Clopidogrel pills 75mg, 28pcs – Biocom

Composition

Per tablet:

Active ingredient:  clopidogrel hydrosulfate – 97.88 mg, in terms of clopidogrel-75.00 mg.

Excipients (core): lactose – 70.00 mg, microcrystalline cellulose-17.00 mg, croscarmellose sodium-5.52 mg, colloidal silicon dioxide-1.80 mg, magnesium stearate-1.80 mg.

Excipients (shell):  hypromellose-3.30 mg, macrogol-4000-0.90 mg, iron oxide red dye-0.06 mg, titanium dioxide-1.74 mg

Pharmacological action

Pharmacotherapy group

Antiplatelet agent

ATX code

B01AC04

Pharmacodynamics :

Clopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation.

The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor P2Y12 and the subsequent ADP-mediated activation of the glycoprotein complex IIb/IIIa, thereby suppressing platelet aggregation. Reduces platelet aggregation caused by other agonists (other than ADP) does not affect the activity of phosphodiesterase.

Due to the irreversibility of binding, the exposed platelets are damaged for the rest of their life (approximately 7-10 days). and the restoration of normal platelet function occurs at a rate corresponding to the platelet cycle. Platelet aggregation caused by agonists other than ADP is also inhibited by blocking the increased platelet activation that occurs under the influence of released ADP.

Since the active metabolite of clopidogrel is formed with the participation of the CYP2C19 isoenzyme, some of which are polymorphic or inhibited by other drugs, platelet suppression is not sufficient in all patients.

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

Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular damage, in particular in lesions of the cerebral coronary or peripheral arteries.

In patients with a recent myocardial infarction, ischemic stroke and/or diagnosed peripheral arterial occlusive disease, taking clopidogrel at a dose of 75 mg per day significantly reduces the risk of vascular complications (myocardial infarction, stroke, and cardiovascular mortality).

In acute coronary syndrome without ST segment elevation on the ECG (unstable angina, myocardial infarction), taking clopidogrel (a loading dose of 300 mg once followed by 75 mg / day) in combination with acetylsalicylic acid at a dose of 75-325 mg/day and other standard therapy significantly and independently of other types of treatment reduces the risk of vascular complications.

In ST-segment elevation myocardial infarction, ECG use of clopidogrel (a loading dose of 300 mg once during the first 12 hours of the disease, then 75 mg/day) in combination with acetylsalicylic acid (a loading dose of 150-325 mg, then 75-162 mg/day), fibrinolytic therapy and, as indicated, heparin reduces the frequency of occlusion of the infarct-related coronary artery (according to coronary angiography at hospital discharge) of repeated myocardial infarction and deaths.

In patients who did not have a coronary angiography at discharge, clopidogrel use according to the indicated scheme reduces the frequency of deaths and recurrent myocardial infarction until the 8th day of the disease or until discharge from the hospital.

In general, in patients with myocardial infarction, regardless of ECG changes (ST segment elevation, ST segment depression, or first-time complete blockage of the left bundle branch), taking clopidogrel at a dose of 75 mg / day in combination with acetylsalicylic acid 162 mg / day leads to a decrease in overall mortality and the total frequency of recurrent myocardial infarction, ischemic stroke, and deaths.

The results of a clinical study 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 (compared with the use of acetylsalicylic acid alone) reduced the overall incidence of strokes, myocardial infarction, systemic thromboembolism outside the central nervous system or vascular death to a greater extent by reducing the risk of stroke.

Pharmacokinetics:

Absorption and distribution: with regular oral use of clopidogrel at a dose of 75 mg/day, it is rapidly absorbed.

The maximum concentration (Cmax) of unchanged clopidogrel after a single oral dose of 75 mg is approximately 22-25 ng/ml; the time to reach the maximum concentration (cmax) of clopidogrel is approximately 45 minutes. Based on data on the elimination of the clopidogrel metabolite by the kidneys, the absorption of clopidogrel is at least 50%.

In vitro, clopidogrel and its main circulating inactive metabolite reversibly bind to plasma proteins (98% and 94%, respectively). This bond is unsaturated in a wide range of concentrations.

