Zyllt, pills 75mg, 84pcs

Composition

for 1 tablet

Core:

Active ingredient:

Clopidogrel Hydrosulfate 97.875 mg, equivalent to clopidogrel 75 mg

Excipients: lactose, microcrystalline cellulose, pregelatinized starch, macrogol 6000, hydrogenated castor oil

Film shell: hypromellose, titanium dioxide (E171), talc, iron oxide red dye (E172), propylene

glycol Pharmacological action

antiplatelet agent

Clinical Pharmacology

Pharmacodynamics

Clopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. To form an active metabolite that inhibits platelet aggregation, clopidogrel must be metabolized by cytochrome p450 (CYP450) isoenzymes. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to platelet P2Y12 receptors and the subsequent ADP-mediated activation of the GPIIb/IIIa glycoprotein complex, which leads to inhibition of platelet aggregation. Due to irreversible binding, platelets remain immune to ADP stimulation throughout the entire cell life cycle (approximately 7-10 days), and the restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal.

Platelet aggregation caused by agonists other than ADP is also inhibited due to the blockade of enhanced platelet activation by released ADP.

Since the formation of the active metabolite occurs with the help of cytochrome P450 isoenzymes, some of which may differ in polymorphism or be inhibited by other drugs, not all patients can adequately suppress platelet aggregation.

When taking clopidogrel daily at a dose of 75 mg from the first day of use, there is a significant suppression of ADP-induced platelet aggregation, which gradually increases over 3-7 days and then reaches a constant level (when an equilibrium state is reached). At steady state, platelet aggregation is suppressed by an average of 40-60%. After discontinuation of clopidogrel, platelet aggregation and bleeding time gradually return to baseline over an average of 5 days.

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

The effectiveness of taking clopidogrel in combination with ASA was detected early and persisted for up to 5 years. A reduction in the risk of major vascular complications in the group of patients taking clopidogrel in combination with ASA was observed mainly due to a greater reduction in the frequency of strokes. The risk of stroke of any severity was reduced when taking clopidogrel in combination with ASA, and there was a tendency to decrease the incidence of MI in the group treated with clopidogrel in combination with ASA, but there were no differences in the frequency of non-CNS thromboembolism or vascular death. In addition, taking clopidogrel in combination with ASA reduced the total number of days of hospitalization for cardiovascular reasons.

The transition from therapy with a potent P2Y12 receptor inhibitor to treatment with clopidogrel in combination with ASA after the end of the acute phase of acute MI was studied in two randomized, researcher-initiated clinical trials (TOPIC and TROPICAL-ACS).

The TOPIC randomized open-label clinical trial included patients who had experienced acute MI and underwent percutaneous coronary intervention (PCI). Patients treated with ASA and one of the more potent P2Y12 receptor inhibitorswho did not develop adverse events within one month, or were transferred to a fixed combination of ASA and clopidogrel (de-escalation of dual antiplatelet therapy (DAT)) or continued to take previously prescribed medications (unchanged DAT).

Events included in the combined primary endpoint (death from complications of cardiovascular diseases (CVD), stroke, emergency revascularization, and type 2 bleeding or more severe bleeding according to the BARC (Research Academic Consortium on Bleeding) scale), one year after acute MI, were reported in 43 of 322 patients (13.4%) in the DAT de-escalation group and 85 of 323 patients (26.3%) in the unchanged DAT group (p

The statistically significant difference is mainly due to a reduction in the number of cases of bleeding, including bleeding that is more or equal to 2 on the BARC scale (4% in the de-escalation group and 14.9% in the group receiving unchanged DAT), while there were no significant differences in the frequency of ischemic complications (p = 0.36).

The TROPICAL-ACS randomized open-label clinical trial included 2,610 patients with acute MI confirmed by biomarker analysis after PCI. Patients were randomly assigned to receive prasugrel (days 0-14) or prasugrel (days 0-7), and then clopidogrel (days 8-14) in combination with ASA.

Platelet function was evaluated on day 14. Patients in the first prasugrel-only treatment group continued to take prasugrel for 11.5 months.

Patients in the replacement therapy group underwent a high platelet reactivity test (ART). Patients with ART of 3 46 units were again transferred to prasugrel therapy, which they received for 11.5 months. Patients with ART Thus, in the managed replacement therapy group, patients received either prasugrel (40%) or clopidogrel (60%). All patients received ASA and were followed up for one year.

The primary endpoint included a combination of cardiovascular death, MI, stroke, and type 2 or more severe bleeding on the BARC scale. The study showed that there were no differences between the groups for the primary endpoint according to the non inferiority criterion. Controlled replacement therapy did not lead to an increased risk of ischemic complications (2.5% in the de-escalation group and 3.2% in the control group), as well as the frequency of bleeding of type 2 or more on the BARC scale.

Suction

After a single and repeated oral dose of 75 mg per day, clopidogrel is rapidly absorbed.

The average value of the maximum concentration (cmax) of unchanged clopidogrel in blood plasma (approximately 2.2-2.5 ng / ml after oral use of a single dose of 75 mg) is reached approximately 45 minutes after taking the drug. According to a study of the excretion of clopidogrel metabolites by the kidneys, the degree of absorption is approximately 50%.

