal platelet function gradually returns at a rate consistent with platelet turnover.

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 values within an average of 5 days after discontinuation of treatment.

Pharmacokinetics.

Absorption. After oral administration of single and multiple daily doses of 75 mg, 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 within about 45 minutes after intake. 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 (which accounts for 85% of all circulating metabolites in plasma), and another involving cytochrome P450 enzyme system. Initially, clopidogrel is converted into an intermediate metabolite, 2-oxo-clopidogrel. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of a thiol derivative—the active metabolite. This active metabolite is formed predominantly by the CYP2C19 enzyme, with contributions from several other CYP enzymes, including CYP1A2, CYP2B6, and CYP3A4. The active metabolite of clopidogrel (thiol derivative), isolated in vitro, rapidly and irreversibly binds to platelet receptors, thereby preventing platelet aggregation.

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 approximately 6 hours. The elimination half-life of the main (inactive) circulating metabolite is 8 hours after both single and multiple dosing.

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

The CYP2C19*1 allele corresponds to fully functional metabolism, whereas the CYP2C19*2 and CYP2C19*3 alleles correspond to non-functional metabolism. The CYP2C19*2 and CYP2C19*3 alleles constitute the majority of alleles in Caucasian (85%) and Mongoloid (99%) patients with reduced metabolism. Other alleles associated with absent or diminished metabolism occur less frequently and include CYP2C19*4, *5, *6, *7, and *8. Patients with reduced metabolism have two non-functional alleles, as described above. According to published data, CYP2C19 genotypes associated with reduced metabolism occur in 2% of Caucasian populations, 4% of African-American patients, and 14% of Chinese patients. Currently, tests are available to determine CYP2C19 genotype.

In a crossover study involving 40 healthy volunteers (10 in each of four groups corresponding to a specific CYP2C19 metabolic phenotype: ultrarapid, extensive, intermediate, and poor), the pharmacokinetics and antiplatelet effects were evaluated after a 300 mg loading dose followed by 75 mg daily, and after a 600 mg loading dose followed by 150 mg daily. Each treatment regimen was administered for a total of 5 days (to reach steady state). No significant differences in plasma concentrations of the active metabolite or mean platelet aggregation inhibition (PAI) were observed between individuals with ultrarapid, extensive, and intermediate metabolism. In poor metabolizers, plasma concentrations of the active metabolite were reduced by 63–71% compared to extensive metabolizers. After the 300 mg/75 mg dosing regimen, antiplatelet effects in poor metabolizers were less pronounced, with mean PAI values (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 metabolic phenotype groups receiving the 300 mg/75 mg regimen. Based on clinical effect studies, an appropriate dosing regimen for this patient group has not yet been established.

Consistent with the above findings, a meta-analysis of 6 studies including steady-state data from 335 patients receiving clopidogrel demonstrated that plasma concentrations of the active metabolite were reduced by 28% in intermediate metabolizers and by 72% in poor metabolizers; platelet aggregation inhibition (5 µM ADP) was also reduced, with differences in PAI of 5.9% and 21.4%, respectively, compared 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 available genotyping data: CURE (n = 2721), CHARISMA (N = 2428), CLARITY-TIMI 28 (n = 227), TRITON-TIMI 38 (n = 1477), and ACTIVE-A (n = 601). Additionally, results from several published cohort studies are available.

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

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

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

None of these analyses included a sufficient number of patients to detect differences in clinical outcomes among 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 repeated daily administration of 75 mg clopidogrel 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 daily administration of 75 mg clopidogrel for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean prolongation of bleeding time was also comparable between both groups.

Racial considerations. The prevalence of CYP2C19 alleles associated with intermediate and poor 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.

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

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation.

Clopidogrel in combination with ASA is indicated in adult patients with atrial fibrillation who have at least one risk factor for vascular events, in whom vitamin K antagonist (VKA) therapy is contraindicated, and who have a low risk of bleeding, for the prevention of atherothrombotic and thromboembolic events, including stroke.

For additional information, see section "Pharmacological properties".

Contraindications.

Hypersensitivity to the active substance or to any component of the medicinal product. Severe hepatic impairment. Acute bleeding (e.g., peptic ulcer or intracranial hemorrhage). Hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

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

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

Glycoprotein IIb/IIIa 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 affect the inhibitory action of clopidogrel on ADP-induced platelet aggregation, whereas 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"). Nevertheless, clopidogrel and ASA have been used concomitantly for up to 1 year (see section "Pharmacological properties").

