Lopirel, 75 mg 100 pcs.

Pharmacotherapeutic group: anti-aggregant drug

ATX code:

Pharmacological properties

Pharmacodynamics

Mechanism of action

Clopidogrel is a prodrug, one of whose metabolites is active and inhibits platelet aggregation. The active metabolite clopidogrel selectively inhibits adenosine diphosphate (ADP) binding to the P2Y₁₂ receptor of platelets and subsequent ADP-mediated activation of the glycoprotein IIb/IIIa complex, leading to suppression of platelet aggregation. Through irreversible binding, platelets remain immune to ADP stimulation for the remainder of their lives (approximately 7-10 days), and recovery of normal platelet function occurs at a rate consistent with the rate of platelet renewal.

The aggregation of platelets caused by agonists other than ADP is also inhibited by blocking the enhanced activation of platelets by the released ADP. Because the formation of the active metabolite occurs via P450 system isoenzymes, some of which may be polymorphic or may be inhibited by other drugs, adequate inhibition of platelet aggregation is not possible in all patients.

Pharmacodynamic properties

When clopidogrel is taken daily at a dose of 75 mg, significant inhibition of ADP-induced platelet aggregation is noted from the first day of administration, which gradually increases over 3-7 days and then reaches a constant level (when the equilibrium state is reached). In the equilibrium state at a dose of 75 mg/day, platelet aggregation is suppressed by an average of 40-60%. After stopping clopidogrel administration, platelet aggregation and bleeding time gradually return to baseline within an average of 5 days.

Clinical efficacy and safety

Clopidogrel can prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, particularly in lesions of the cerebral, coronary or peripheral arteries.

.The ACTIVE-A clinical trial showed that patients with atrial fibrillation who had at least one risk factor for vascular complications but were unable to take indirect anticoagulants, clopidogrel combined with acetylsalicylic acid (compared with taking acetylsalicylic acid alone) reduced the incidence of stroke, myocardial infarction, systemic thromboembolism outside the central nervous system (CNS), or vascular mortality combined, more by reducing the risk of stroke.

The efficacy of clopidogrel in combination with acetylsalicylic acid was detected early and persisted for up to 5 years. The reduction in the risk of major vascular complications in the group of patients who took clopidogrel in combination with acetylsalicylic acid was mainly due to a greater reduction in the incidence of strokes. The risk of stroke of any severity when receiving clopidogrel in combination with acetylsalicylic acid decreased, and there was a tendency to a lower incidence of myocardial infarction in the group treated with clopidogrel in combination with acetylsalicylic acid, but there were no differences in the frequency of non-CNS thromboembolism or vascular death. In addition, taking clopidogrel in combination with acetylsalicylic acid reduced the total number of days of hospitalization for cardiovascular causes.

Pharmacokinetics

absorption

Clopidogrel is rapidly absorbed after a single dose and when taken orally at a dose of 75 mg/day. Mean values of maximum plasma concentrations (C_max) of unchanged clopidogrel are about 2.2-2.5 ng/ml and are reached about 45 minutes after intake. According to the excretion of clopidogrel metabolites by the kidneys, its absorption is at least 50%.

Distribution

In vitro clopidogrel and its major circulating inactive metabolite are reversibly bound to plasma proteins by 98% and 94%, respectively. In vitro this binding is unsaturated over a wide range of concentrations.

Metabolism

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo clopidogrel is metabolized in two ways: the first is through esterases and subsequent hydrolysis to form an inactive carboxylic acid derivative (85%) from metabolites circulating in the systemic bloodstream, and the second way is through the cytochrome P450 system. Initially, clopidogrel is metabolized to 2-oxoclopidogrel, which is an intermediate metabolite. Subsequent metabolism of
2-oxoclopidogrel leads to the formation of the active metabolite of clopidogrel – thiol derivative of clopidogrel. In vitro this metabolic pathway occurs with the participation of the CYP3A4, CYP2C19, CYP1A2 and CYP2B6 isoenzymes. The active thiol metabolite of clopidogrel, which has been isolated in in vitro studies, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.

The C_max of the active metabolite is 2 times greater than the C_max when clopidogrel is taken at a single loading dose of 300 mg for 4 days. C_max active metabolite is reached 30-60 min after clopidogrel administration.