Distribution

In vitro, clopidogrel and its main circulating inactive metabolite reversibly bind to human plasma proteins (98% and 94%, respectively), and this bond is unsaturated to a concentration of 100 mg/ml.

Metabolism

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, clopidogrel is metabolized in two ways: the first is mediated by esterases and leads to hydrolysis of clopidogrel to form an inactive metabolite-a derivative of carboxylic acid (85% of the circulating metabolites), and the second pathway is carried out using cytochrome P 450 isoenzymes.

Initially, clopidogrel is metabolized to an intermediate metabolite,2-oxo-clopidogrel. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of the active metabolite of clopidogrel, the thiol derivative of clopidogrel. Under in vitro conditions, this active metabolite is formed mainly by the isoenzyme CYP2C19, but some other isoenzymes, including CYP1A2, CYP2B6 and CYP3A4, are also involved in its formation. The active thiol metabolite of clopidogrel, isolated in vitro studies, binds rapidly and irreversibly to platelet receptors, thus blocking platelet aggregation.

The_cmax of the active metabolite of clopidogrel in blood plasma after a single 300 mg loading dose is 2 times higher than the_cmax after a 4-day clopidogrel maintenance dose of 75 mg / day. _Cmax in blood plasma is reached in approximately 30-60 minutes.

Deduction

Within 120 h after ingestion of 14C-labeled clopidogrel, approximately 50% of the radioactivity is excreted by the kidneys in the urine and approximately 46% of the radioactivity is excreted through the intestine. After a single oral use of clopidogrel at a dose of 75 mg, the half-life (T_1/2) is approximately 6 hours. After a single and repeated use of clopidogrel, the T_1/2 of the main inactive metabolite circulating in the blood plasma is 8 hours

. Pharmacogenetics

The CYP2C19 isoenzyme is involved in the formation of both the active metabolite and the intermediate metabolite – 2-oxo-clopidogrel. Pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel, in the study of platelet aggregation under the conditions ofex vivo, differ depending on the genotype of the CYP2C19 isoenzyme. The allele of the CYP2C19*1 isoenzyme gene corresponds to fully functional metabolism, whereas the alleles of the CYP2C19 isoenzyme genes correspond to fully functional metabolism. *2 and CYP2C19*3 are non-functional. Alleles of CYP2C19 isoenzyme genes*2 and CYP2C19 * 3 are the cause of decreased metabolism in the majority of Caucasian (85%) and Mongoloid (99%) races. Other alleles associated with an absence or decrease in metabolism are less common and include, but are not limited to, alleles of the CYP2C19 isoenzyme genes*4, *5, *6, *7 and *8. Patients with low activity of the CYP2C19 isoenzyme should have the two above-mentioned alleles of the gene with loss of function. Published data indicate that the frequency of occurrence of phenotypes of patients with low activity of the CYP2C19 isoenzyme in Caucasian patients is approximately 2%, in black patients-4%, and in Mongolian patients-14%. There are special tests to determine the patient’s genotype of the CYP2C19 isoenzyme.

According to a cross-sectional study (40 volunteers), which included individuals with very high, high, intermediate and low activity of the CYP2C19 isoenzyme, no significant differences were found in the exposure of the active metabolite and in the average values of inhibition of platelet aggregation (IAT) induced by ADP in volunteers with very high, high and intermediate activity of the CYP2C19 isoenzyme. In volunteers with low activity of the CYP2C19 isoenzyme, exposure to the active metabolite decreased by 63-71% compared to individuals with high activity of the CYP2C19 isoenzyme. When using regimens of 300 mg loading dose/75 mg maintenance dose (300 mg/75 mg) in volunteers with low activity of isoenzyme CYP2C19 antiplatelet effect decreased with the average values of IAT constituting 24% (after 24 h) and 37% (on day 5 of treatment) compared to the values of IAT constituting 39% (after 24 h) and 58% (on day 5 of treatment), in volunteers with high activity of isoenzyme CYP2C19 and 37% (after 24 h) and 60% (5 day treatment) in volunteers with intermediate activity of the isoenzyme CYP2C19.

When volunteers with low activity of the CYP2C19 isoenzyme received the drug according to the treatment regimen 600 mg loading dose/150 mg maintenance dose (600 mg/150 mg), the exposure of the active metabolite was higher than with the treatment regimen 300 mg/75 mg. In addition, IAT was 32% (after 24 hours) and 61% (on day 5 of the study), which was higher than in individuals with low activity of the CYP2C19 isoenzyme treated with the 300 mg/75 mg scheme, and was similar to that in groups of patients with a higher intensity of CYP2C19 metabolism treated with the 300 mg/75 mg scheme. However, in studies based on clinical outcomes, the dosage regimen of clopidogrel for patients in this group (patients with low activity of the CYP2C19 isoenzyme) has not yet been established.

Similarly to the results of this study, a meta-analysis of six studies, which included data from 335 volunteers treated with clopidogrel and who were in a state of reaching equilibrium concentration, showed that compared with volunteers with high activity of the CYP2C19 isoenzyme, in volunteers with intermediate activity of the CYP2C19 isoenzyme, exposure to the active metabolite decreased by 28%, and in volunteers with low activity of the CYP2C19 isoenzyme – by 72%, while IAT was reduced with differences in IAT values,5.9% and 21.4%, respectively.