Heparin. Clinical study data in healthy volunteers indicate that clopidogrel does not require dose adjustment of heparin and does not alter heparin's effect on coagulation. Concomitant administration of heparan did not alter the inhibitory effect of clopidogrel on platelet aggregation. However, since a pharmacodynamic interaction between clopidogrel and heparin with an increased risk of bleeding is possible, concomitant use of these agents requires caution.

Thrombolytic agents. The safety of concomitant administration of clopidogrel with fibrin-specific or non-fibrin-specific thrombolytic agents and heparins has been 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 clinical study involving healthy volunteers, concomitant administration of clopidogrel and naproxen increased the number of occult gastrointestinal bleedings. However, due to the lack of studies on the interaction of the drug 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, as SSRIs affect platelet activation and increase the risk of bleeding.

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

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

Antiretroviral therapy

There are data on reduced effect of the active metabolite of clopidogrel and reduced platelet inhibition in HIV-infected patients receiving antiretroviral therapy boosted with ritonavir or cobicistat (ART). Although the clinical significance of these findings is unknown, spontaneous reports have been observed in HIV-infected patients receiving boosted ART who experienced recurrent occlusive events after revascularization or thrombotic events during clopidogrel treatment. The effect of clopidogrel and the mean platelet inhibition may be reduced when co-administered with ritonavir. Concomitant use of clopidogrel with boosted antiretroviral therapy is not recommended.

Proton pump inhibitors (PPIs). Omeprazole 80 mg once daily, when co-administered 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 by 40% (maintenance dose). This reduction was associated with a decrease in platelet aggregation inhibition by 39% (loading dose) and by 21% (maintenance dose). A similar interaction with clopidogrel is expected with esomeprazole.

Observational and clinical studies have yielded conflicting data regarding the clinical consequences of these pharmacokinetic and pharmacodynamic interactions in terms of 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 concentrations in blood was observed with pantoprazole or lansoprazole.

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

These results suggest the possibility of concomitant use of clopidogrel and pantoprazole.

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.

Combination with other medicinal products. Several clinical studies have been conducted with clopidogrel and other drugs to investigate potential pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interaction was observed when clopidogrel was administered concomitantly with atenolol, nifedipine, or both. Furthermore, the pharmacodynamic activity of clopidogrel remained practically unchanged when administered concomitantly with phenobarbital and estrogen.

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

Antacid agents did not affect the absorption of clopidogrel.

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

Drugs that are substrates of CYP2C8 enzyme. It has been shown that clopidogrel increases exposure to repaglinide in healthy volunteers. In vitro studies 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 with medicinal products primarily eliminated via metabolism mediated by the CYP2C8 enzyme (such as repaglinide, paclitaxel) requires caution (see section "Special precautions for use").

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

Special precautions for use.

Hemorrhage and hematological disorders. Due to the risk of hemorrhage and hematological adverse reactions, a complete blood count and/or other appropriate tests should be performed immediately if symptoms suggesting possible bleeding occur during drug administration (see section "Adverse reactions"). As with other antiplatelet agents, clopidogrel should be used with caution in patients with an increased risk of bleeding due to trauma, surgical procedures, or other pathological conditions, and also when patients are receiving acetylsalicylic acid (ASA), heparin, glycoprotein IIb/IIIa inhibitors, nonsteroidal anti-inflammatory drugs including COX-2 inhibitors, selective serotonin reuptake inhibitors (SSRIs), 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"). Patients should be carefully monitored for signs of bleeding, including occult bleeding, especially during the first weeks of treatment and/or following invasive cardiac procedures or 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").

In case of planned surgical intervention, when the antiplatelet effect is temporarily undesirable, clopidogrel treatment should be discontinued 7 days prior to surgery. Patients should inform their physician (including dentists) that they are taking clopidogrel before any surgical procedure or before starting any new medicinal product. Clopidogrel prolongs bleeding time; therefore, it should be used cautiously in patients with an increased risk of bleeding (particularly gastrointestinal and intraocular bleeding).

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

Thrombotic thrombocytopenic purpura (TTP). Cases of thrombotic thrombocytopenic purpura (TTP) have been reported very rarely following clopidogrel use, sometimes even after short-term administration. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia with neurological signs, renal dysfunction, or fever. TTP is a potentially life-threatening condition that may be fatal and therefore requires immediate treatment, including plasma exchange.

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

Recent ischemic stroke. Due to insufficient data, clopidogrel is not recommended within the first 7 days after an acute ischemic stroke.

Cytochrome P450 2C19 (CYP2C19). Pharmacogenetics: In patients with genetically reduced CYP2C19 function, lower plasma concentrations of the active metabolite of clopidogrel and a less pronounced antiplatelet effect are observed when standard recommended doses of clopidogrel are administered.