Elimation

For 120 hours after human oral administration of ¹⁴C-labeled clopidogrel, approximately 50% of the radioactivity is excreted through the kidneys and approximately 46% of the radioactivity through the gut. After a single oral dose of 75 mg, the half-life (T_1/2) of clopidogrel is about 6 hours. After a single dose and repeated doses, the T_1/2 of the main circulating inactive metabolite in blood is 8 hours.

Pharmacogenetics

The CYP2C19 isoenzyme is used to form both the active metabolite and the intermediate metabolite, 2-oxlopidogrel. The pharmacokinetics and antiaggregant effects of the active metabolite clopidogrel, when studied in platelet aggregation ex vivo, vary depending on the genotype of the CYP2C19 isoenzyme.

The CYP2C19*1 gene allele corresponds to fully functional metabolism, whereas the CYP2C19*2 and CYP2C19*3 gene alleles are nonfunctional. The CYP2C19*2 and CYP2C19*3 gene alleles are responsible for reduced metabolism in most Caucasoid (85%) and Mongoloid races (99%). Other alleles that are associated with absence or reduced metabolism are less common and include, but are not limited to, CYP2C19*4, *5, *6, *7, and *8 alleles. Patients who are poor metabolizers must have the two loss-of-function gene alleles listed above. The published frequencies of CYP2C19 weak metabolizer phenotypes are 2% in Caucasian race individuals, 4% in non-Hispanic race individuals, and 14% in Chinese individuals.

.In a cross-sectional study conducted on 40 volunteers, 10 people in each group with four subtypes of the CYP2C19 isoenzyme (ultrafast metabolizers, intensive metabolizers, intermediate metabolizers, weak metabolizers) were evaluated for pharmacokinetics and antiplatelet effects when clopidogrel was given at a dose of 300 mg followed by 75 mg/day and when clopidogrel was given at a dose of 600 mg followed by 150 mg/day for 5 days (reaching equilibrium). No significant differences in active metabolite exposure and mean values of platelet aggregation inhibition (IAT) (induced by ADP) were found in ultrafast, intensive and intermediate metabolizers. Weak metabolizers had a 63-71% reduction in active metabolite exposure compared with intensive metabolizers. When the 300 mg/75 mg treatment regimen was used, antiplatelet action was reduced in weak metabolizers with average IAT values of 24% (after 24 h) and 37% (by day 5 of treatment) compared to IAT values of 39% (after 24 h) and 58% (by day 5 of treatment) in intensive metabolizers and 37% (after 24 h) and 60% (by day 5 of treatment) in intermediate metabolizers. When weak metabolizers received the 600 mg/150 mg treatment regimen, exposure to the active metabolite was higher than when receiving the 300 mg/75 mg treatment regimen. In addition, IAT was 32% (after 24 h) and 61% (on day 5 of treatment), which was higher in weak metabolizers receiving the 300 mg/75 mg regimen and was similar to that in the groups of patients with higher CYP2C19-metabolism intensity receiving the 300 mg/75 mg regimen. However, the dosing regimen of clopidogrel for patients in this group has not yet been established in studies with clinical outcomes.

.Consistent with the results of this study, a meta-analysis of six studies that included data from 335 volunteers who received clopidogrel and were at equilibrium concentrations showed that intermediate metabolizers had a 28% reduction in active metabolite exposure and weak metabolizers had a 72% reduction in exposure, although IAT was reduced compared with intensive metabolizers with differences in IAT of 5.9% and 21.4%, respectively.

No impact of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has been evaluated in prospective, randomized, controlled trials. However, several retrospective analyses are currently available. Genotyping results are available in the following clinical trials: CURE (n=2721), CHARISMA (n=2428), CLARITY-TIMI 28 (n=227), TRITON-TIMI 38 (n=1477) and ACTIVE-A (n=601) as well as several published cohort studies.

In the TRITON-TIMI 38 study and 3 cohort studies (Collet, Sibbing, Giusti), patients in the combined group with intermediate or poor metabolism had a higher incidence of cardiovascular complications (death, myocardial infarction, and stroke) or stent thrombosis compared with those in intensive metabolizers.

In the CHARISMA study and one cohort study (Simon), increased rates of cardiovascular complications were observed only in weak metabolizers (when compared with intensive metabolizers).

In the CURE, CLARITY, ACTIVE-A, and one cohort study (Trenk), there was no increase in the incidence of cardiovascular complications as a function of CYP2C19-metabolism intensity.

The clinical studies conducted to date have not had sufficient sample size to detect differences in clinical outcome in patients with low CYP2C19 isoenzyme activity.