Metabolism: As a prodrug, clopidogrel is extensively metabolized in the liver. In vivo and in vitro, clopidogrel is metabolized in two ways: first, through enzymes and subsequent hydrolysis to form an inactive carboxylic acid derivative (85% of the circulating metabolites), and second, through the cytochrome P 450 isoenzyme system. Initially, clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of the active metabolite of clopidogrel, the thiol derivative of clopidogrel. In vitro, this pathway is metabolized by the isoenzymes CYP3A4, CYP2C19, CYP1A2, and CYP2B6.

The active thiol metabolite can only be isolated in vitro studies; in in vivo, it binds rapidly and irreversibly to the platelet P2Y12 receptor, thus inhibiting platelet aggregation.

The cmax of the active metabolite of clopidogrel after taking its loading dose of 300 mg is 2 times higher than the Cmax after 4 days of taking a maintenance dose of clopidogrel 75 mg. At the same time, when taking 300 mg of clopidogrel, Cmax is reached within approximately 30-60 minutes.

After repeated oral use of clopidogrel at a dose of 75 mg per day, the cmax of the main inactive metabolite is about 3 mg/l and the CMAX of the inactive metabolite is reached in 1 hour.

Elimination: within 120 hours of human oral use of 14C-labeled clopidogrel, approximately 50% of the dose is excreted by the kidneys and approximately 46% by the intestines.

After a single oral dose of 75 mg, the half-life (T 1/2) is approximately 6 hours. After a single dose and repeated doses, T 1/2 of its main metabolite is 8 hours.

Pharmacogenetics

Both the active metabolite and the intermediate metabolite 2 – oxo-clopidogrel are formed by the CYP2C19 isoenzyme. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel in the study of platelet aggregation in vivo vary depending on the genotype of the CYP2C19 isoenzyme. The allele of the CYP2C19*1 gene corresponds to a fully functional metabolism, while the alleles of the CYP2C19 genes correspond to a fully functional metabolism. *2 and CYP2C19 * 3 are the cause of decreased metabolism in most representatives of the Caucasian (85%) and Mongoloid race (99%). Other alleles associated with an absence or decrease in metabolism are less common and include but are not limited to alleles of the CYP2C19 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. The published frequency of occurrence of phenotypes of patients with low activity of the CYP2C19 isoenzyme is 2% in Caucasians,4% in Negroes, and 14% in Chinese.

There are tests to determine the patient’s CYP2C19 genotype. These tests can be used as an auxiliary tool in determining treatment tactics.

In a cross-sectional study involving 40 healthy volunteers (10 volunteers each with very fast extensive intermediate and slow metabolism), the pharmacokinetics and antiplatelet effect of clopidogrel were studied using two regimens: 1) 300 mg once followed by a dose of 75 mg per day for 5 days and 2) 600 mg once followed by a dose of 150 mg per day for 5 days (until the equilibrium state is reached). There were no significant differences in the effect of the active metabolite and the average level of inhibition of platelet aggregation (IAT) between groups of volunteers with very rapid extensive and intermediate metabolism. In volunteers with a reduced metabolic rate, exposure to the active metabolite was 63-71% lower compared to volunteers extensively metabolizing clopidogrel.

When using the drug according to the scheme 300 mg once / 75 mg per day, the platelet response (with stimulation of 5 µm ADP) in volunteers with delayed clopidogrel metabolism was reduced: IAT was 24% (after 24 hours) and 37% (Day 5). For comparison, in volunteers with extensive metabolism, IAT was 39% (after 24 hours) and 60% (Day 5).

When using clopidogrel according to the scheme 600 mg once /150 mg per day in volunteers with a reduced metabolic rate of clopidogrel, the effect of the drug was more pronounced than when using the drug in doses of 300 mg once /75 mg per day: IAT was 32% (after 24 hours) and 61% (Day 5), which is comparable to the IAT values in the groups of volunteers with a different metabolic rate of clopidogrel who received the drug according to the 300 mg/75 mg scheme. A suitable dosage regimen for the population of patients with a reduced metabolic rate of clopidogrel has not been established in clinical studies.

