Medogrel

Ukraine
Brand name Medogrel
Form tablets, film-coated
Active substance / Dosage
clopidogrel · 75 mg
Prescription type prescription only
ATC code
B01AC04
Registration number UA/12149/01/01
Manufacturer Medocemi Limited (manufacturing of unpackaged product, quality control, batch release; primary and secondary packaging)
Medogrel tablets, film-coated

Table of Contents

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

Composition:

Active substance: 1 tablet contains 97.86 mg of clopidogrel bisulfate, equivalent to 75 mg of clopidogrel;

Excipients: anhydrous lactose, microcrystalline cellulose, crospovidone, glyceryl dibehenate, talc, film coating Opadry II 85G34669 Pink (contains: polyvinyl alcohol, talc, titanium dioxide (E 171), macrogol 3350, lecithin (E 322), iron oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, pink film-coated tablets, approximately 9 mm in diameter, with the imprint «I» on one side.

Pharmacotherapeutic group. Platelet aggregation inhibitors, excluding heparin.

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. For the formation of the active metabolite, which inhibits platelet aggregation, clopidogrel must undergo biotransformation by cytochrome CYP 450 enzymes. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its P2Y12 receptors on the platelet surface and subsequent ADP-induced activation of the glycoprotein IIb/IIIa complex, thereby inhibiting platelet aggregation. Since binding is irreversible, platelets exposed to clopidogrel remain altered throughout their lifespan (approximately 7–10 days), and normal platelet function recovery occurs 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 ADP. Since the active metabolite is formed via cytochrome CYP 450 enzymes, some of which are polymorphic or inhibited by other medicinal products, adequate platelet aggregation inhibition 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 therapies.