The effect of the CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel was not evaluated in prospective, randomized, or controlled trials. However, there are currently several retrospective analyses available. Genotyping results were obtained in the following clinical trials: CURE, CHARISMA, CLARITY-TIMI 28, TRITON-TIMI 38, and ACTIVE, as well as in several published cohort studies.

In TRITON-TIMI study 38 and 3 cohort studies (Collet, Sibbing, Giusti), patients in the combination group with intermediate or low activity of the CYP2C19 isoenzyme had a higher incidence of cardiovascular complications (death, myocardial infarction, and stroke) or stent thrombosis compared to those in patients with high activity of the CYP2C19 isoenzyme.

In the CHARISMA study and one cohort study (Simon), an increase in the incidence of cardiovascular complications was observed only in patients with low activity of the CYP2C19 isoenzyme (when compared with patients with high activity of the CYP2C19 isoenzyme).

In the CURE, CLARITY, ACTIVE-A study and one of the cohort studies (Trenk), there was no increase in the frequency of cardiovascular complications depending on the intensity of CYP2C19 metabolism.

Pharmacokinetics in special patient groups

The pharmacokinetics of the active metabolite of clopidogrel in special patient groups have not been studied.

Patients over 75 years of age

No differences in platelet aggregation and bleeding time were found in volunteers over 75 years of age when compared with young volunteers. No dose adjustment is required.

Children under 18 years of age

No clinical data are available.

Impaired renal function

After repeated use of clopidogrel 75 mg / day in patients with severe renal impairment (creatinine clearance 5-15 ml / min), the inhibition of ADP-induced platelet aggregation was lower (by 25%) than in healthy volunteers, but the prolongation of bleeding time was similar to that in healthy volunteers receiving clopidogrel 75 mg/day.

Impaired liver function

There were no significant differences in the degree of inhibition of ADP-induced platelet aggregation after taking clopidogrel 75 mg daily for 10 days in patients with severe hepatic impairment compared to healthy volunteers. The mean bleeding time was also comparable in both groups.

Racial background

The prevalence of alleles of the CYP2C19 isoenzyme genes that cause intermediate or low activity of this isoenzyme differs among representatives of different racial groups. There are limited literature data on their prevalence in representatives of the Mongoloid race, which does not allow us to assess the significance of genotyping of the CYP2C19 isoenzyme for the development of ischemic complications.

Indications

Secondary prevention of atherothrombotic complications:

• in adult patients after recent myocardial infarction (with a prescription from a few days to 35 days), recent ischaemic stroke (with a prescription from 7 days to 6 months) or when diagnosed occlusive disease peripheral arterial clopidogrel reduced the frequency of the composite end point that included recurrent ischemic stroke (fatal or not), recurrent myocardial infarction (fatal or not) and other cardiovascular death
• in adult patients with acute coronary syndrome:

non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave myocardial infarction), including patients who should receive medical treatment and patients who require percutaneous coronary intervention (with or without stenting) or coronary artery bypass grafting (CABG). Taking clopidogrel reduced the frequency of the combined endpoint, which included cardiovascular death, myocardial infarction or stroke, as well as the frequency of the combined endpoint, which included cardiovascular death, myocardial infarction, stroke, refractory ischemia;

acute ST-segment elevation myocardial infarction. Taking clopidogrel reduced all-cause mortality, as well as the incidence of a combined endpoint that included death, recurrent myocardial infarction, or stroke.

Prevention of atherothrombotic and thromboembolic complications in adult patients with atrial fibrillation (atrial fibrillation)

It has been shown that in patients with atrial fibrillation at increased risk of vascular complications, treatment with indirect anticoagulants that are vitamin K antagonists (VKA) is associated with greater clinical benefits compared to the use of ASA alone or a combination of clopidogrel with ASA in terms of reducing the risk of stroke.

Patients with atrial fibrillation (atrial fibrillation), having at least one risk factor for vascular complications, which can’t accept AVC (e. g. available at special risk of bleeding, the patient’s inability, in the opinion of the attending physician, adequate control of international normalized ratio (INR) or in case of rejection by the patient’s treatment AVC), for the prevention of atherothrombotic and thromboembolic events, including stroke, are shown clopidogrel in combination with ASA.

Clopidogrel in combination with ASA was shown to reduce the frequency of the combined endpoint, which included stroke, myocardial infarction, systemic thromboembolism outside the central nervous system, or cardiovascular death, mainly by reducing the incidence of stroke (see section “Pharmacodynamics”).

Use during pregnancy and lactation

Pregnancy

Animal studies have shown no direct or indirect adverse effects on pregnancy, fetal development, delivery, or postnatal development.Since it is not always possible to predict a reaction in humans based on animal studies, and due to the lack of data from controlled clinical studies on the use of clopidogrel in pregnant women, it is not recommended to take clopidogrel during pregnancy as a precautionary measure, except in cases where, in the opinion of the doctor, its use is urgently necessary.

Breast-feeding period

Studies in rats have shown that clopidogrel and / or its metabolites are excreted in breast milk. Whether clopidogrel penetrates human breast milk is unknown. Since many medications can be excreted in breast milk and have an adverse effect on the infant, the attending physician, based on the importance of taking Ziltol for the mother, should recommend that she either stop taking the drug, or take the drug, but refuse to breastfeed.