Similarly, a meta-analysis of six studies that included data from 335 healthy volunteers who received clopidogrel and were in a state of reaching equilibrium concentration showed that the exposure of the active metabolite to intermediate metabolizers decreased by 28% and that of weak metabolizers-by 72%. In comparison with intensive metabolizers, the inhibition of platelet aggregation in intermediate and weak metabolizers was reduced by 59% and 214%, respectively.

The effect of the SUR2 C19 genotype on clinical outcomes in patients treated with clopidogrel was not evaluated in prospective randomized controlled trials. Existing data from retrospective analyses of clinical trials for which patient genotyping results are available do not have sufficient power to assess the difference in clinical outcomes between weak clopidogrel metabolizers compared to intensive and intermediate metabolizers.

Special patient groups

Elderly people

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

The pharmacokinetics of clopidogrel in children under 18 years of age have not been studied.

Impaired renal function

After repeated use of clopidogrel at a dose of 75 mg / day in patients with severe chronic renal failure (creatinine clearance (CC) 5-15 ml/min), the inhibition of ADP-induced platelet aggregation was 25% lower than in healthy volunteers, but there was no prolongation of bleeding time.

Impaired liver function

After taking clopidogrel 75 mg daily for 10 days in patients with severe liver damage, the inhibition of ADP-induced platelet aggregation did not differ from that in healthy volunteers. The mean bleeding time in patients with severe liver damage and in healthy volunteers was comparable.

Racial background

The prevalence of alleles of the CYP2C19 isoenzyme genes responsible for intermediate or reduced metabolism differs among representatives of different racial groups. The available literature data are insufficient to assess the significance of genotyping of the CYP2C19 isoenzyme for predicting the development of ischemic complications.

Indications

Prevention of atherothrombotic disorders in adult patients:

– after a previous myocardial infarction (with a prescription of several days to less than 35 days), ischemic stroke (with a prescription of 7 days to less than 6 months) or with a diagnosed occlusive disease of the peripheral arteries;

– with acute coronary syndrome:

• without ST-segment elevation (unstable angina or myocardial infarction without Q wave), including patients who were held stenting in percutaneous coronary intervention (in combination with acetylsalicylic acid);
• with ST-segment elevation (acute myocardial infarction with ST-segment elevation) with medical 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 adult patients with atrial fibrillation (atrial fibrillation) patients 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).

Use during pregnancy and lactation

The use of Clopidogrel is not recommended during pregnancy due to the lack of clinical data on its use in pregnant women, although animal studies have not revealed any direct or indirect adverse effects on the course of pregnancy, embryonic development, childbirth and postnatal development.

Studies in rats have shown that clopidogrel and / or its metabolites are excreted in the milk of lactating rats. There are no data on the excretion of clopidogrel in breast milk. During therapy with Clopidogrel, it is recommended to stop breastfeeding.

Fertility

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

Contraindications

-Hypersensitivity to clopidogrel or any of the excipients included in the drug.

– Severe liver failure.

– Active bleeding (including bleeding from a peptic ulcer or intracranial hemorrhage).

– Pregnancy and lactation period.

– Age up to 18 years (efficacy and safety of use have not been established).

– Rare hereditary lactose intolerance lactase deficiency and glucose-galactose malabsorption syndrome (due to the presence of lactose in the drug).

With caution:

– Moderate hepatic insufficiency (7-9 points on a scale child-Pugh) (where a possible predisposition to bleeding) – experience in clinical use are limited;

– chronic renal failure (CRF) easy and moderate (creatinine clearance 60-30 ml/min), clinical experience is limited;

– diseases in which there is predisposition to bleeding (especially gastrointestinal or intraocular), including injuries, surgical interventions;

– concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) (including cyclooxygenase-2 inhibitors (COX-2);

– concomitant use of oral anticoagulants heparin inhibitors of glycoprotein receptor IIb/IIIa selective inhibitors of serotonin reuptake (SSRIs) and thrombolytic drugs;

– hereditary decrease in the activity of isoenzyme CYP2C19 (as they have in the application of clopidogrel at recommended doses produce less of the active metabolite of clopidogrel and weaker expressed its antiplatelet effect in connection with the admission is usually recommended doses of clopidogrel in acute coronary syndrome or percutaneous coronary intervention possible higher incidence of cardiovascular complications than patients with normal CYP2C19 isozyme activity);

– when there is a history of hypersensitivity reactions to other thienopyridine (such as tiklopidin have prasugrel) due to the possibility of cross-reactions of hypersensitivity (see the section “Special instructions”).