Recent myocardial infarction (MI), stroke, or established peripheral arterial disease. In the CAPRIE study, 19,185 patients with atherothrombosis, manifested by recent myocardial infarction (<35 days ago), recent ischemic stroke (7 days to 6 months ago), or established peripheral arterial disease (PAD), were included. Patients were randomized to receive clopidogrel 75 mg/day or ASA 325 mg/day and were then monitored for 1–3 years. In the MI subgroup, most patients received ASA in the first few days after the event. Clopidogrel significantly reduced the incidence of new ischemic events (composite endpoint consisting of MI, ischemic stroke, and vascular death) compared to ASA. In the analysis according to the treatment assigned at the beginning of the study, 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 corresponding diseases (MI, ischemic stroke, and PAD) showed the greatest effect (statistically significant at p = 0.003) in patients with PAD (especially those who had experienced 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 recently experiencing MI, the effect of clopidogrel was numerically smaller but statistically not different from ASA (RRR = -4%; CI: -22.5–11.7 [p = 0.639]). Additionally, subgroup analysis by age suggests that the favorable effect of clopidogrel is lower in patients over 75 years of age compared to those ≤75 years. Since the power of the CAPRIE study was insufficient to evaluate 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 12,562 patients with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave MI), 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 therapies. Treatment duration was up to 1 year. In the CURE study, 823 (6.6%) patients also received concomitant therapy with GPIIb/IIIa glycoprotein receptor antagonists. More than 90% of patients received heparins. This concomitant therapy did not statistically significantly affect the relative frequency of bleeding with clopidogrel versus placebo. The number of patients reaching the primary endpoint [cardiovascular death (CVD), MI, or stroke] was 582 (9.3%) in the clopidogrel group and 719 (11.4%) in the placebo group. Relative risk reduction was 20% (95% CI 10%–28%; p = 0.00009) in the clopidogrel group (17% with conservative treatment, 29% if patients underwent percutaneous 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, beyond 3 months of treatment, the favorable effect observed in the clopidogrel + ASA group no longer increased, while the risk of bleeding remained (see section "Special precautions for use"). Clopidogrel use during the CURE study reduced the need for thrombolytic therapy (RRR = 43.3%; CI: 24.3–57.5%) and GPIIb/IIIa glycoprotein receptor inhibitors (RRR = 18.2%; CI: 6.5–28.3%). The number of patients reaching the combined primary endpoint (CVD, MI, stroke, or refractory ischemia) was 1035 (16.5%) in the clopidogrel group and 1187 (18.8%) in the placebo group. Relative risk reduction was 14% (95% CI: 6–21%, p = 0.0005) in the clopidogrel group. This effect was primarily due to a statistically significant reduction in the frequency of MI [287 (4.6%) in the clopidogrel group and 363 (5.8%) in the placebo group]. No changes in the frequency of rehospitalizations for unstable angina were observed. Results 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 2172 patients (17% of the total CURE group) who received a stent (Stent-CURE) showed a significant RRR (26.2%) favoring clopidogrel in preventing the primary endpoint (CVD, MI, stroke), as well as a significant RRR (23.9%) for the second combined primary endpoint (CVD, MI, stroke, or refractory ischemia). Moreover, the safety profile of clopidogrel in this subgroup raised no particular concerns. Thus, results from the subgroup analysis are consistent with the overall study findings. The favorable effect of clopidogrel was demonstrated independently of receiving immediate or 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 was independent of ASA dose (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 last 12 hours and were planned 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. Subsequent patient follow-up lasted 30 days. The primary endpoint was occlusion of the infarct-related artery, detected on angiogram before hospital discharge, fatal outcome, or recurrent MI before coronary angiography. For patients not undergoing angiography, the primary endpoint was fatal outcome or recurrent MI by day 8 or hospital 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 favoring clopidogrel (95% CI: 24–47%; p < 0.001), primarily due to reduced incidence of occlusion of the infarct-related artery. This advantage was observed across all predefined patient subgroups categorized by age, sex, infarct location, and type of fibrinolytic or heparin therapy received. The two-factor design of the COMMIT study included 45,852 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, 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 all-cause mortality. 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% (p = 0.029) and the relative risk of the composite of recurrent MI, stroke, or mortality 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 occurred 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 ACS patients was evaluated in two investigator-sponsored randomized trials (ISS) – TOPIC and TROPICAL-ACS – with data on clinical outcomes. The clinical benefit provided by more potent P2Y12 receptor inhibitors, ticagrelor and prasugrel, in pivotal trials was due to a statistically significant reduction in the frequency of recurrent ischemic events (including acute and subacute stent thrombosis, MI, and emergency revascularization). Although benefits regarding ischemic events were consistently confirmed during the first year, the reduction in recurrent ischemic events after ACS was greater during the first days of treatment. In contrast, post hoc analyses demonstrated a statistically significant increase in bleeding risk with more potent P2Y12 receptor inhibitors, occurring predominantly during the maintenance phase, after the first month post-ACS. The TOPIC and TROPICAL-ACS trials were designed to investigate the possibility of reducing bleeding events while maintaining clopidogrel efficacy. The TOPIC trial ("Timing of Platelet Inhibition After Acute Coronary Syndrome"). This randomized open-label trial included ACS patients requiring percutaneous coronary intervention (PCI). Patients who were on 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). Data from 645 of 646 patients with STEMI (ST-elevation MI), NSTEMI (non-ST-elevation MI), 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. Characteristics of the study cohort were similar in both groups. The primary endpoint, a composite of cardiovascular death, stroke, emergency revascularization, and bleeding events ≥ grade 2 according to BARC (Bleeding Academic Research Consortium) criteria one year after ACS, was reached in 43 patients (13.4%) in the de-escalation DAPT group and 85 patients (26.3%) in the unchanged DAPT group (p < 0.01). This statistically significant difference was primarily due to fewer bleeding events; no difference was reported for ischemic event endpoints (p = 0.36), while bleeding events ≥ grade 2 according to BARC 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 occurred in 30 patients (9.3%) in the de-escalation DAPT group and 76 patients (23.5%) in the unchanged DAPT group (p < 0.01). The TROPICAL-ACS trial ("Testing Platelet Reactivity to Guide Maintenance Antiplatelet Therapy in Acute Coronary Syndromes"). This randomized open-label trial included 2610 ACS patients with positive biomarker results who successfully underwent PCI. Patients were randomized 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 on prasugrel alone 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 ASA, and follow-up was conducted for one year. The primary endpoint (composite endpoint of cardiovascular death, MI, stroke, and bleeding ≥ grade 2 according to BARC criteria at 12 months) demonstrated non-inferiority of clopidogrel. The endpoint occurred in 95 patients (7%) in the guided de-escalation group and 118 patients (9%) in the control group (p for non-inferiority = 0.0004). Guided de-escalation did not increase the combined risk of ischemic events (2.5% in the de-escalation group vs. 3.2% in the control group; p for non-inferiority = 0.0115), nor did it differ significantly 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).

