What can replace Plavix? Plavix analogues: which is better, comparative characteristics and prices

Plavix is ​​a French drug containing clopidogrel to thin the blood. It is used for the prevention and prevention of atherothrombotic complications in the elderly, patients after myocardial infarction, bypass surgery and other manipulations. The drug is prescribed by a cardiologist, or less often by a therapist, after studies have been carried out. Dispensed with a doctor's prescription.

Often in the extract, the specialist indicates several drugs of the same group: for example, Clopidogrel, Zilt and other analogues. The current question is which replacement for Plavix is ​​safe and effective.

According to the instructions for use, the medication contains the active substance clopidogrel and is classified as an antiplatelet agent. Therapeutic actions provided:

• thins the blood;
• restores normal platelet function;
• reduces the risk of stroke, myocardial infarction, thromboembolism, vascular death;
• when combined with acetylsalicylic acid, reduction of major vascular complications;
• reduction in the total number of days of hospitalization.

Indications for use of Plavix

A drug based on clopidogrel is prescribed when other antithrombotic agents (in particular, acetylsalicylic acid) are ineffective, in combination with ASA in the following cases:

1. acute coronary syndrome;
2. after stenting and coronary artery bypass surgery;
3. acute myocardial infarction;
4. prevention and treatment of recurrent heart attack and stroke.

The medicine is available by prescription and is taken strictly as prescribed by the doctor after blood tests for clotting.

Plavix - instructions for use

The medication is taken once a day, mainly in the morning. The dosage depends on the indications and the patient’s condition - from 75 to 600 mg. In the first days of use, it is possible to load the body with a maximum dose of 300 or 600 mg.

How to take Plavix - in the morning or in the evening, you need to check with your cardiologist. This depends on additionally prescribed medications, therapy with acetylsalicylic acid or drugs containing it.

Plavix analogs

The drug for thinning the blood and preventing vascular complications has good reviews from doctors and patients and is well tolerated. The disadvantage is the high price (from 900 rubles for 30 tablets, up to 3500 for 100 pieces) and availability only in certain pharmacy organizations. Therefore, the question of Plavix and its analogues, which drugs are better, and the characteristics of administration is relevant.

Prices for analogues of Plavix 75 mgand producing countries

Analogue	Price, in rubles	Manufacturer country
	900-3500	France
	130-400	Germany or Denmark
Aspirin Cardio	800-300	Germany
	1100-4500	France
Acetylsalicylic acid	3-50	Russia
Lopirel	250-1400	Malta
Eliquis	800-2700	Puerto Rico
Thrombo ass	40-180	Austria
	1800-11000	Germany
	400-750	India
	2500-15500	Sweden
Xarelto	1300-12000	Germany
	150-1300	Russia
	500-2300	Slovenia

An analogue of Plavix, Cardiomagnyl, is based on the action of acetylsalicylic acid. Available in two dosages - 75 and 150 mg, available freely without a doctor's prescription. Additionally contains magnesium hydroxide, which protects the gastric mucosa from irritation. Substitutes for Cardiomagnyl with the same composition are Trombital, Fazostabil, Trombomag.

Patients are interested in the question of whether to take Plavix and Cardiomagnil together or separately. It is possible to prescribe antithrombotic drugs together: Plavix in the morning, Cardiomagnyl before bedtime. Upon discharge, you should check with the treating cardiologist, since the order of administration may be affected by additional medications used.

Aspirin Cardio

The source of acetylsalicylic acid for thinning the blood and preventing heart attack, stroke and thromboembolism is the German medicine Aspirin Cardio. It is sold freely from pharmacies and is produced in two dosages - 100 and 300 mg. Possible combination with Plagril, Plavix and structural analogues.

A substitute for Plavix is ​​the French drug Coplavix, containing 75 mg of clopidogrel and 100 mg of acetylsalicylic acid (ASA). The advantage of the analogue is its convenient use and replacement of individual medications. As a result, improved platelet functionality is observed and the risk of vascular complications is reduced. Structural analogs of Coplavix are Plagril A (75 mg clopidogrel and 75 mg ASA), Clopigrant A (75+100) and Lopirel Combi (75+100). Used after stenting.

