clopidogrel | Plavix tablets are coated. 75 mg 100 pcs.

Pharmacological action

Anti-aggregation.

Pharmacodynamics

Clopidogrel is a prodrug, one of the metabolites of which is active and inhibits platelet aggregation. The active clopidogrel metabolite selectively inhibits the binding of ADP to the P2Y12 platelet receptor and subsequent ADP-mediated activation of the glycoprotein IIb / IIIa complex, leading to a suppression of platelet aggregation.

Due to irreversible binding, platelets remain immune to ADP stimulation for the rest of their life (approximately 7–10 days), and normal platelet function is restored at a rate corresponding to platelet renewal rate. Platelet aggregation caused by agonists other than ADP is also inhibited by the blockade of increased platelet activation by the released ADP.

Since the formation of an active metabolite occurs using isoenzymes of the P450 system, some of which may differ in polymorphism or be inhibited by other drugs, not all patients may have adequate inhibition of platelet aggregation (see. Pharmacokinetics, Pharmacogenetics).

With daily intake of clopidogrel at a dose of 75 mg from the first day of administration, there is a significant suppression of ADP-induced platelet aggregation, which gradually increases over 3–7 days and then reaches a constant level (upon reaching equilibrium). In equilibrium, platelet aggregation is suppressed by an average of 40-60%.

After stopping clopidogrel, platelet aggregation and bleeding time gradually return to baseline, on average over 5 days.

When comparing the pharmacodynamic properties of clopidogrel in men and women, less inhibition of ADP-induced platelet aggregation is observed in women, but gender differences in lengthening of time of bleeding are not revealed.

In patients with recent myocardial infarction (MI), stroke, and peripheral arterial disease diagnosed with occlusion, taking Plavix® at a dose of 75 mg / day significantly reduces the risk of developing ischemic complications (a combined indicator of MI, stroke, and cardiovascular death), moreover it is most effective in patients with peripheral arterial occlusion disease, especially in combination with a history of MI, and is also more effective in patients under 75 years of age.

In patients with acute coronary syndrome without ST-segment elevation (unstable angina pectoris, MI), the use of Plavix® (loading dose - 300 mg, then - 75 mg / day) in combination with acetylsalicylic acid (ASA) (75–325 mg 1 time per day) and other standard therapies, regardless of the concurrent treatment (heparin therapy, glycoprotein IIb / IIIa blockers, lipid-lowering drugs, beta -adrenoblockers, ACE inhibitors) and doses of ASA, significantly reduces the total risk of developing ischemic complications: acute myocardial infarction, stroke and cardiovascular death with a decrease in relative risk with conservative treatment - by 17% after percutaneous transluminal cortex of external angioplasty (PTCA) with or without stenting - by 29% and after coronary artery bypass grafting - by 10%.

In patients with acute myocardial infarction with ST segment elevation, taking Plavix® (during the first 12 hours, MI loading dose is 300 mg, then - at 75 mg / day) in combination with ASA (loading dose of 150–325 mg, then - at 75–162 mg once a day) and fibrinolytic, and (according to indications) with heparin reduces the combined rate of the frequency detected by angiography by the moment of discharge from the hospital for occlusion of the coronary artery related to the infarction zone, or death, or the development of re-MI, and for patients who did not have angiography at discharge, the frequency of death or re-MI until the 8th day of the MI, or until discharge from the hospital, mainly by reducing cha Toty coronary artery occlusion related to the infarcted area.

In patients with acute myocardial infarction with ST segment elevation, a decrease in the ST segment or blockade of the left bundle of His bundle, taking Plavix® 75 mg / day in combination with ASA 162 mg once a day leads to a decrease in the frequency of deaths for any reason and the total frequency of the first repeated MI, stroke, and fatal outcomes.

Pharmacokinetics

Absorption

Absorption data obtained by ingestion of 75 mg of clopidogrel. After a single dose and with a course of oral administration at a dose of 75 mg / day, clopidogrel is rapidly absorbed.

Average Cmax of unchanged clopidogrel in blood plasma (approximately 2.2–2.5 ng / ml after oral administration of a single dose of 75 mg) is reached approximately 45 minutes after administration. According to the excretion of clopidogrel metabolites through the kidneys, its absorption is approximately 50%.

Distribution of

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

Metabolism

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, clopidogrel is metabolized in two ways: the first through esterases and subsequent hydrolysis to form an inactive derivative of carboxylic acid (85% of the metabolites circulating in the systemic circulation), and the second through the cytochrome P450 system.