Since clopidogrel is partially converted 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 established. Therefore, 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").

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

Cross-sensitivity of thienopyridines. Patients should be evaluated for history of hypersensitivity to other thienopyridines (such as clopidogrel, ticlopidine, prasugrel), as cross-hypersensitivity reactions among thienopyridines have been reported. Use of thienopyridines may lead to allergic reactions ranging from mild to severe, such as rash, Quincke's edema, or hematological reactions such as thrombocytopenia and neutropenia.

Patients with a history of allergic or hematological reactions to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for signs of hypersensitivity is recommended in patients with known allergy to thienopyridines.

Renal function impairment. Clinical experience with clopidogrel use in patients with renal impairment is limited; therefore, the drug should be administered with caution in such patients (see section "Method of administration and dosage").

Hepatic function impairment. Experience with the use of the drug in patients with moderate liver disease and a risk of hemorrhagic diathesis is limited; therefore, clopidogrel should be used with caution in such patients (see section "Method of administration and dosage").

Excipients. Each tablet of the medicinal product Onecloplaz contains lactose. Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this product.

Each tablet of Onecloplaz contains hydrogenated castor oil, which may cause gastrointestinal upset and diarrhea.

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

Use during pregnancy or breastfeeding.

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

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

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

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

Ability to affect reaction speed when driving or operating machinery. Onecloplaz has no effect or a negligible effect on the ability to drive or operate machinery (see section "Adverse reactions").

Dosage and Administration

Adults and elderly patients. Onecplaz is administered at a dose of 75 mg once daily, independent of food intake.

In patients with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), treatment should be initiated with a single loading dose of 300 mg, followed by a maintenance dose of 75 mg once daily (in combination with aspirin at a daily dose of 75–325 mg). Since higher aspirin doses increase the risk of bleeding, aspirin doses exceeding 100 mg are not recommended. The optimal duration of treatment has not been formally established. Clinical trial data support treatment for up to 12 months, with maximum benefit observed after 3 months of therapy.

In patients with acute ST-segment elevation myocardial infarction, clopidogrel should be administered at 75 mg once daily, initiated with a single 300 mg loading dose in combination with aspirin (with or without thrombolytics). In patients aged 75 years and older, treatment should be initiated without a clopidogrel 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 with aspirin beyond 4 weeks in this condition has not been studied. In patients with atrial fibrillation, clopidogrel is administered at a single daily dose of 75 mg. Aspirin (75–100 mg daily) should be initiated and continued concomitantly with clopidogrel (see section "Pharmacological Properties").

Missed dose:

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

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

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

Children.

Clopidogrel should not be used in children and adolescents under 18 years of age, as efficacy has not been established in pediatric populations (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 can be reversed by platelet transfusion.

Adverse Reactions

The safety of clopidogrel has been evaluated in more than 44,000 patients who participated in clinical trials (including over 12,000 patients with treatment duration of 1 year or longer). Clinically significant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE-A studies are described below. In the CAPRIE study, the overall tolerability of clopidogrel at a dose of 75 mg once daily was comparable to that of aspirin (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 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 highest incidence occurring during the first month of treatment.

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

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

In the CLARITY study, an overall increased incidence of bleeding was observed in the clopidogrel plus aspirin group compared to the placebo plus aspirin group. However, the rate of major bleeding was similar in both groups. This rate 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 plus aspirin group compared to the placebo plus aspirin group (6.7% vs. 4.3%). In both groups, major bleeding events were predominantly extracranial (5.3% in the clopidogrel plus aspirin group vs. 3.5% in the placebo plus aspirin group), mainly gastrointestinal bleeding (3.5% vs. 1.8%). An increased incidence of intracranial bleeding was observed in the clopidogrel plus aspirin group compared to the placebo plus aspirin 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 plus aspirin group vs. 0.7% in the placebo plus aspirin group) or hemorrhagic stroke (0.8% vs. 0.6%, respectively).

List of adverse reactions in table format.

Adverse reactions observed during clinical trials or during clinical use of the medicinal product are listed in the table below. Adverse reactions are categorized by organ system, and their frequency is defined as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and frequency not known. Within each organ system, adverse reactions are listed in order of decreasing severity.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after authorization of the medicinal product is an important procedure. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report all suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 2 years.

Storage conditions.

Keep out of reach and sight of children. Store at a temperature not exceeding 30 °C.

Packaging. 10 tablets in a blister, 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Aurobindo Pharma Limited (Unit III), India.

Address of the manufacturer and location of the manufacturing site.

Survey No. 313, 314, Blocks I, II, III and IV, Bachupally Village, Kukatpally Mandal, Ranga Reddy District (A.R), India.