Pharmacokinetics in special clinical cases

The pharmacokinetics of the active metabolite clopidogrel in selected groups of patients has not been studied.

In elderly volunteers (over 75 years of age), no differences in platelet aggregation and bleeding time were obtained when compared to younger volunteers. No dose adjustment is required in elderly patients.

Pharmacokinetics of clopidogrel in children has not been studied.

.In patients with severe renal impairment (creatinine clearance (CK) 5-15 ml/min) after repeated doses of clopidogrel at 75 mg/day initiation of ADP-induced platelet aggregation was lower (25%) compared to that in healthy volunteers, but prolongation of bleeding time was similar to that in healthy volunteers receiving clopidogrel at 75 mg/day. Clopidogrel was well tolerated in all patients.

In patients with severe liver injury, inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers after daily clopidogrel doses of 75 mg/day for 10 days. The mean bleeding time was also comparable in both groups.

The prevalence of CYP2C9 isoenzyme gene alleles responsible for intermediate and reduced metabolism is different between racial groups. There are very few literature data among members of the Mongoloid race, which makes it impossible to assess the significance of CYP2C19 isoenzyme genotyping for the development of ischemic complications.

Indications

Prevention of heart attacks and strokes, Thrombosis prevention

Prevention of atherothrombotic complications

In adult patients with myocardial infarction (several days to 35 days old), ischemic stroke (7 days to 6 months old), or diagnosed peripheral arterial occlusive disease.

In adult patients with acute coronary syndrome:

• without ST-segment elevation (unstable angina or myocardial infarction without Q-wave), including patients who have had stenting for percutaneous coronary intervention (in combination with acetylsalicylic acid);
• with ST-segment elevation (acute myocardial infarction) with drug treatment and the possibility of thrombolysis (in combination with acetylsalicylic acid).

Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation (atrial fibrillation).

In patients with atrial fibrillation (atrial fibrillation) who have at least one risk factor for vascular complications, cannot take indirect anticoagulants and have a low risk of bleeding (in combination with acetylsalicylic acid).

Active ingredient

Clopidogrel

Composition

1 tablet contains the active substance: clopidogrel hydrosulfate 97.87 mg, corresponding to 75.00 mg of clopidogrel base. Excipients: lactose, microcrystalline cellulose, crosspovidone (type A), glyceryl dibegenate, talc, Opadray II 85G34669 Pink (polyvinyl alcohol, talc, titanium dioxide (E171), macrogol 3350, lecithin (E322), iron oxide red dye (E172)).

How to take, the dosage

Lopirel is taken orally, regardless of meals.

Adults and elderly persons with normal CYP2C19 isoenzyme activity

Adults and elderly persons with normal CYP2C19 isoenzyme activity

The drug is taken at 75 mg once daily.

Acute coronary syndrome without ST-segment elevation (unstable angina pectoris, myocardial infarction without Q-wave)

.Treatment with clopidogrel should be started with a single loading dose of 300 mg and then continued with a dose of 75 mg once daily (in combination with acetylsalicylic acid in doses of 75-325 mg/day). Since the use of higher doses of acetylsalicylic acid is associated with an increased risk of bleeding, the recommended dose of acetylsalicylic acid for this indication should not exceed 100 mg. The optimal duration of treatment is not officially defined. Data from clinical trials support use of the drug for up to 12 months, and the maximum favorable effect was observed by the third month of treatment.

Acute coronary syndrome with ST-segment elevation (acute ST-segment elevation myocardial infarction)

.Clopidogrel should be taken once at 75 mg/day with an initial single loading dose of clopidogrel 300 mg in combination with acetylsalicylic acid in combination with thrombolytics or without combination with thrombolytics. In patients over 75 years old, treatment with clopidogrel should be started without its loading dose. Combination therapy should be started as soon as possible after the onset of symptoms, and continued for at least 4 weeks. The efficacy of the combination of clopidogrel and acetylsalicylic acid in this indication beyond 4 weeks has not been studied.

Atrial fibrillation (atrial fibrillation)

Clopidogrel should be taken once daily in a dose of 75 mg. In combination with clopidogrel, acetylsalicylic acid (75-100 mg/day) should be started and then continued.

Missing another dose

1. If less than 12 hours have passed since the next dose was missed, take the missed dose immediately and then take the next doses at the usual time.
2. If more than 12 hours have passed since the next dose was missed, the patient should take the next dose at the usual time (do not take a double dose).