Atrial fibrillation. The ACTIVE-W and ACTIVE-A trials, separate studies within the ACTIVE program, included patients with atrial fibrillation (AF) who had at least one risk factor for vascular complications. Based on inclusion criteria, physicians enrolled patients in the ACTIVE-W trial if they were candidates for vitamin K antagonist (VKA) therapy (e.g., warfarin). ACTIVE-A included patients who could not receive VKA therapy due to contraindications or unwillingness to receive this treatment. ACTIVE-W demonstrated that anticoagulant therapy with VKAs was more effective than treatment with clopidogrel and ASA. ACTIVE-A (n = 7554) was a multicenter, randomized, double-blind, placebo-controlled trial comparing clopidogrel 75 mg/day + ASA (n = 3772) with placebo + ASA (n = 3782). The recommended ASA dose was 75–100 mg/day. Patients received treatment for up to 5 years. Patients randomized in the ACTIVE program had documented AF, i.e., permanent AF or at least 2 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, or diabetes requiring medication, or documented previous MI, or documented ischemic heart disease; previous treatment for systemic arterial hypertension; prior stroke, transient ischemic attack (TIA), systemic embolism without CNS structural 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 last 6 months; history of intracranial hemorrhage, severe thrombocytopenia (platelet count <50×10⁹/L); need for clopidogrel or oral anticoagulants (OAC) or intolerance to either substance. 73% of patients in ACTIVE-A 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 due to physician judgment based on patient unwillingness to receive VKA. 41.8% of patients were women. The mean age was 71 years, 41.6% of patients were ≥75 years. Overall, 23% received antiarrhythmics, 52.1% beta-blockers, 54.6% ACE inhibitors, and 25.4% statins. The number of patients reaching the primary endpoint (time to first occurrence of stroke, MI, systemic embolism without CNS structural involvement, or death) was 832 (22.1%) in the clopidogrel + ASA group and 924 (24.4%) in the placebo + ASA group (relative risk reduction 11.1%, 95% CI: 2.4–19.1%; p = 0.013), primarily due to a significant reduction in stroke incidence. Strokes occurred in 296 (7.8%) patients receiving clopidogrel + ASA and 408 (10.8%) 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 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/day.

In a randomized, double-blind, parallel-group study (CLARINET), 906 children (newborns and infants) with cyanotic congenital heart defects who underwent palliative surgery creating a systemic-pulmonary arterial shunt were randomized to receive clopidogrel 0.2 mg/kg (n = 467) or placebo (n = 439) with concomitant background therapy until the second surgical stage. The mean time between palliative shunt surgery and first study drug administration was 20 days. Approximately 88% of patients simultaneously received ASA (1–23 mg/kg/day). No significant differences between groups were observed regarding the achievement of the primary composite endpoint, consisting of death, shunt thrombosis, or surgical intervention due to thrombosis by day 120 of life (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 frequency were observed between groups. During the subsequent long-term safety follow-up period, 26 patients with a functioning shunt at 1 year of age received clopidogrel until 18 months of age. During this period, the drug's safety profile remained unchanged. The reconstituted clopidogrel solution was used in the CLARINET and PICOLO studies. In a relative bioavailability study in adults, the reconstituted clopidogrel solution demonstrated a similar extent and slightly faster absorption rate of the main circulating (inactive) metabolite compared to the registered tablet form.

Pharmacokinetics.

Absorption. After oral administration of single and multiple 75 mg daily doses, 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 circulating (inactive) metabolite reversibly bind to human plasma proteins in vitro (98% and 94%, respectively). This binding remains unsaturated in vitro over a wide concentration range.