Aspirin

Pure Aspirin or acetylsalicylic acid is available in 500 mg tablets. One-fourth of the tablet is taken for high blood pressure and the risk of heart attack to prevent thrombosis and complications. The price of this analogue of Plavix is ​​up to 50 rubles. Aspirin has a negative effect on the mucous membrane of the stomach and intestines and can lead to erosions, ulcers and bleeding. The disadvantage of the drug is the need for division; it is possible that the required amount of ASA is exceeded or undersupplied.

Lopirel

A cheaper analogue of Plavix is ​​Lopirel. Also contains clopidogrel at a dosage of 75 mg. It has the same indications, contraindications, and adverse reactions. It is possible to use it together with acetylsalicylic acid to enhance the effect or use the complex drug Lopirel Combi.

Eliquis

The original drug Eliquis is based on the substance apixaban, which is a direct anticoagulant. It is used for the prevention and treatment of thromboembolism, thrombosis and stroke, after knee and hip joint replacement. Dispensed with a doctor's prescription. The frequency of administration is twice a day for a long time.

Thrombo ACC

The Austrian analogue of Trombo ACC is a source of acetylsalicylic acid, available without a prescription. Indicated for the prevention of acute heart attack in the presence of risk factors, stroke, cerebrovascular accident, thromboembolism and thrombosis. Available in two dosages - 50 and 100 mg. Taken once a day.

Xarelto

The German drug Xarelto is available in dosages of 2.5, 10, 15 and 20 mg and is an anticoagulant. The medicinal properties are provided by the active component included in the composition - rivaroxaban. Used after surgery on the lower extremities to prevent thromboembolism once a day. Which is better, Plavix or Xarelto, depends on the indications and condition of the patient.

A substitute for Plavix, Pradaxa, is an original anticoagulant that has been clinically studied in patients. Belongs to the group of direct thrombin inhibitors. Based on the active substance – dabigatran.

Used to prevent and treat deep vein thrombosis, thromboembolism, better after stenting than similar analogues.

Available in capsules of different dosages (75, 110, 150 mg) and taken 1-2 times a day. The dosage and frequency of administration is determined by a specialist individually.

Which is better, Plavix or Pradaxa, depends on the indications and condition of the patient. Pradaxa is prescribed in cases where a patient develops bleeding while taking Clopidogrel or Acetylsalicylic acid.

Plagril or Plavix – which is better?

Plagril and Plavix are imported generics based on clopidogrel. Available in tablets, they have the same indications and contraindications. They differ in manufacturer and price. It is difficult to say for sure which is better - Plagril or Plavix, since clinical trials have not been conducted to compare the two medications.

Plavix is ​​a French medicine from 900 to 3500 rubles. It is produced in two dosages - 75 and 300 mg.

Plagril is an analogue from India. The price of the medicine is from 400 to 750 rubles. The difference is that it is produced in a dosage of 75 mg or with prefix A containing acetylsalicylic acid.

Brilinta or Plavix

Brilinta is an antiplatelet drug based on ticagrelor. Available in tablets of two dosages - 60 and 90 mg. It is used to prevent atherothrombotic complications in patients who had a heart attack a year ago or more in combination with acetylsalicylic acid twice a day.

Plavix is ​​also used to prevent and treat acute myocardial infarction and recurrent cases. Whether it is possible to replace Brilinta with Plavix is ​​determined by a cardiologist based on your medical history.

Plavix or Clopidogrel – which is better after stenting

Clopidogrel is an analogue of Plavix in Russia. Produced by domestic manufacturers (Izvarino, Severnaya Zvezda, Canon, Biokom, Tatkhimfarm) and imported factories (Teva, Richter).

Buyers are concerned with the question of what is the difference between Clopidogrel or Plavix. It contains the same substance – clopidogrel, which provides the same medicinal properties, indications and contraindications. They differ in price (Plavix is ​​several times more expensive), country of origin, quality of raw materials, technology. When replacing Plavix, you should check with your cardiologist which brand of analogue to choose.