Patients with genetically determined reduced CYP2C19 isoenzyme activity

Low CYP2C19 isoenzyme activity is associated with decreased antiaggregant effect of clopidogrel. The regimen of higher doses (600 mg – loading dose, then – 150 mg once daily) in patients with low CYP2C19 isoenzyme activity increases the antiplatelet effect of clopidogrel (see section Pharmacokinetics). However, the optimal dosing regimen for clopidogrel for patients with decreased metabolism due to genetically determined low activity of the CYP2C19 isoenzyme has not been established in clinical studies considering clinical outcomes.

Special patient groups

Elderly

.There were no differences in platelet aggregation and bleeding time in elderly volunteers (over 75 years of age) when compared to younger volunteers. No dose adjustment is required for the elderly.

Children

Lopirel should not be used in children because there is no experience with this group of patients.

Patients with impaired renal function

.After repeated doses of clopidogrel at a dose of 75 mg/day in patients with severe renal impairment (CK of 5 to 15 ml/min) inhibition of ADP-induced platelet aggregation (25%) was lower compared to that in healthy volunteers, but prolongation of bleeding time was similar to that in healthy volunteers receiving clopidogrel at a dose of 75 mg/day. In addition, all patients had good tolerability of the drug.

Patients with hepatic impairment

After 10 days of daily clopidogrel administration at a daily dose of 75 mg, inhibition of ADP-induced platelet aggregation in patients with severe liver damage was similar to that in healthy volunteers. The mean bleeding time was also comparable in both groups.

Patients of different ethnicities

The prevalence of CYP2C19 isoenzyme gene alleles responsible for the intermediate and reduced metabolism of clopidogrel to its active metabolite varied among different ethnic groups (see section Pharmacogenetics). Only limited data are available for mongoloid races to assess the effect of CYP2C19 isoenzyme genotype on clinical outcome events.

Female and male patients

.In a small study comparing the pharmacodynamic properties of clopidogrel in men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but there were no differences in prolongation of bleeding time. In the large controlled CAPRIE trial (clopidogrel versus acetylsalicylic acid in patients at risk for ischemic complications), the incidence of clinical outcomes, other adverse events, and abnormal clinical and laboratory parameters was similar in both men and women.

Interaction

Indirect anticoagulants:Continuous administration of clopidogrel and indirect anticoagulants is not recommended due to possible increased bleeding intensity (see section Special Precautions). Although administration of clopidogrel at a dose of 75 mg/day did not affect the pharmacokinetics of S-warfarin or the international normalized ratio in patients receiving long-term warfarin therapy, concomitant administration of clopidogrel with warfarin increases the risk of bleeding due to independent effects on hemostasis.

IIb/IIIa-receptor blockers:The administration of IIb/IIIa-receptor blockers together with clopidogrel requires caution (see Special Precautions).

Acetylsalicylic acid does not alter the effect of clopidogrel inhibiting ADP-induced platelet aggregation, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, concomitant administration of acetylsalicylic acid at a dose of 500 mg twice daily for 1 day with clopidogrel did not significantly increase bleeding time caused by clopidogrel administration. There may be pharmacodynamic interaction between clopidogrel and acetylsalicylic acid, which leads to an increased risk of bleeding. Therefore, caution should be exercised when using them concomitantly (see section Cautions), although in clinical trials patients received combined therapy with clopidogrel and acetylsalicylic acid for up to one year.

Heparin: According to a clinical trial conducted with healthy subjects, no change in heparin dose was required when clopidogrel was taken and its anticoagulant effect was not altered. Concomitant use of heparin did not alter the antiaggregant effect of clopidogrel. There is a possible pharmacodynamic interaction between clopidogrel and heparin, which may increase the risk of bleeding, so the concomitant use of these drugs requires caution (see section Special indications).

Thrombolytics:The safety of concomitant use of clopidogrel, fibrin-specific or fibrin-nonspecific thrombolytics and heparin has been studied in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed when thrombolytics and heparin were used together with acetylsalicylic acid (see section Side effects).

DNAPs: In a clinical study conducted with healthy volunteers, coadministration of clopidogrel and naproxen increased latent blood loss through the gastrointestinal tract. However, due to the lack of studies on the interaction of clopidogrel with other NSAIDs, it is currently unknown whether there is an increased risk of gastrointestinal bleeding when clopidogrel is taken together with other NSAIDs. Therefore, administration of NSAIDs, including COX-2 inhibitors, in combination with clopidogrel should be performed with caution (see section Special indications).