Side effects

The frequency of adverse reactions is determined as follows: very often-more than 1/10 often-more than 1/100 and less than 1/10 infrequently-more than 1/1000 and less than 1/100 rarely-more than 1/10000 and less than 1/1000 very rarely-less than 1/10000 including individual reports unknown frequency (it is impossible to determine the frequency of occurrence of an adverse reaction from the available data). Within each organ-system frequency class, undesirable effects are presented in decreasing order of severity.

From the side of hematopoietic organs: infrequently-thrombocytopenia leukopenia eosinophilia; rarely-neutropenia including severe neutropenia; very rarely-thrombotic thrombocytopenic purpura aplastic anemia pancytopenia agranulocytosis severe thrombocytopenia granulocytopenia anemia; frequency unknown-acquired hemophilia A.

From the immune system:unknown frequency-anaphylactoid reactions serum sickness cross-allergic and hematological reactions with other thienopyridines (such as ticlopidine prasugrel)

From the side of the blood coagulation system: often-hematoma nosebleeds gastrointestinal bleeding bruises bleeding at the puncture site; sometimes-intracranial bleeding eye hemorrhage (conjunctival ocular retinal) prolongation of bleeding time; rarely-retroperitoneal bleeding; very rarely-severe bleeding from the operating wound bleeding from the respiratory system (hemoptysis pulmonary bleeding) hemarthrosis.

From the nervous system: infrequently-intracranial hemorrhage, including fatal headache, paresthesia, dizziness; very rarely-violations of taste sensations.

From the side of the psyche: very rarely – confusion hallucinations.

From the side of the organ of vision: infrequently-ocular hemorrhages (conjunctival in the tissues and retina of the eye).

From the side of the hearing organ: rarely-vertigo.

From the cardiovascular system: often-hematoma; very rarely-heavy bleeding from the surgical wound vasculitis low blood pressure.

Respiratory system disorders: often-nosebleeds; very rarely-bronchospasm interstitial pneumonitis pulmonary hemorrhage hemoptysis; eosinophilic pneumonia.

From the digestive system: very often-gastrointestinal bleeding diarrhea abdominal pain dyspepsia; infrequently-gastric and duodenal ulcers gastritis vomiting nausea constipation flatulence; rarely-retroperitoneal bleeding; very rarely-gastrointestinal bleeding and retroperitoneal hemorrhage with fatal outcome pancreatitis colitis (including ulcerative colitis or lymphocytic colitis) stomatitis.

Liver and biliary tract disorders: very rare – hepatitis (non-infectious) acute liver failure hepatitis abnormal liver function indicators.

From the side of the skin:often-subcutaneous hemorrhage; infrequently-skin rash pruritus purpura; very rarely / unknown frequency-bullous dermatitis (toxic epidermal necrolysis Stevens-Johnson syndrome erythema multiforme) angioedema drug hypersensitivity syndrome drug rash with eosinophilia and systemic manifestations (DRESS-syndrome) erythematous or exfoliative rash urticaria eczema lichen planus

From the musculoskeletal system:very rare-musculoskeletal hemorrhage (hemarthrosis) arthritis arthralgia (joint pain) myalgia.

From the genitourinary system: infrequently-hematuria; very rarely-glomerulopathy (including glomerulonephritis) hypercreatininemia.

Laboratory parameters: infrequently-prolongation of bleeding time decrease in the number of neutrophils platelets in peripheral blood disorders of liver function tests increased creatinine concentration in blood plasma.

General disorders and disorders at the injection site: often-bleeding from the site of vascular puncture very rarely-fever.