Contraindications

Hypersensitivity to clopidogrel or any of the excipients of the drug.

Severe liver dysfunction.

Acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage.

Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

Pregnancy and lactation (see the section “Use during pregnancy and lactation”).

Children under 18 years of age (safety and efficacy have not been established).

Side effects

Data from clinical trials

The safety of clopidogrel has been studied in more than 44,000 patients, including more than 12,000 patients treated for a year or more. Overall, the tolerability of clopidogrel 75 mg/day in the CAPRIE study was consistent with that of ASA 325 mg/day, regardless of age, gender, or race. The following are clinically significant adverse events observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE A.

Bleeding and hemorrhage

Comparison of clopidogrel monotherapy with ASA

In the CAPRIE clinical trial, the overall incidence of all bleeding events in patients treated with clopidogrel and in patients treated with ASA was 9.3%. The incidence of severe bleeding events with clopidogrel and ASA was comparable: 1.4% and 1.6%, respectively.

Overall, the incidence of gastrointestinal bleeding in patients treated with clopidogrel and in patients treated with ASA was 2.0% and 2.7%, respectively, including the incidence of gastrointestinal bleeding requiring hospitalization was 0.7% and 1.1%, respectively.

The overall incidence of non-local bleeding with clopidogrel compared to ASA was higher (7.3% vs. 6.5%, respectively). However, the incidence of severe bleeding with clopidogrel and ASA was comparable (0.6% or 0.4%, respectively). The following bleeding events were most frequently reported: purpura / bruising, nosebleeds. Less frequently, hematomas, hematuria, and ocular hemorrhages (mainly conjunctival) were reported.

The incidence of intracranial hemorrhage with clopidogrel and ASA was comparable (0.4% or 0.5%, respectively).

Comparison of combination therapy with clopidogrel + ASA and placebo + ASA

In the CURE clinical trial, patients treated with clopidogrel + ASA experienced an increased incidence of major bleeding (3.7% vs. 2.7%) and minor bleeding (5.1% vs. 2.4%) compared to patients treated with placebo + ASA. The main sources of major bleeding were the gastrointestinal tract (GIT) and arterial puncture sites.

The incidence of life-threatening bleeding in patients treated with clopidogrel + ASA compared to patients treated with placebo + ASA did not significantly differ (2.2% and 1.8%, respectively), the incidence of fatal bleeding was the same (0.2% with both types of therapy).

The incidence of non-life-threatening major bleeding was significantly higher in patients taking clopidogrel + ASA compared to patients taking placebo + ASA (1.6% and 1%, respectively), but the incidence of intracranial hemorrhage was the same (0.1% for both types of therapy).

The incidence of bleeding in a large group of clopidogrel + ASA was dependent on the dose of ask (< 100 mg of 2.6%; 100-200 mg: a 3.5%; > 200 mg: 4.9%) and as the incidence of large bleeding in the placebo + ASA (< 100 mg: 2,0%; 100-200 mg: a 2.3%; > 200 mg: 4,0%).

Patients who stopped antiplatelet therapy more than 5 days before CABG did not have an increased incidence of major bleeding within 7 days after the intervention (4.4% in the clopidogrel + ASA group and 5.3% in the placebo + ASA group). In patients who continued antiplatelet therapy for the last five days before CABG, the incidence of these events after intervention was 9.6% (in the clopidogrel + ASA group) and 6.3% (in the placebo + ASA group).

In the CLARITY clinical trial, the incidence of major bleeding (defined as intracranial bleeding or bleeding with a decrease in hemoglobin > 5 g/dl) in both groups (clopidogrel + ASA and placebo + ASA) was comparable in both treatment groups (1.3% vs. 1.1% in the clopidogrel + ASA and placebo + ASA groups, respectively). It was the same in subgroups of patients divided by baseline characteristics and by types of fibrinolytic therapy or heparin therapy.

The incidence of fatal bleeding (0.8% vs. 0.6%) and intracranial hemorrhage (0.5% vs. 0.7%) with clopidogrel + ASA and placebo + ASA, respectively, was low and comparable in both treatment groups.

In the COMMIT clinical trial, the overall incidence of non-cerebral major bleeding or cerebral hemorrhage was low and similar (0.6% in the clopidogrel + ASA group and 0.5% in the placebo + ASA group).

In the ACTIVE-A clinical trial, the incidence of major bleeding in the clopidogrel + ASA group was higher than in the placebo + ASA group (6.7% vs. 4.3%, respectively). Major hemorrhages were mostly extracranial in both groups (5.3% vs. 3.5%), mainly from the gastrointestinal tract (3.5% vs. 1.8%). There were more intracranial hemorrhages in the clopidogrel + ASA group than in the placebo + ASA 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% vs. 0.7%) and hemorrhagic stroke (0.8% vs. 0.6%).

Blood disorders

In the CAPRIE study, severe neutropenia (< 0.45 109 / L) was observed in 4 patients (0.04%) taking clopidogrel and 2 patients (0.02%) taking ASA.