Selective serotonin reuptake inhibitors (SSRIs): because SSRIs affect platelet activation and increase the risk of bleeding, concomitant use with clopidogrel requires caution.

Other combination therapy Since clopidogrel is metabolized to its active metabolite partially by the CYP2C19 system, use of drugs that inhibit this system may decrease plasma concentrations of the active metabolite clopidogrel and decrease its clinical effectiveness. The clinical significance of this interaction is unknown. As a precautionary measure, concomitant administration of strong and moderate inhibitors of CYP2C19 isoenzyme should be avoided (see section Special indications and Pharmacokinetics).

Drugs that inhibit the CYP2C19 isoenzyme include omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbamazepine and chloramphenicol.

Special Instructions

Bleeding and hematological disorders

Because of the risk of bleeding and hematological undesired effects (see Side effects). Side effects), if clinical symptoms suspected of bleeding occur during treatment are present, a clinical blood count, activated partial thromboplastin time (APT), platelet count, platelet function tests, and other appropriate tests should be performed urgently.

.Clopidogrel, as well as other antiplatelet agents, should be used with caution in patients who have an increased risk of bleeding associated with trauma, surgery or other pathological conditions, as well as in patients receiving acetylsalicylic acid, other NSAIDs, including COX-2 inhibitors, heparin, SSRIs or glycoprotein IIb/IIIa inhibitors.

When treating with clopidogrel, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients should be closely monitored for signs of bleeding, including hidden bleeding.

Combined use of clopidogrel with warfarin may increase the intensity of bleeding (see section Interactions with Warfarin. Interaction with other medications), therefore, except in very rare clinical situations (such as the presence of a flotation thrombus in the left ventricle and stenting in patients with atrial fibrillation) the combined use of clopidogrel and warfarin is not recommended.

If the patient is to undergo elective surgery and there is no need for antiplatelet effect, clopidogrel should be discontinued 7 days prior to surgery.

People should inform their physician (including their dentist) about clopidogrel before any upcoming surgery and before starting any new medication.

Clopidogrel prolongs bleeding time and should be used with caution in patients with conditions that predispose to bleeding (especially gastrointestinal and intraocular bleeding).

Patients should be advised that it may take longer to stop bleeding when clopidogrel (alone or in combination with acetylsalicylic acid) is taken and that if they have unusual bleeding (in location or duration) they should inform their physician.

Thrombotic thrombocytopenic purpura

Very rare cases of TTP, characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever, have been reported after clopidogrel use (sometimes even briefly). TTP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

Acquired hemophilia

Acquired hemophilia has been reported with clopidogrel. If prolongation of the ATTB with or without bleeding is confirmed, the presence of acquired hemophilia should be questioned. If acquired hemophilia is diagnosed, appropriate treatment should be initiated and clopidogrel should be discontinued.

A recent ischemic stroke

Lopirel is not recommended for acute ischemic stroke less than 7 days old (because there are no data on its use for this condition).

In patients with recent ischemic stroke or transient ischemic attack and a high risk of recurrent atherothrombotic events, combination therapy with clopidogrel and acetylsalicylic acid has not demonstrated greater efficacy compared with clopidogrel monotherapy, but may increase the risk of major bleeding.

CYP2C19 cytochrome P450 isoenzyme

Pharmacogenetics: In patients with delayed metabolism of the CYP2C19 isoenzyme, when clopidogrel is taken at recommended doses, the active metabolite clopidogrel is formed in lower amounts and there is a weaker effect on platelet aggregation. Tests are available to determine the genotype of CYP2C19 isoenzyme in patients.

As clopidogrel is metabolized to active metabolites partially with the participation of CYP2C19 isoenzyme, use of drugs that inhibit the activity of this enzyme will lead to decreased concentration of the active metabolite of clopidogrel. The clinical significance of this interaction is unknown. As a precautionary measure, concomitant administration of strong and moderate CYP2C19 isoenzyme inhibitors is not recommended (see section Interaction with other medicinal products to clarify medicinal products and section Pharmacokinetics).

Cross reactions with thienopyridines

.Because cross-reactions of hypersensitivity have been reported during treatment with thienopyridines, it is necessary to clarify with the patient the history of hypersensitivity reactions to thienopyridines (clopidogrel, ticlopidine, prasugrel) before starting treatment (see Side effects).