Metabolism. Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, two main metabolic pathways exist: one involving esterases leading to hydrolysis and formation of an inactive carboxylic acid derivative (accounting for 85% of circulating metabolites in plasma), and another involving cytochrome P450 system enzymes. Initially, clopidogrel is converted to the intermediate metabolite 2-oxo-clopidogrel. Further metabolism of 2-oxo-clopidogrel produces a thiol derivative – the active metabolite. This active metabolite is primarily formed via the CYP2C19 enzyme, with contributions from several other CYP system 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 preventing platelet aggregation. The Cmax value for the active metabolite is twice as high after a single 300 mg loading dose of clopidogrel compared to after 4 days of maintenance 75 mg dosing. 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 75 mg dose, the elimination half-life of clopidogrel is about 6 hours. The half-life of the main circulating (inactive) 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, based on ex vivo platelet aggregation measurements, vary depending on CYP2C19 genotype. The CYP2C19*1 allele corresponds to fully functional metabolism, while 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%) patients with reduced metabolism. Other alleles associated with absent or reduced metabolism are less common and include CYP2C19*4, *5, *6, *7, and *8. A patient with reduced metabolism has two non-functional alleles as described above. According to published data, CYP2C19 genotypes associated with reduced metabolism occur in 2% of Caucasians, 4% of African descent patients, and 14% of Chinese patients. Tests are now available to determine CYP2C19 genotype. In a crossover study with 40 healthy volunteers, 10 in each of four groups corresponding to specific CYP2C19 metabolic types (ultrarapid, extensive, intermediate, and poor), the pharmacokinetics and antiplatelet effects were evaluated after a 300 mg dose followed by 75 mg/day, and a 600 mg dose followed by 150 mg/day. Each treatment regimen was administered for 5 days (to reach steady state). No significant differences in active metabolite blood concentration and mean platelet aggregation inhibition (PAI) levels were observed between individuals with ultrarapid, extensive, and intermediate metabolism. In poor metabolizers, active metabolite blood concentration was reduced by 63–71% compared to extensive metabolizers. After the 300 mg/75 mg dosing regimen, antiplatelet effects in poor metabolizers were less pronounced, with mean PAI (5 μM ADP) of 24% (24 hours) and 37% (day 5) compared to 39% (24 hours) and 58% (day 5) in extensive metabolizers and 37% (24 hours) and 60% (day 5) in intermediate metabolizers. When poor metabolizers received the 600 mg/150 mg regimen, active metabolite blood concentration was higher than with the 300 mg/75 mg regimen. Additionally, PAI values were 32% (24 hours) and 61% (day 5), higher than in poor metabolizers receiving 300 mg/75 mg, and similar to values 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 including steady-state data from 335 patients receiving clopidogrel, active metabolite blood concentration was reduced by 28% in intermediate metabolizers and 72% in poor metabolizers; platelet aggregation inhibition (5 μM ADP) was also reduced, with PAI differences of 5.9% and 21.4%, respectively, compared to extensive metabolizers. The impact of CYP2C19 genotype on clinical outcomes in patients receiving clopidogrel has not been studied in prospective randomized controlled trials. However, several retrospective analyses have been conducted to assess this effect in patients receiving clopidogrel with available genotyping results: 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 and three cohort studies (Collet, Sibbing, Giusti), the combined group of intermediate and poor metabolizers had a higher incidence of cardiovascular events (death, MI, stroke) or stent thrombosis compared to extensive metabolizers. In the CHARISMA and one cohort study (Simon), poor metabolizers had increased event rates compared to extensive metabolizers. In the CURE, CLARITY, ACTIVE-A, and one cohort study (Trenk), cardiovascular event rates did not significantly depend on metabolic characteristics. None of these analyses included enough patients to detect differences in clinical outcomes in 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 regular administration of 75 mg clopidogrel daily in patients with severe renal impairment (creatinine clearance 5–15 mL/min), ADP-induced platelet aggregation inhibition was less pronounced (25%) compared to 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, ADP-induced platelet aggregation inhibition 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 CYP2C19 metabolic activity varies by racial/ethnic origin (see section "Pharmacogenetics"). Limited data are available for Mongoloid patients to assess the clinical significance of genotyping this CYP.