Two of the 9599 patients treated with clopidogrel showed a complete absence of neutrophils in the peripheral blood, which was not observed in any of the 9586 patients treated with ASA. Although the risk of developing myelotoxic effects when taking clopidogrel is quite low, if the patient taking clopidogrel has a fever or other signs of infection, the patient should be examined for possible neutropenia.

In one case, the development of aplastic anemia was observed during treatment with clopidogrel.

The incidence of severe thrombocytopenia (< 80*109/L) was 0.2% in patients treated with clopidogrel and 0.1% in patients treated with ASA, and very rare cases of reduced platelet counts < 30·109/L were reported.

The CURE and CLARITY studies observed a comparable number of patients with thrombocytopenia or neutropenia in both treatment groups.

Other clinically significant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A

clinical trials The frequency of adverse reactions observed during the above clinical trials is presented in accordance with the World Health Organization (WHO) classification: very common (≥ 1/10); (often ≥ 1/100 and < 1/10); infrequently (≥ 1/1000 and < 1/100); rarely (≥ 1/10000 and < 1/1000); very rarely (

Nervous system disorders:

infrequently: headache, dizziness, paresthesia;

rarely: vertigo.

Disorders of the gastrointestinal tract:

common: dyspepsia, abdominal pain, diarrhea;

uncommon: nausea, gastritis, bloating, constipation, vomiting, stomach ulcer, duodenal ulcer.

Skin and subcutaneous tissue disorders:

infrequently: skin rash, pruritus.

Disorders of the blood and lymphatic system:

infrequently: increased bleeding time, decreased platelet count in peripheral blood, leukopenia, decreased neutrophil count in peripheral blood, eosinophilia.

Post-marketing experience with the drug

Disorders of the blood and lymphatic system:

frequency unknown: serious cases of bleeding, mainly subcutaneous, musculoskeletal, eye bleeding (conjunctival, in the tissue and the retina of the eye), bleeding from the airway (hemoptysis, pulmonary hemorrhage), nasal bleeding, hematuria, and bleeding from surgical wounds and cases of bleeding with fatal outcome (especially intracranial hemorrhage, gastrointestinal bleeding and retroperitoneal hemorrhage), agranulocytosis, granulocytopenia, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired haemophilia A.

Cardiac disorders:

frequency unknown: Kounis syndrome (vasospastic allergic angina/allergic myocardial infarction) due to a hypersensitivity reaction to clopidogrel.

Immune system disorders:

frequency unknown: anaphylactoid reactions, serum sickness, cross-allergic and hematological reactions with other thienopyridines (such as ticlopidine, prasugrel) (see section “Special instructions”), autoimmune insulin syndrome (may lead to severe hypoglycemia, especially in patients with HLA DRA4 serotype).

Mental disorders:

frequency unknown: confusion, hallucinations.

Nervous system disorders:

frequency unknown: taste disorders, ageusia.

Vascular disorders:

frequency unknown: vasculitis, low blood pressure.

Respiratory, thoracic and mediastinal disorders:

frequency unknown: bronchospasm, interstitial pneumonia, eosinophilic pneumonia.

Disorders of the digestive system:

frequency unknown: colitis (including ulcerative colitis or lymphocytic colitis), pancreatitis, stomatitis.

Liver and biliary tract disorders:

frequency unknown: hepatitis (non-infectious), acute liver failure.

Skin and subcutaneous tissue disorders:

frequency unknown: maculopapular erythematous or exfoliative rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), acute generalized exanthematous pustulosis, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations (DRESS-syndrome), eczema, flat ringworm.

Musculoskeletal and connective tissue disorders:

frequency unknown: arthralgia (joint pain), arthritis, myalgia.

Kidney and urinary tract disorders:

frequency unknown: glomerulonephritis.

Genital and breast disorders:

frequency unknown: gynecomastia.

General disorders and disorders at the injection site:

frequency unknown: fever.

Laboratory and instrumental data:

the frequency is unknown: deviation from the norm of laboratory parameters of the functional state of the liver, increased creatinine concentration in the blood.

Interaction

Medications that are associated with a risk of bleeding

There is an increased risk of bleeding due to their potential additive effect with clopidogrel. Concomitant use of medications with clopidogrel that are associated with a risk of bleeding should be carried out with caution.

Warfarin

Although clopidogrel 75 mg / day did not alter the pharmacokinetics of warfarin (a substrate of the CYP2C9 isoenzyme) or INR in patients receiving long-term warfarin treatment, concomitant use of clopidogrel increases the risk of bleeding due to its independent additional effect on blood clotting. Therefore, caution should be exercised when taking warfarin and clopidogrel at the same time.

IIb/IIIa receptor blockers

Due to the possible pharmacodynamic interaction between clopidogrel and IIb/IIIa receptor blockers, their combined use requires caution, especially in patients with an increased risk of bleeding (due to injuries and surgical interventions or other pathological conditions) (see the section “Special Instructions”).

ASK

ASA does not alter the ADP-induced platelet aggregation inhibitory effect of clopidogrel, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. However, concomitant use of ASA 500 mg twice daily for one day with clopidogrel did not significantly increase the bleeding time caused by clopidogrel. Since there may be a pharmacodynamic interaction between clopidogrel and ASA, which leads to an increased risk of bleeding, caution should be exercised when using them simultaneously. However, in clinical trials, patients received combination therapy with clopidogrel and ASA (75-325 mg once daily) for up to one year.