The thienopyridines may cause allergic reactions of varying severity, such as rash, angioneurotic edema, or hematologic cross-reactions (thrombocytopenia and neutropenia). Patients who have had allergic reactions and/or hematological reactions during previous treatment with one of the thienopyridines may have an increased risk of developing similar reactions or reactions of a different kind when taking another thienopyridine. Monitoring of hypersensitivity symptoms in patients with a history of allergic reactions to thienopyridines is recommended.

Renal dysfunction

The experience with clopidogrel in patients with impaired renal function is limited, so it should be used with caution in this group of patients (see. See Terms of Use and Doses).

Hepatic Impairment

The experience with Lopirel® has been limited in patients with moderate hepatic impairment who have a risk of hemorrhagic diathesis. Lopirel should be used with caution in this group of patients (see Term of Use and Dosage).

Lactose content of the drug

Lopirel should not be used in patients with rare hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome (see Contraindications for use. Contraindications).

Influence on driving and operating ability

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

Synopsis

Round, biconvex, film-coated, pink tablets with “I” engraved on one side.

Contraindications

• high sensitivity to clopidogrel or any excipient of the drug;
• severe hepatic impairment;
• acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage;
• common hereditary lactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome;
• pregnancy and lactation period;
• children under 18 years of age (safety and effectiveness of use not established).

Cautions

• in moderate hepatic impairment with possible susceptibility to bleeding (limited clinical experience of use);
• in renal impairment (limited clinical experience of use);
• in case of trauma, surgery (risk of increased bleeding);
• in cases with a predisposition to bleeding (especially gastrointestinal or intraocular bleeding);
• concomitant administration of nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors;
• concomitant administration of warfarin, heparin, glycoprotein IIb/IIIa inhibitors;
• with a history of allergic and hematologic reactions to other thienopyridines (such as ticlopidine, prasugrel) due to possible cross-allergic and hematologic reactions (see section “Special Precautions. patients with genetically determined decreased CYP2C19 isoenzyme function (patients with weak CYP2C19 metabolizers have less active clopidogrel metabolite and poorer antiplatelet effects when using clopidogrel at recommended doses); Weak metabolites receiving clopidogrel at recommended doses in acute coronary syndrome or percutaneous coronary intervention may have a higher incidence of cardiovascular complications than patients with normal CYP2C19 isoenzyme function).

.

Side effects

Safety of clopidogrel has been studied in more than 44,000 patients, including more than 12,000 patients treated for one year or longer. The overall tolerability of clopidogrel was similar to that of acetylsalicylic acid, regardless of patient age, sex, or race. Listed below are the clinically significant adverse effects observed in the clinical trials: CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE A. Tolerability of clopidogrel at a dose of 75 mg/day in the CAPRIE trial was consistent with tolerability of acetylsalicylic acid at a dose of 325 mg/day. Including adverse reactions have been reported in spontaneous reports.

The most frequently reported adverse reactions in clinical trials as well as in post-marketing use of clopidogrel were bleeding events, most of which developed in the first month of treatment.

In the clinical trial CAPRIE the overall incidence of bleeding in patients receiving clopidogrel or acetylsalicylic acid was 9.3%. The incidence of major bleeding with clopidogrel was similar to that with acetylsalicylic acid.

In the clinical trial CURE there was no increase in the incidence of major bleeding when clopidogrel was used with acetylsalicylic acid for seven days after aortocoronary bypass surgery in patients who suspended therapy more than 5 days before surgery. In patients who continued therapy for five days before coronary artery bypass surgery, the rate of this event was 9.6% for the combination of clopidogrel with acetylsalicylic acid and 6.3% for placebo in combination with acetylsalicylic acid.

The clinical trial CLARITY observed an overall increase in bleeding rates in the clopidogrel + acetylsalicylic acid group compared with the placebo + acetylsalicylic acid group. The incidence of major bleeding was similar in both groups and was virtually independent of patients’ baseline characteristics and the type of fibrinolytic or heparin therapy.

In the clinical trial,COMMIT the overall incidence of noncerebral major bleeding or cerebral hemorrhage was low and did not differ significantly in either group.