Initially, clopidogrel is metabolized to 2-oxoclopidogrel, an intermediate metabolite. Subsequent metabolism of 2-oxoclopidogrel leads to the formation of an active metabolite of clopidogrel - a thiol derivative of clopidogrel. In vitro, this active metabolite is formed mainly by the CYP2C19 isoenzyme, but several other isoenzymes, including CYP1A2, CYP2B6 and CYP3A4, are also involved in its formation.

The active thiol metabolite of clopidogrel, which was isolated in in vitro studies, quickly and irreversibly binds to platelet receptors, thus inhibiting their aggregation.

Cmax of the active metabolite of clopidogrel after a single administration of a loading dose of Plavix® (300 mg) is 2 times higher than that after 4 days of taking a maintenance dose of Plavix® (75 mg). Cmax of the active metabolite is reached 30-60 minutes after taking Plavix®.

Excretion of

Within 120 hours after human ingestion of 14C-labeled clopidogrel, about 50% of the radioactivity is excreted through the kidneys with urine and approximately 46% of the radioactivity is excreted through the intestines with feces. After a single oral dose of 75 mg T1 / 2, clopidogrel is approximately 6 hours. After a single dose and repeated doses of T1 / 2, the main inactive metabolite in the blood is 8 hours.

Pharmacogenetics

Using the isoenzyme CYP2C19, an active metabolite is formed, so and the intermediate metabolite is 2-oxoclopidogrel. The pharmacokinetics and antiplatelet effect of the active clopidogrel metabolite, when examining platelet aggregation ex vivo, vary depending on the genotype of CYP2C19 isoenzyme. The allele of the CYP2C19 * 1 gene corresponds to a fully functional metabolism, whereas alleles of the CYP2C19 * 2 and CYP2C19 * 3 genes are non-functional.

Alleles of the CYP2C19 * 2 and CYP2C19 * 3 genes cause a decrease in metabolism in most representatives of the Caucasoid (85%) and Mongoloid races (99%). Other alleles associated with a lack or decrease in metabolism are less common and include, but are not limited to, alleles of the CYP2C19 * 4, * 5, * 6, * 7 and * 8 genes.

Patients with low CYP2C19 isoenzyme activity should have the two function alleles mentioned above with loss of function. The published frequencies of phenotypes of individuals with low activity of the CYP2C19 isoenzyme are 2% in individuals of the Caucasian race, 4% in individuals of the Negroid race, and 14% in Chinese. There are special tests to determine the patient’s genotype for the CYP2C19 isoenzyme.

In a cross-sectional study, conducted in 40 volunteers, 10 people in each group (individuals with very high, high, intermediate and low activity of the CYP2C19 isoenzyme), evaluated the pharmacokinetics and antiplatelet effect when taking 300 mg of clopidogrel, followed by 75 mg / day and 600 mg clopidogrel with its subsequent intake of 150 mg / day for 5 days (achievement of the state of Css).

There were no significant differences in the exposure of the active metabolite and the mean inhibition of platelet aggregation (IAT) (induced ADP) in individuals with very high, high and intermediate activity of the CYP2C19 isoenzyme. In volunteers with low activity of the CYP2C19 isoenzyme, the exposure of the active metabolite decreased by 63–71% compared with individuals with high activity of the CYP2C19 isoenzyme.

When using the treatment regimen, 300 mg - loading dose / 75 mg - maintenance dose (300/75 mg) in volunteers with low activity of the CYP2C19 isoenzyme decreased antiplatelet effect with average IAT values ​​of 24% (after 24 hours) and 37% (by 5th day of treatment) compared with IAT, constituting 39% (after 24 hours) and 58% (on the 5th day of treatment) in volunteers with high activity of CYP2C19 isoenzyme and 37% (after 24 hours) and 60% (on 5th day of treatment) in volunteers with intermediate activity of the CYP2C19 isoenzyme. When volunteers with low activity of CYP2C19 isoenzyme received a treatment regimen of 600 mg - loading dose / 150 mg - maintenance dose (600/150 mg), the exposure of the active metabolite was higher than when taking a treatment regimen of 300/75 mg.

In addition, IAT was 32% (after 24 hours) and 61% (on the 5th day of treatment), which was greater than that in individuals with low activity of the CYP2C19 isoenzyme receiving the 300/75 mg treatment regimen, and was similar to that in groups of patients with a higher CYP2C19 metabolism intensity receiving the 300/75 mg treatment regimen.

However, in studies with clinical outcomes, the dosage regimen of clopidogrel for patients in this group has not yet been established. Similar to the results of this study, a meta-analysis of six studies, which included data from 335 volunteers who received clopidogrel and were able to achieve Css, showed that, compared with volunteers with high activity of the isoenzyme CYP2C19, in volunteers with intermediate activity of the isoenzyme CYP2C19, the exposure of the active metabolite decreased by 28%, and in volunteers with low activity of the isoenzyme СYP2C19 - by 72%, while IAT was reduced with differences in IAT of 5.9 and 21.4%, respectively.