Heparin

According to a clinical study conducted in healthy subjects, clopidogrel did not require a change in the dose of heparin and did not change its anticoagulant effect. Concomitant use of heparin did not alter the antiplatelet effect of clopidogrel. There may be a pharmacodynamic interaction between clopidogrel and heparin, which may increase the risk of bleeding, so the simultaneous use of clopidogrel and heparin requires caution.

Thrombolytics

The safety of co-use of clopidogrel, fibrin-specific or fibrin-non-specific thrombolytics, and heparin has been studied in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the case of combined use of thrombolytics and heparin with ASA.

NSAIDs

In a clinical study conducted in healthy volunteers, the combined use of clopidogrel and naproxen increased hidden 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 taking clopidogrel together with other NSAIDs. Therefore, the use of NSAIDs, including COX-2 inhibitors, in combination with clopidogrel should be carried out with caution (see the section “Special instructions”).

SSRIs

Since SSRIs interfere with platelet activation and increase the risk of bleeding, concomitant use of SSRIs with clopidogrel should be carried out with caution.

Strong to moderate inhibitors of the CYP2C9 isoenzyme

Since clopidogrel is metabolized to form its active metabolite partly by the CYP2C19 isoenzyme, the use of drugs that inhibit this isoenzyme may lead to a decrease in the formation of the active metabolite of clopidogrel.

The clinical significance of this interaction has not been established. As a precautionary measure, concomitant use of clopidogrel and strong or moderate inhibitors of the CYP2C9 isoenzyme should be avoided. Strong and moderate inhibitors of the CYP2C9 isoenzyme are omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol, efavirenz.

Concomitant use with clopidogrel of proton pump inhibitors that are strong or moderate inhibitors of the CYP2C19 isoenzyme (for example, omeprazole, esomeprazole) should be avoided (see section “Pharmacokinetics, subsection, “Pharmacogenetics”, section “Special instructions”). If proton pump inhibitors are to be taken concomitantly with clopidogrel, a proton pump inhibitor with the least inhibition of the CYP2C19 isoenzyme, such as pantoprazole and lansoprazole, should be taken.

There is no evidence for the effect of other drugs that reduce gastric acidity, such as_H2-receptor blockers or antacids, on the antiplatelet effect of clopidogrel.

In HIV-infected patients receiving antiretroviral therapy (ART) enhanced with ritonavir or cobicistat, a significant decrease in the plasma concentration of the active metabolite of clopidogrel and a decrease in the suppression of platelet aggregation were demonstrated.

Although the clinical significance of these results has not been definitively confirmed, spontaneous reports have described HIV-infected patients receiving enhanced ART who experienced repeated occlusion after deobstruction or experienced thrombotic events when using a loading dose of clopidogrel. The effect of clopidogrel and the average inhibition of platelet aggregation may be reduced when co-administered with ritonavir. Therefore, concomitant use of clopidogrel with enhanced ART is not recommended.

A number of clinical studies have been conducted with clopidogrel and other concomitant medications to investigate possible pharmacodynamic and pharmacokinetic interactions, which have shown that:

· no clinically significant pharmacodynamic interaction was observed when clopidogrel was co-administered with atenolol, nifedipine, or both of these drugs taken simultaneously;

· the concomitant use of phenobarbital and estrogens did not significantly affect the pharmacodynamics of clopidogrel;

· the pharmacokinetic parameters of digoxin and theophylline did not change when they were co-administered with clopidogrel;

· antacids did not reduce the absorption of clopidogrel;

· phenytoin and tolbutamide can be safely used simultaneously with clopidogrel (CAPRIE study). It is unlikely that clopidogrel may affect the metabolism of other drugs, such as phenytoin and tolbutamide and the NSAIDs, which are metabolized through CYP2C9 isoenzyme of cytochrome P-450;

· ACE inhibitors, diuretics, beta-blockers, blockers of “slow” calcium channels, lipid-lowering means, coronary vasodilators, hypoglycaemic agents (including insulin), antiepileptic remedies, hormone replacement therapy and blockers of GPIIb/IIIa receptors: clinical studies have not revealed clinically significant undesirable interactions.

Drugs that are substrates of the CYP2C8 isoenzyme

Clopidogrel was shown to increase systemic exposure to repaglinide in healthy volunteers. In vitro studies have shown that increased systemic exposure to repaglinide is due to inhibition of the CYP2C8 isoenzyme by the glucuronide metabolite of clopidogrel. Caution should be exercised when concomitantly using clopidogrel and drugs that are mainly eliminated from the body by metabolism using the CYP2C8 isoenzyme (for example, repaglinide, paclitaxel) due to the risk of increasing their plasma concentrations.

How to take, course of use and dosage

Clopidogrel should be taken orally, regardless of the meal time.

Adults and elderly patients

Myocardial infarction, ischemic stroke, and diagnosed peripheral arterial occlusive disease

The drug is taken at 75 mg 1 time a day.

In patients with myocardial infarction, treatment can be started from the first days to the 35th day of MI, and in patients with ischemic stroke (IS) – in the period from 7 days to 6 months after IS.