Interaction

Concomitant use of clopidogrel and oral anticoagulants may increase the intensity of bleeding, and therefore the use of this combination is not recommended. Clopidogrel at a dose of 75 mg per day does not affect the pharmacokinetics of warfarin and does not change the value of the International Normalized Ratio (INR) in patients taking warfarin for a long time. However, co-use of warfarin with clopidogrel may increase the risk of bleeding due to the independent effect of these drugs on hemostasis.

The use of glycoprotein IIb / IIIa receptor inhibitors in combination with clopidogrel requires caution, especially in patients with an increased risk of bleeding (due to injuries and surgical interventions or other pathological conditions).

Acetylsalicylic acid (ASA)has no effect on clopidogrel-induced ADP-induced platelet aggregation suppression, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. However, concomitant use of 500 mg ASA twice daily did not significantly affect the increase in bleeding time caused by clopidogrel. There may be a pharmacodynamic interaction between clopidogrel and ASA that leads to an increased risk of bleeding. Therefore, caution should be exercised when using them simultaneously, although in clinical studies patients received combination therapy with clopidogrel and ASA for one year.

When used concomitantly with heparin, according to a clinical study conducted on healthy volunteers, clopidogrel did not require a change in the dose of heparin and did not change the anticoagulant effect of heparin.

Co-use of heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation. There may be a pharmacodynamic interaction between clopidogrel and heparin that may increase the risk of bleeding so the use of this combination requires caution.

The safety of concomitant use of clopidogrel, fibrin-specific or non-specific thrombolytics, and heparin was 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.

Appointment NSAIDs (including COX-2 inhibitors)in combination with clopidogrel require caution. In a clinical study conducted in healthy volunteers, the combined use of clopidogrel and naproxen increased occult gastrointestinal bleeding. 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.

Selective serotonin reuptake inhibitors (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.

Since clopidogrel is metabolized to its active metabolite partly with the participation of the CYP2C19 isoenzyme, the use of drugs that inhibit the activity of this enzyme can lead to a decrease in the level of the active metabolite. The clinical significance of this interaction is unknown. As a precautionary measure, it is recommended to avoid concomitant use of clopidogrel with drugs that inhibit the CYP2C19 isoenzyme (omeprazole esomeprazole fluvoxamine fluoxetine moclobemide voriconazole fluconazole ticlopidine ciprofloxacin cimetidine carbamazepine oxcarbazepine chloramphenicol). If it is necessary to prescribe proton pump inhibitors simultaneously with clopidogrel, drugs with the lowest inhibition of the CYP2C19 isoenzyme (for example, pantoprazole or lansoprazole) should be used.

There is no evidence that other drugs that reduce the acidity of gastric juice, such as H2 blockers (except for cimetidine, which is an inhibitor of the CYP2C19 isoenzyme) or antacids, affect the antiplatelet properties of clopidogrel.

A number of clinical studies were conducted with clopidogrel and other concomitant medications to investigate possible pharmacodynamic and pharmacokinetic interactions which showed that:

• not observed clinically significant pharmacodynamic interactions when used clopidogrel together with atenolol and/or nifedipine;
• couse of phenobarbital cimetidine and estrogens has no significant effect on the pharmacodynamics of clopidogrel;
• antacids reduce the absorption of clopidogrel;
• phenytoin and tolbutamide can be safely used in conjunction with clopidogrel is unlikely that clopidogrel can affect the metabolism of other drugs such as phenytoin and tolbutamide and the NSAIDs, which are metabolized via CYP2C19 isoenzyme groups of cytochrome P-450.

In addition to the information presented above, no other drug interaction studies have been conducted. However patients who participated in clinical trials with clopidogrel received a number of other medications at the same time including diuretics beta-blockers ACE inhibitors calcium channel blockers lipid-lowering agents (including insulin) coronary vasodilators antiepileptic drugs and glycoprotein IIb/IIIa receptor blockers without evidence of a clinically significant adverse interaction.

How to take, course of use and dosage

Clopidogrel should be taken orally regardless of the meal time.