The impact of the CYP2C19 genotype on clinical outcomes in patients receiving clopidogrel has not been evaluated in prospective, randomized, controlled trials.

However, at the moment there are several retrospective analyzes. Genotyping results are available in the following clinical studies: CURE, CHARISMA, CLARITY-TIMI 28, TRITON-TIMI 38 and ACTIVE-A, as well as in several published cohort studies.

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

In the CHARISMA study and one cohort study (Simon), an increase in the frequency 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.

Selected patient groups

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

Elderly patients. In elderly volunteers (over 75 years old), when compared with young volunteers, there were no differences in platelet aggregation and bleeding time. No dose adjustment is required in the elderly.

Children. No data available.

Patients with impaired renal function. After repeated doses of clopidogrel at a dose of 75 mg / day in patients with severe renal impairment (creatinine Cl from 5 to 15 ml / min), the inhibition of ADP-induced platelet aggregation was 25% lower than that of healthy volunteers, however, the elongation of time bleeding was similar to that in healthy volunteers who received clopidogrel at a dose of 75 mg / day.

Patients with impaired liver function. After daily intake of 75 mg of clopidogrel daily for 10 days in patients with severely impaired liver function, inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. Mean bleeding time was also comparable in both groups.

Race. The prevalence of alleles of the CYP2C19 isoenzyme genes, causing an intermediate and low activity of this isoenzyme, differs among representatives of different racial groups.

There is limited literature on their prevalence in representatives of the Mongoloid race, which does not allow them to evaluate the importance of genotyping of the CYP2C19 isoenzyme for the development of ischemic complications.

Indications

Prevention of atherothrombotic disorders in patients with severe atherosclerosis, including

After a myocardial infarction, ischemic stroke, or with a diagnosed peripheral artery disease.

In acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without abnormal Q wave) in combination with acetylsalicylic acid.

In acute coronary syndrome with ST segment elevation (acute myocardial infarction) in combination with acetylsalicylic acid, receiving medication with the possible use of thrombolytic therapy.

Contraindications

hypersensitivity to clopidogrel or any of the excipients of the

preparation severe liver failure

acute bleeding, such as peptic ulcer bleeding or intracranial hemorrhage

rare hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption

pregnancy

period of breastfeeding (see. Use during pregnancy and lactation)

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

Precautions: moderate hepatic insufficiency, in which a predisposition to bleeding is possible (limited clinical experience), renal failure (limited clinical experience) trauma, surgical interventions (see "Special Instructions") diseases in which there is a predisposition to bleeding ( especially gastrointestinal or intraocular) simultaneous administration of drugs that can cause damage to the gastrointestinal mucosa (such as acetylsalicylic acid (ASA) and NSAIDs, including selective COX-2 inhibitors) in patients treated with ASA, heparin, warfarin, IIb / IIIa glycoprotein inhibitors, NSAIDs, including selective COX-2 inhibitors, as well as other drugs, the use of which is associated with the risk of bleeding, SSRIs (see “Interaction”, “Special instructions ”) in patients with low activity of the CYP2C19 isoenzyme (see“ Pharmacokinetics ”subsection“ Pharmacogenetics ”,“ Dosage and administration ”,“ Special instructions ”) history of allergic reactions to thienopyridines (eg ticlopidine, prasugrel - the possibility of cross allergic of hematological reactions, see the section “Special Instructions”) a recent transient disorder of cerebral circulation or ischemic stroke (when combined with ASA, see “Special Instructions”).

Use during pregnancy and lactation

Due to lack of data, it is not recommended to prescribe Plavix during pregnancy and during lactation (breastfeeding).

Special instructions

When using Plavix, a blood test should be performed during the first week of treatment if the drug is combined with acetylsalicylic acid, NSAIDs, heparin, IIb / IIIa glycoprotein inhibitors or fibrinolytics, as well as in patients at increased risk of bleeding associated with trauma, surgical interventions or other pathological conditions.

Due to the risk of bleeding and hematological side effects, if clinical symptoms suggesting this appear during treatment, a blood test (APTT, platelet count, platelet functional activity tests) and liver functional activity should be performed immediately.

For planned surgical interventions, Plavix treatment should be discontinued 7 days before surgery.

Clopidogrel should be used with caution in patients at risk of bleeding (especially gastrointestinal and intraocular).

Patients should be warned that they should inform the doctor about each case of bleeding.