In the clinical trial ACTIVE–A the incidence of major bleeding was higher in the clopidogrel+acetylsalicylic acid group than in the placebo+acetylsalicylic acid group (6.7% vs. 4.3%). Major bleeding was mostly extracranial in both groups (5.3% vs. 3.5%), mainly gastrointestinal bleeding (3.5% vs. 1.8%). There were more intracranial hemorrhages in the clopidogrel+acetylsalicylic acid group compared with the placebo+acetylsalicylic acid group (1.4% vs. 0.8%, respectively). There were no statistically significant differences between these treatment groups in the incidence of fatal bleeding (1.1% versus 0.7%) and hemorrhagic stroke (0.8% versus 0.6%).

The following are the adverse reactions that were observed in clinical trials or reported spontaneously. The frequency of reactions is presented according to the following classification: very common (≥1/10); common (≥1/100, <1/10); infrequent (>1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), frequency unknown (cannot be determined from available data). In each of the organ and organ system classification subgroups, adverse reactions are presented in decreasing order of severity.

Blood and lymphatic system disorders: infrequent – thrombocytopenia, leukopenia, eosinophilia; rare – neutropenia, including severe neutropenia; very rare – thrombotic thrombocytopenic purpura (TTP) (see Special Indications), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired hemophilia type A, granulocytopenia, anemia.

Cardiac side: frequency unknown – Conyers syndrome (vasospastic allergic angina/allergic myocardial infarction) in the context of clopidogrel-induced hypersensitivity reaction.

Injury to the immune system:very rarely, serum sickness, anaphylactoid reactions; frequency unknown, cross-reactions of hypersensitivity with thienopyridines (such as ticlopidine, prasugrel) (see Special Indications).

Mental disorders:very rarely, hallucinations, confusion.

Nervous system disorders: infrequent – intracranial hemorrhage (some cases were fatal), headache, paresthesia, dizziness; very rare – taste disorder, aguesia.

Visual organ: infrequent – ocular hemorrhages (in the conjunctiva, eye tissue, retina).

Hearing organ and labyrinth disorders: rarely – vertigo.

Vascular aspects:often – hematomas, very rarely – severe bleeding, bleeding from surgical wounds, vasculitis, decreased blood pressure.

As to the respiratory system, thorax and mediastinum:often – nasal bleeding; very rarely – bleeding from the respiratory system (hemoptysis, pulmonary bleeding), bronchospasm, intestinal pneumonitis, eosinophilic pneumonia.

Gastrointestinal tract side: often – gastrointestinal bleeding, diarrhea, abdominal pain, dyspepsia; infrequently – gastric and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence; rare – retroperitoneal bleeding; very rare – gastrointestinal and retroperitoneal bleeding with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic), stomatitis.

Hepatic and biliary tract disorders:very rarely, acute liver failure, hepatitis, abnormalities in laboratory tests of liver function status.

Skin and subcutaneous tissue side: often – bruising; infrequently – rash, skin itching, purpura (fine-spotted capillary hemorrhages in the skin, under the skin or in the mucous membranes); very rare – bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, acute generalized exanthematous pustulosis (OGEP)), angioedema, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), erythematous or exfoliative rash, urticaria, eczema, squamous lichen.

Musculoskeletal and connective tissue disorders:very rarely – hemorrhage in the musculoskeletal system (hemarthrosis), arthritis, arthralgia, myalgia.

Kidney and urinary tract disorders: infrequent – hematuria; very rare – glomerulonephritis, increased blood creatinine concentration.

Gender and breast disorders: rarely – gynecomastia.

General disorders and disorders at the injection site:often – bleeding from the puncture site; very rarely – fever.

Laboratory and instrumental data: infrequent – prolongation of bleeding time, decreased neutrophil count, decreased platelet count.

Overdose

Symptoms:An overdose of clopidogrel may lead to prolonged bleeding time with subsequent complications in the form of bleeding development.

Treatment:In case of bleeding, appropriate treatment measures are required. If rapid correction of prolonged bleeding time is necessary, platelet transfusion is recommended. No antidote for clopidogrel has been established.

Pregnancy use

Pregnancy

Lopirel is contraindicated in pregnancy due to the lack of clinical data on its use in pregnant women, although animal studies of clopidogrel have shown no direct or indirect adverse effects on pregnancy, fetal development, labor and postnatal development.

Breastfeeding

Breastfeeding should be discontinued if treated with Lopirel, as clopidogrel and/or its metabolites have been shown to be excreted into breast milk in rat studies. Whether clopidogrel passes into human breast milk is unknown.

Similarities

Clopidogrel, Zilt, Egithromb, Lopirel, Plagril, Clopidex, Clopidogrel-SZ