Non-ST-segment elevation acute coronary syndrome (unstable angina, non-Q-wave myocardial infarction)

Treatment with clopidogrel should be started with a single loading dose of 300 mg, and then continued with a dose of 75 mg once a day (in combination with ASA in doses of 75-325 mg per day). Since the use of higher doses of ASA is associated with an increased risk of bleeding, the recommended dose of ASA for this indication should not exceed 100 mg. The maximum beneficial effect is observed by the third month of treatment. The course of treatment is up to 1 year.

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

Clopidogrel is prescribed once at a dose of 75 mg once a day with an initial single loading dose in combination with ASA and thrombolytics (or without thrombolytics). Combination therapy should be initiated as early as possible after the onset of symptoms and continued for at least four weeks. In patients over 75 years of age, treatment with clopidogrel should begin without taking its loading dose.

Atrial fibrillation (atrial fibrillation)

The drug Zilt® is prescribed at a dose of 75 mg once a day. In combination with clopidogrel, you should start therapy and then continue taking acetylsalicylic acid at a dose of 75-100 mg per day.

Patients with a genetically determined decrease in the function of the CYP2C19 isoenzyme

A decrease in the activity of the CYP2C19 isoenzyme may lead to a decrease in the effect of clopidogrel. The optimal dosage regimen for patients with reduced activity of the CYP2C19 isoenzyme has not yet been established.

Overdose

Symptoms

Overdose of clopidogrel can lead to prolonged bleeding time with subsequent complications in the form of the development of bleeding.

Treatment

If bleeding occurs, appropriate treatment measures are required. The antidote of clopidogrel has not been established. If a rapid correction of the prolonged bleeding time is required, platelet transfusion is recommended.

Description

Round, slightly biconvex tablets, covered with a film-coated pink color.

View at the break: white to almost white rough mass with a pink film shell.

Special instructions

* Moderate hepatic impairment with a predisposition to bleeding (limited clinical experience).

* Impaired renal function (limited clinical experience).

* Diseases in which there is a predisposition to the development of bleeding (in particular gastrointestinal and intraocular), and especially with the simultaneous use of drugs that can cause damage to the mucous membrane of the gastrointestinal tract (such as ASA and nonsteroidal anti-inflammatory drugs [NSAIDs]).

·  In patients who have an increased risk of bleeding: due to injury, surgery or other pathological conditions, as well as in patients receiving treatment with ASA, heparin, warfarin, glycoprotein IIb/IIIa inhibitors, NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, as well as other drugs that are associated with the risk of bleeding, selective serotonin reuptake inhibitors (SSRIs) (see the sections “Interaction with other medicinal products”, “Special instructions”).

·  When used concomitantly with drugs that are substrates of the CYP2C8 isoenzyme (repaglinide, paclitaxel) (see the section “Interaction with other drugs”).

·  In patients with low activity of the CYP2C19 isoenzyme (see section “Pharmacokinetics”, subsection “Pharmacogenetics”, sections “Dosage and use”, “Special instructions”).

·  If there is a history of allergic and hematological reactions to other thienopyridines (such as ticlopidine, prasugrel) (the possibility of cross-allergic and hematological reactions, see the section “Special instructions”).

·  In case of a recent transient cerebral circulatory disorder or ischemic stroke (in combination with ASA, see the section “Special instructions”).

It is contraindicated in persons under 18 years of age (safety and effectiveness of use have not been established).

Elderly patients

Myocardial infarction, ischemic stroke, and diagnosed peripheral arterial occlusive disease

The drug is taken at 75 mg 1 time a day.

In patients with myocardial infarction, treatment can be started from the first days to the 35th day of MI, and in patients with ischemic stroke (IS) – in the period from 7 days to 6 months after IS.

Non-ST-segment elevation acute coronary syndrome (unstable angina, non-Q-wave myocardial infarction)

Treatment with clopidogrel should be started with a single loading dose of 300 mg, and then continued with a dose of 75 mg once a day (in combination with ASA in doses of 75-325 mg per day). Since the use of higher doses of ASA is associated with an increased risk of bleeding, the recommended dose of ASA for this indication should not exceed 100 mg. The maximum beneficial effect is observed by the third month of treatment. The course of treatment is up to 1 year.

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

Clopidogrel is prescribed once at a dose of 75 mg once a day with an initial single loading dose in combination with ASA and thrombolytics (or without thrombolytics). Combination therapy should be initiated as early as possible after the onset of symptoms and continued for at least four weeks. In patients over 75 years of age, treatment with clopidogrel should begin without taking its loading dose.

Atrial fibrillation (atrial fibrillation)

The drug Zilt® is prescribed at a dose of 75 mg once a day. In combination with clopidogrel, you should start therapy and then continue taking acetylsalicylic acid at a dose of 75-100 mg per day.

Patients with a genetically determined decrease in the function of the CYP2C19 isoenzyme

A decrease in the activity of the CYP2C19 isoenzyme may lead to a decrease in the effect of clopidogrel. The optimal dosage regimen for patients with reduced activity of the CYP2C19 isoenzyme has not yet been established.

During treatment with clopidogrel, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients should be carefully monitored for signs of bleeding, including latent bleeding.