Cases of thrombotic thrombocytopenic purpura (TTP) after clopidogrel have been reported. This was characterized by thrombocytopenia and microangiopathic hemolytic anemia in combination with either neurological symptoms, impaired renal function, or fever. The development of TTP can be life threatening and may require urgent action, including plasmapheresis.

Due to insufficient data, clopidogrel should not be prescribed in the acute period of ischemic stroke (in the first 7 days).

The drug should be prescribed with caution in patients with impaired renal function.

Clopidogrel should be used with caution in patients with moderate hepatic impairment in whom hemorrhagic diathesis may occur.

Clopidogrel should not be taken in patients with congenital galactose intolerance, glucose-galactase malabsorption syndrome and lactase deficiency.

Influence on the ability to drive vehicles and control mechanisms

No signs of deterioration in the ability to drive a car or decrease mental performance after taking Plavix were found.

Composition

Active ingredient:

Clopidogrel hydrosulfate 97.875 mg in 1 tablet, which is equivalent to 75 mg of clopidogrel base.

Excipients Mannitol.

Macrogol 6000.

Microcrystalline cellulose.

Hydrated castor oil.

Low-substituted hyprolose.

Composition of the Opadry white shell (lactose, hypromellose, triacetin, titanium dioxide (E171).

Iron oxide red (E172)).

Carnauba wax.

Dosage and administration of

For the prevention of ischemic disorders.

For the prevention of ischemic disorders in patients after myocardial infarction, ischemic stroke and diagnosed peripheral artery disease, adults (including elderly patients) are prescribed 75 mg 1 time / day, regardless of food intake. Treatment should begin in the period from several days to 35 days after myocardial infarction with the formation of a pathological Q wave and from 7 days to 6 months after an ischemic stroke.

In acute coronary syndrome.

In acute coronary syndrome without ST-segment elevation (unstable angina or myocardial infarction without Q wave), treatment should be started with a single loading dose of 300 mg, and then continue to use the drug at a dose of 75 mg 1 time / day (with the simultaneous administration of acetylsalicylic acid in dose of 75-325 mg / day). Since the use of acetylsalicylic acid in large doses is associated with a high risk of bleeding, the recommended dose should not be higher than 100 g. The course of treatment is up to 1 year.

In acute myocardial infarction.

In acute myocardial infarction with ST segment elevation, the drug is prescribed at a dose of 75 mg 1 time / day using the initial loading dose in combination with acetylsalicylic acid with or without thrombolytics. For patients over the age of 75 years, treatment with clopidogrel should be carried out without the use of a loading dose. Combination therapy is started as soon as possible after the onset of symptoms and continues for at least 4 weeks.

Drug Interactions

Co-administration with warfarin.

The combined use of clopidogrel with warfarin is not recommended, since such a combination can increase the intensity of bleeding.

Co-administration of glycoprotein IIb / IIIa

Prescribing glycoprotein IIb / IIIa inhibitors with Plavix requires caution.

Co-administration with acetylsalicylic acid. Acetylsalicylic acid does not change the inhibitory effect of Plavix on ADP-induced platelet aggregation, but Plavix enhances the effect of acetylsalicylic acid on collagen-induced platelet aggregation. The combined use of these drugs requires caution. However, in acute coronary syndrome without ST segment elevation, prolonged combined use of Plavix and acetylsalicylic acid (up to 1 year) is recommended.

Co-administration with heparin. With simultaneous use with heparin, according to a clinical trial, conducted on healthy volunteers, Plavix does not change either the general need for heparin nor the effect of heparin on blood coagulation. The simultaneous use of heparin did not change the inhibitory effect of Plavix on platelet aggregation. However, the safety of such a combination has not yet been established, and the simultaneous use of these drugs requires caution.

The safety of co-administration of clopidogrel, fibrin-specific or fibrin-non-specific thrombolytic drugs and heparin has been investigated in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the case of the combined use of thrombolytic agents and heparin with acetylsalicylic acid.

Combined use with non-steroidal anti-inflammatory drugs. The appointment of NSAIDs in conjunction with Plavix requires caution.

No clinically significant pharmacodynamic interaction was observed with Plavix in combination with atenolol, nifedipine, phenobarbital, cimetidine, estrogens, digoxin, theophylline, tolbutamide, antacids.

Overdose of

Symptoms of

Elongation of bleeding time and the resulting complications.

Treatment

If bleeding occurs, appropriate therapy should be given. If rapid correction of an extended bleeding time is needed, platelet transfusion is recommended. There is no specific antidote.

Deystvuyuschee substances

clopidogrel

Terms and conditions

prescription

Dosage form

tablets

Appointment

Vzrosl m in naznacheniyu Vracha

Indications

Prevention ynfarktov and ynsultov, for Prevention trombozov

Sanofi-Aventis, France