Adults and elderly patients with normal activity of the CYP2C19 isoenzyme:

Myocardial infarction ischemic stroke and diagnosed occlusive disease of peripheral arteries

Clopidogrel is taken 75 mg once a day.

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

Treatment with Clopidogrel begins with a single loading dose of 300 mg and then takes 75 mg / day (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 maximum beneficial effect develops after 3 months. The results of clinical studies confirm the feasibility of taking the drug up to 12 months after the development of acute coronary syndrome without ST-segment elevation.

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

Clopidogrel should be taken once a day at a dose of 75 mg with an initial single loading dose of 300 mg in combination with acetylsalicylic acid in combination with thrombolytics or without combination with thrombolytics.

In patients over 75 years of age, treatment with Clopidogrel should begin without taking its loading dose. Combination therapy should be initiated as early as possible after the onset of symptoms and continued for at least 4 weeks.

The effectiveness of combination therapy with Clopidogrel and acetylsalicylic acid for this indication for more than 4 weeks has not been studied.

Atrial fibrillation (atrial fibrillation)

Clopidogrel should be taken once a day at a dose of 75 mg. In combination with Clopidogrel, you should start and then continue taking acetylsalicylic acid (75-100 mg / day).

Skipping the next dose

• if less than 12 hours have passed since skipping the next dose of the drug, then you should immediately take the missed dose of the drug and then take the next dose at the usual time.
• if more than 12 hours have passed since skipping the next dose of the drug, the patient should take the next dose of the drug at the usual time (do not double the dose).

Patients with genetically determined reduced activity of the CYP2C19 isoenzyme

Low activity of the CYP2C19 isoenzyme is associated with a decrease in the antiplatelet effect of Clopidogrel.

A higher dose regimen (600 mg-loading dose then 150 mg once daily) in patients with low CYP2C19 isoenzyme activity increases the antiplatelet effect of clopidogrel.

Currently, clinical trials that take into account clinical outcomes have not established the optimal dosage regimen of clopidogrel for patients with reduced metabolism due to the genetically determined low activity of the CYP2C19 isoenzyme.

Special patient groups

Elderly patients

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

Patients with impaired renal function

After repeated use of Clopidogrel at a dose of 75 mg / day in patients with severe renal impairment (creatinine clearance (CC) from 5 to 15 ml/min), the inhibition of ADP-induced platelet aggregation (25%) was lower compared to those in healthy volunteers, but the prolongation of bleeding time was the same as in healthy volunteers receiving clopidogrel at a dose of 75 mg/day.

Patients with impaired liver function

Experience with clopidogrel in patients with hepatic insufficiency is limited. After 10 days of daily use of clopidogrel at a daily dose of 75 mg in patients with severe hepatic impairment, the inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean bleeding time was comparable in both groups.

Ethnicity

The prevalence of alleles of the CYP2C19 isoenzyme genes responsible for intermediate and reduced metabolism of clopidogrel to its active metabolite varies among representatives of different ethnic groups.

There are limited data available only for representatives of the Mongolian race to assess the effect of the CYP2C19 isoenzyme genotype on clinical outcomes (see section Pharmacogenetics).

Female and male patients

In a small study comparing the pharmacodynamic properties of clopidogrel in men and women, women showed less inhibition of ADP-induced platelet aggregation, but there were no differences in prolongation of bleeding time.

In the CAPRIE controlled clinical trial (clopidogrel versus acetylsalicylic acid in patients at risk of developing ischemic complications), the frequency of clinical outcomes of side effects and deviations of clinical laboratory parameters from the norm was the same in men and women.

Overdose

Symptoms: overdose with clopidogrel can lead to prolonged bleeding time and subsequent hemorrhagic complications in the form of bleeding.

Treatment: If bleeding is detected, appropriate treatment should be given.

The antidote of clopidogrel has not been established.

If a rapid correction of prolonged bleeding time is required, platelet transfusion is recommended.