Preclinical safety data. The most frequently observed adverse effects in preclinical animal studies were liver changes. These occurred at doses leading to clopidogrel blood concentrations nearly 25 times higher than those observed in humans receiving the clinical dose of 75 mg clopidogrel daily and were due to the drug's effect on enzymes involved in hepatic metabolism. No effect on enzymes involved in hepatic metabolism was observed in humans receiving therapeutic doses of clopidogrel. Poor gastric tolerance (gastritis, erosive gastric lesions, and/or vomiting) was observed in rats and baboons receiving high doses of clopidogrel. No evidence of carcinogenicity was obtained in mice treated with clopidogrel for 78 weeks and rats for 104 weeks at doses up to 77 mg/kg/day (nearly 25 times higher than concentrations observed in humans receiving the clinical dose of 75 mg/day). Numerous in vitro and in vivo genotoxicity studies on clopidogrel were conducted, none of which revealed genotoxic effects. Clopidogrel did not affect reproductive function in rats and had no teratogenic effects in rats or rabbits. Administration of clopidogrel to lactating rats resulted in minor developmental delays in offspring. Special pharmacokinetic studies with radiolabeled clopidogrel demonstrated that the parent substance and its metabolites are excreted in breast milk. Therefore, both direct (minor toxic effect) and indirect (due to impaired milk palatability) 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), ischemic stroke (treatment initiation – within 7 days, but no later than 6 months after onset), or 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 acetylsalicylic acid (in patients receiving standard medical therapy and for whom thrombolytic therapy is indicated).

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

1 Age, blood pressure, clinical symptoms, 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, 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).

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 Medogrel with oral anticoagulants is not recommended, as this combination may increase the risk and severity of bleeding (see section "Special precautions for use"). Although administration of clopidogrel at a dose of 75 mg daily does not alter the pharmacokinetic profile of S-warfarin or the international normalized ratio (INR) in patients on long-term warfarin therapy, concomitant use of clopidogrel and warfarin increases the risk of bleeding due to their independent effects on 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 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 does not significantly prolong 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. Clopidogrel did not require adjustment of heparin dosage and did not alter heparin's effect on coagulation. Concomitant administration of heparin did not change 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, fibrin-specific or non-fibrin-specific thrombolytic agents, and heparin was evaluated in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed with concomitant use of thrombolytic agents and heparin with ASA (see section "Adverse reactions").

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

Selective serotonin reuptake inhibitors (SSRIs). Concomitant use of SSRIs with clopidogrel should be done with caution due to their effects on platelet activation and increased risk of bleeding.

Concomitant use of other medicinal products.

CYP2C19 inducers. Since clopidogrel is partially metabolized by CYP2C19, the use of drugs that induce the activity of this enzyme will lead to an increased level of the active metabolite of clopidogrel. Rifampicin is a strong inducer of CYP2C19; therefore, its use leads to both increased levels of the active metabolite of clopidogrel and platelet inhibition, which may increase the risk of bleeding. As a precaution, concomitant use of strong CYP2C19 inducers with clopidogrel should be avoided (see section "Special precautions for use").

CYP2C19 inhibitors. Since clopidogrel is converted to its active metabolite partially via CYP2C19, the use of drugs 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 "Pharmacokinetics" and "Special precautions for use"). Medicinal products that are strong or moderate inhibitors of CYP2C19 include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, and efavirenz.

Proton pump inhibitors (PPIs). Omeprazole 80 mg once daily, when co-administered with clopidogrel or within 12 hours 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 accompanied by 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 risk 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 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 accompanied by a decrease in the mean platelet aggregation inhibition by 15% and 11%, respectively. These results suggest that pantoprazole may be used concomitantly with clopidogrel. There is no evidence that other acid-reducing agents, 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. Significantly reduced platelet inhibition was observed in HIV patients receiving ART boosted with ritonavir or cobicistat. Although the clinical significance of these data is not established, spontaneous reports have been received of HIV-infected patients receiving ritonavir-boosted ART who experienced recurrent occlusive events after revascularization or thrombotic events despite high-dose clopidogrel therapy. Concomitant use of clopidogrel and ritonavir may result in reduced mean platelet inhibition. Therefore, concomitant use of clopidogrel with boosted ART should be avoided.