Due to the risk of bleeding and undesirable effects from the blood (see the section “Side effects”), if clinical symptoms appear during treatment that are suspicious of the occurrence of bleeding, a general clinical blood test should be urgently performed, activated partial thromboplastin time (APTT), platelet count, platelet functional activity indicators should be determined, and other necessary studies should be carried out.

Clopidogrel, like other antiplatelet agents, should be used with caution in patients who have an increased risk of bleeding associated with injuries, surgery or other pathological conditions, as well as in patients taking ASA, NSAIDs, including COX-2 inhibitors, heparin or glycoprotein IIb/IIIa inhibitors, SSRIs or other medications that are associated with a risk of bleeding, such as pentoxifylline.

Concomitant use of clopidogrel with warfarin may increase the risk of bleeding (see section “Interactions with other medications”), so caution should be exercised when using clopidogrel and warfarin simultaneously.

If the patient is going to undergo elective surgery, and there is no need for an antiplatelet effect, then clopidogrel should be discontinued 5-7 days before the operation.

Clopidogrel prolongs the bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (especially gastrointestinal and intraocular). Medications that can cause damage to the gastrointestinal mucosa (such as ASA, NSAIDs) Caution should be exercised in patients taking clopidogrel.

Patients should be warned that it may take longer to stop bleeding when taking clopidogrel (alone or in combination with ASA), and that if they experience unusual (by location or duration) bleeding, they should inform their doctor about this. Patients should inform their doctor (including their dentist) about taking clopidogrel before any upcoming surgery and before starting any new medication.

Very rarely, after the use of clopidogrel (sometimes even for a short time), cases of TTP have been observed, which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever. TTP is a potentially life-threatening condition that requires immediate treatment, including plasmapheresis.

The combination of ASA and clopidogrel has been shown to increase the incidence of major bleeding in patients with a recent transient cerebrovascular accident or stroke who are at high risk of developing recurrent ischemic complications. Therefore, such combination therapy should be carried out with caution and only in the case of proven clinical benefits from its use.

Cases of acquired hemophilia have been reported with clopidogrel. If there is a confirmed isolated increase in APTT, accompanied or not accompanied by the development of bleeding, the possibility of developing acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated by specialists for this condition and stop taking clopidogrel.

In patients with low activity of the CYP2C19 isoenzyme, when using clopidogrel at the recommended doses, less of the active metabolite of clopidogrel is formed and its antiplatelet effect is less pronounced, and therefore, when taking the usually recommended doses of clopidogrel in acute coronary syndrome or percutaneous coronary intervention, a higher incidence of cardiovascular complications is possible than in patients with normal activity of the CYP2C19 isoenzyme. There are tests for determining the CYP2C19 genotype that can be used to help choose a therapeutic strategy. The use of higher doses of clopidogrel in patients with low activity of the CYP2C19 isoenzyme is being considered (see section “Pharmacokinetics”, subsection “Pharmacogenetics”, sections “With caution”, “Method of use and doses”).

Since clopidogrel is partially metabolized to the active metabolite by the CYP2C19 isoenzyme, the use of drugs that inhibit this isoenzyme may lead to a decrease in the concentration of the active metabolite of clopidogrel. The clinical significance of this interaction has not been established. As a precautionary measure, concomitant use of clopidogrel and potent or moderate inhibitors of the CYP2C19 isoenzyme is not recommended.

Caution should be exercised when concomitantly using clopidogrel and drugs that are substrates of the CYP2C8 isoenzyme.

Patients should have a history of previous allergic and/or hematological reactions to other thienopyridines (such as ticlopidine, prasugrel), as cross-allergic and / or hematological reactions between thienopyridines have been reported (see section “Side effects”). Thienopyridines can cause moderate to severe allergic reactions (such as skin rash, angioedema) or hematological reactions (such as thrombocytopenia and neutropenia). Patients who have previously experienced allergic and / or hematological reactions to one of the thienopyridine drugs may have an increased risk of developing similar reactions to another thienopyridine drug. Monitoring of cross-allergic and/or hematological reactions is recommended.

During treatment, it is necessary to monitor the functional state of the liver. With severe liver damage, you should be aware of the risk of developing hemorrhagic diathesis.

Taking clopidogrel is not recommended for acute stroke with a duration of less than 7 days (since there are no data on its use in this condition).

Special information on excipients

Zilt® should not be used in patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome, as it contains lactose.

Zilt ® contains hydrogenated castor oil, which may cause stomach upset and diarrhea in patients.

Zilt® does not significantly affect the ability to drive vehicles or engage in other potentially dangerous activities.

Form of production

Film-coated tablets,75 mg.

7 or 10 tablets in a contour cell package made of a combined OPA/Al/PVC material and aluminum foil.

2,4,8 or 12 contour cell packs of 7 tablets, or 3 or 9 contour cell packs of 10 tablets, together with the instructions for use, are placed in a cardboard pack.

Storage conditions

At a temperature not exceeding 25 ° C, in the original packaging.

Keep out of reach of children.

Shelf

life is 3 years.

Do not use the drug after the expiration date.

Active ingredient

Clopidogrel

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

Adults as prescribed by a doctor

Indications

Prevention of thrombosis, Prevention of thromboembolism, Prevention of heart attacks and strokes, Prevention of acute myocardial infarction