Special instructions

A history of hypersensitivity to other thienopyridine derivatives (ticlopidine prasugrel) should be clarified, as cases of cross-allergic reactions between thienopyridines have been described. Patients who have previously experienced hypersensitivity to other thienopyridines should be closely monitored throughout the treatment period for signs of hypersensitivity to clopidogrel.

During treatment, it is necessary to monitor indicators of the hemostatic system (activated partial thromboplastin time (APTT) platelet count tests of platelet functional activity); regularly examine the functional activity of the liver.

Clopidogrel should be used with caution in patients at risk of severe bleeding from trauma, surgery, patients with injuries prone to bleeding (especially gastrointestinal and intraocular), as well as in patients receiving acetylsalicylic acid, nonsteroidal anti-inflammatory drugs (including COX-2 inhibitors), heparin or glycoprotein IIb/IIIa inhibitors, SSRIs and thrombolytic drugs. Patients should be carefully monitored for any signs of bleeding, including latent bleeding, especially during the first weeks of use of the drug and/or after invasive heart procedures or surgical operations.

Concomitant use of clopidogrel and warfarin should be carried out with extreme caution as it may increase bleeding.

In the case of surgical interventions, if the antiplatelet effect is undesirable, the course of treatment should be discontinued 7 days before the operation.

Patients should be warned that since stopping bleeding that occurs with clopidogrel (with or without acetylsalicylic acid) requires more time, they should inform the doctor about each case of bleeding. Patients should also inform the doctor about taking the drug if they are going to undergo surgery.

After taking clopidogrel, thrombotic thrombocytopenic purpura (TTP) was detected very rarely, sometimes after short-term use. This condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia in combination with neurological signs of impaired renal function or fever. TTP is a potentially fatal condition that requires immediate treatment, including plasmapheresis.

Clopidogrel should not be recommended in the acute period (less than 7 days) of ischemic stroke due to the lack of data on the effectiveness and safety of its use.

In patients with a recent ischemic stroke or transient ischemic attack and a high risk of recurrent atherothrombotic events, combination therapy with clopidogrel and acetylsalicylic acid has not been shown to be more effective than monotherapy with clopidogrel, but may increase the risk of major bleeding.

Acquired hemophilia

Cases of acquired hemophilia have been reported with clopidogrel. If there is a confirmed isolated increase in activated partial thromboplastin time (APTT), accompanied or not accompanied by the development of bleeding, the possibility of developing acquired hemophilia should be suspected. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated by specialists in this disease. Clopidogrel should be discontinued.

Cross-allergic and / or hematological reactions between thienopyridines

A history of allergic and/or hematological reactions to other thienopyridine derivatives (such as ticlopidine and prasugrel) should be clarified, as cases of cross-allergic and/or hematological reactions between thienopyridines have been described. Thienopyridines can cause moderate to severe allergic reactions (rash, angioedema) or hematological reactions (thrombocytopenia, neutropenia).

Patients who have previously experienced allergic and / or hematological reactions to one of the thienopyridine derivatives may have an increased risk of developing such reactions when taking another drug from the thienopyridine group. These patients should be closely monitored throughout the treatment period for signs of hypersensitivity to clopidogrel.

Experience with the use of clopidogrel in patients with impaired renal function is limited, so clopidogrel should be administered with caution in such patients.

Patients with severe hepatic impairment should be aware of the risk of hemorrhagic diathesis experience with the drug in patients with moderate hepatic impairment is limited, so these patients should be prescribed clopidogrel with caution.

Since Clopidogrel contains lactose as an excipient, it should not be taken in patients with rare hereditary problems of lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome (see section “Contraindications”).

Influence on the ability to drive vehicles and mechanisms:

Clopidogrel may cause side effects from the nervous system (headache dizziness systemic dizziness confusion hallucinations) that may affect the ability to drive vehicles and engage in other potentially dangerous activities that require increased concentration and speed of psychomotor reactions. However, in most cases, clopidogrel does not significantly affect the ability to drive vehicles and work with mechanisms.

Storage conditions

Store in a dark place at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Shelf

life is 3 years.

Do not use after the expiration date.

Active ingredient

Clopidogrel

Conditions of release from pharmacies

By prescription

Dosage form

Tablets