Combination with other medicinal products. 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 used concomitantly with atenolol, nifedipine, or both. Furthermore, the pharmacodynamic activity of clopidogrel remained practically unchanged when used concomitantly with phenobarbital and estrogen. The pharmacokinetic properties of digoxin or theophylline were not altered when used concomitantly with clopidogrel. Antacids did not affect the absorption of clopidogrel. Results from the CAPRIE study indicate that phenytoin and tolbutamide, which are metabolized by the CYP2C9 enzyme, can be safely used concomitantly with clopidogrel.

Medicinal products that are substrates of the CYP2C8 enzyme. Clopidogrel has been shown to increase repaglinide exposure 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 CYP2C8-mediated metabolism (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 used other drugs concomitantly, 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.

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. Consider using parenteral antiplatelet agents in patients with acute coronary syndrome who require concomitant administration of morphine or other opioid agonists.

Rosuvastatin. Clopidogrel has been shown to increase rosuvastatin exposure in patients by 2-fold (AUC) and 1.3-fold (Cmax) after a 300 mg dose of clopidogrel, and by 1.4-fold (AUC) without affecting Cmax after repeated 75 mg doses of clopidogrel.

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 if symptoms suggesting possible bleeding occur during treatment (see section "Adverse reactions"). As with other antiplatelet agents, clopidogrel should be used with caution in patients with an increased risk of bleeding due to trauma, surgery, or other pathological conditions, and also when patients are receiving acetylsalicylic acid (ASA), heparin, glycoprotein IIb/IIIa inhibitors, nonsteroidal anti-inflammatory drugs including COX-2 inhibitors, selective serotonin reuptake inhibitors (SSRIs), potent CYP2C19 inducers, or other medicinal products associated with an increased risk of hemorrhagic events (see section "Interaction with other medicinal products and other forms of interaction"). Triple antiplatelet therapy (clopidogrel + ASA + dipyridamole) is not recommended for secondary prevention of stroke in patients with acute non-cardioembolic ischemic stroke or transient ischemic attack (TIA) due to increased risk of bleeding (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). Patients should be carefully monitored for signs of bleeding, including occult bleeding, particularly during the first weeks of treatment and/or after invasive cardiac procedures and 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"). In case of planned surgical intervention 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 (especially gastrointestinal and intraocular). Patients should be informed that when treated with clopidogrel (alone or in combination with ASA), bleeding may stop later than usual, and they should report any episodes of unusual bleeding (in site or duration) to their physician. The use of a loading dose of 600 mg clopidogrel is not recommended in patients with non-ST-segment elevation acute coronary syndrome aged ≥75 years due to increased risk of bleeding in this group.

Thrombotic thrombocytopenic purpura (TTP). Very rare cases of thrombotic thrombocytopenic purpura (TTP) have been reported following clopidogrel use, sometimes even after short-term administration. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia with neurological symptoms, renal dysfunction, or fever. TTP is a potentially life-threatening condition that may lead to fatal outcomes and requires immediate treatment, including plasma exchange.

Acquired hemophilia. Cases of acquired hemophilia have been reported following clopidogrel use. In case of confirmed isolated prolongation of activated partial thromboplastin time (aPTT), with or without bleeding, the possibility of acquired hemophilia should be considered. Patients with confirmed diagnosis of acquired hemophilia should be managed under specialist supervision and receive appropriate treatment; clopidogrel 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 within 24 hours of 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 major ischemic stroke, monotherapy with clopidogrel should only be initiated after the first 7 days following the event.
  • Patients with major ischemic stroke (NIHSS >4): dual antiplatelet therapy is not recommended due to lack of data (see section "Indications").
  • Recent minor ischemic stroke or moderate-to-high-risk TIA in patients scheduled for or indicated for intervention. There are no data supporting the use of dual antiplatelet therapy in patients indicated for 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 exhibit lower plasma concentrations of the active metabolite of clopidogrel and a less pronounced antiplatelet effect when standard doses of clopidogrel 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 inhibit this enzyme will most likely reduce plasma concentrations of the active metabolite of clopidogrel. However, the clinical significance of this interaction has not been fully established. As a precaution, concomitant use of strong and moderate CYP2C19 inhibitors should be avoided (see section "Interaction with other medicinal products and other forms of interaction"; list of CYP2C19 inhibitors is provided in section "Pharmacokinetics"). Concomitant use of medicinal products that induce CYP2C19 activity is expected to increase levels of the active metabolite of clopidogrel and may increase the risk of bleeding. As a precaution, concomitant use of strong CYP2C19 inducers should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

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

Cross-sensitivity of thienopyridines. Patients should be screened for history of hypersensitivity to other thienopyridines (such as clopidogrel, ticlopidine, prasugrel), as cross-hypersensitivity reactions among thienopyridines have been reported (see section "Adverse reactions"). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or hematological cross-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 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 "Dosage and administration").

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

Excipients. Medogrel contains lactose. Patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. It also contains lecithin. If a patient has hypersensitivity to peanuts or soy, this medicinal product should be used with caution.

Use during pregnancy or breastfeeding.

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

Animal studies did not reveal any direct or indirect adverse effects on pregnancy, embryonal/fetal development, parturition, or postnatal development.

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 this medicinal product.

Fertility. Preclinical studies in laboratory animals showed no adverse effect of clopidogrel on fertility.

Ability to affect reaction rate when driving or operating machinery. Clopidogrel has no effect or negligible effect on the ability to drive or operate machinery.

Dosage and Administration.

Adults, including elderly patients. Medogrel should be taken at a dose of 75 mg once daily, independently of food intake.

In 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 loading dose of 600 mg may be administered to 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 ASA at 75–325 mg daily). Since higher doses of ASA 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 the use of the drug for up to 12 months, with maximum effect observed after 3 months of treatment (see section "Pharmacological Properties").

In 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 treatment 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 stroke (NIHSS score ≤ 3) should receive a clopidogrel loading dose of 300 mg, followed by continuation of treatment with 75 mg clopidogrel once daily and ASA at 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.

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 concomitantly with clopidogrel (see section "Pharmacological Properties").

In case of missed dose:

  • if less than 12 hours have passed since the scheduled dose: the patient should take the missed dose immediately, and 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 hepatic disease and potential for hemorrhagic diathesis is limited (see section "Special Instructions").

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

Overdose.

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 transfusion of platelet concentrate.

Adverse Reactions

Adverse reactions observed during clinical trials or reported spontaneously have been reported with clopidogrel. Adverse reactions are classified according to the following frequency categories: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data). Within each organ system class, adverse effects are listed in order of decreasing severity.

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

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

Immune system disorders. Very rare, frequency not known* – serum sickness, anaphylactoid reactions, cross-hypersensitivity to thienopyridines (such as ticlopidine, prasugrel) (see section "Special precautions")*, autoimmune insulin syndrome that may lead to severe hypoglycemia, particularly in patients with HLA DRA4 subtype.

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

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

Eye disorders. Uncommon – ocular hemorrhage (conjunctival, ocular, retinal).

Ear and labyrinth disorders. Rare – vertigo.

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

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

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

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

Skin and subcutaneous tissue disorders. Common – subcutaneous hemorrhage; uncommon – rash, pruritus, cutaneous hemorrhages (purpura); very rare, frequency not known* – bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, acute generalized exanthematous pustulosis (AGEP)), angioedema, drug hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), erythematous or exfoliative rash, urticaria, eczema, lichen planus.

Reproductive and breast disorders. Rare – gynecomastia.

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

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

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

Laboratory test abnormalities. Uncommon – prolonged bleeding time, decreased neutrophil and platelet counts.

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

Reporting suspected adverse reactions. Reporting of suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicine via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. For PVC/aluminum foil blisters – 1 year.

For aluminum blisters – 3 years.

Storage conditions. For PVC/aluminum foil blisters: store at a temperature not exceeding 25 °C in the original packaging, out of reach of children.

For aluminum blisters: store at a temperature not exceeding 30 °C in the original packaging, out of reach of children.

Packaging. 10 film-coated tablets in a blister. 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Medocemie Limited / Medochemie Limited.

Manufacturer's location and address of place of business.

Konstantinoupoleos 1-10, Limassol, 3011, Cyprus / Konstantinoupoleos 1-10, Limassol, 3011, Cyprus.