Zilt or Plavix - which is better?

Zilt and Plavix are analogues in terms of active substance and medicinal properties. They contain clopidogrel 75 mg. They differ in price (Plavix is ​​more expensive) and country of origin. According to doctors, both medicines are high-quality and effective. It is possible to replace one with another.

The difference is the dosage of the drugs. If additional load is needed, it is more convenient to use Plavix. It is available in tablets of 75 and 300 mg, which makes it possible not to drink 3-4 tablets per dose at once to achieve the desired dose.

The choice of analogues must be coordinated with a cardiologist, listening to the recommendations regarding the manufacturer, time of administration and duration. The drugs are available with a doctor's prescription and are taken for a long time. If necessary, you should regularly donate blood to determine clotting factors.

pharmachologic effect

Antiplatelet agent. Clopidogrel is a prodrug, one of whose metabolites is active and inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y 12 platelet receptor and subsequent ADP-mediated activation of the glycoprotein IIb/IIIa complex, leading to suppression of platelet aggregation. Due to irreversible binding, platelets remain immune to ADP stimulation for the remainder of their life (approximately 7-10 days), and restoration of normal platelet function occurs at a rate consistent with platelet turnover.

Platelet aggregation caused by agonists other than ADP is also inhibited by blocking enhanced platelet activation by released ADP.

Because the formation of the active metabolite occurs with the help of isoenzymes of the P450 system, some of which may differ in polymorphism or may be inhibited by other drugs; not all patients have adequate inhibition of platelet aggregation. When taking clopidogrel daily 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 (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 returned to baseline levels within an average of 5 days.

When comparing the pharmacodynamic properties of clopidogrel in men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but no sex differences in prolongation of bleeding time were detected.

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

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

In patients with acute myocardial infarction (MI) with ST segment elevation, take Plavix ® (during the first 12 hours of MI, loading dose is 300 mg, then 75 mg/day) in combination with ASA (loading dose 150-325 mg, then - 75-162 mg 1 time / day) and a fibrinolytic and, if indicated, with heparin, reduces the combined rate of occlusion of a coronary artery related to the infarction zone detected by angiography at the time of discharge from the hospital, or deaths, or the development of recurrent myocardial infarction ; and for patients who did not undergo angiography at discharge, the incidence of death or recurrent MI before the 8th day of MI or until discharge from the hospital, mainly due to a decrease in the incidence of coronary artery occlusion related to the infarction zone.

In patients with acute MI with ST segment elevation, ST segment depression, or left bundle branch block, taking Plavix ® 75 mg/day in combination with ASA 162 mg 1 time/day leads to a reduction in the incidence of deaths from any cause and total incidence of first recurrent myocardial infarction, stroke and deaths.

Pharmacokinetics

Suction

Absorption data were obtained when clopidogrel was administered orally at a dose of 75 mg.

After a single dose and during a course of oral administration at a dose of 75 mg/day, clopidogrel is rapidly absorbed. The average C max of unchanged clopidogrel in blood plasma is approximately 2.2-2.5 ng/ml and is achieved approximately 45 minutes after administration. According to the excretion of clopidogrel metabolites by the kidneys, its absorption is approximately 50%.

Distribution

In vitro, clopidogrel and its main inactive metabolite circulating in the blood are reversibly bound to plasma proteins - 98% and 94%, respectively. This bond is unsaturated up 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 with the formation of an inactive carboxylic acid derivative (85%) from metabolites circulating in the systemic circulation), and the second way - through the cytochrome P450 system. Initially, clopidogrel is metabolized to 2-oxoclopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxoclopidogrel leads to the formation of the active metabolite of clopidogrel, the thiol derivative of clopidogrel. In vitro, this metabolic pathway occurs with the participation of the isoenzymes CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite of clopidogrel, which was isolated in in vitro studies, rapidly and irreversibly binds to platelet receptors, thereby inhibiting platelet aggregation.

With a single dose of Plavix ® at a loading dose of 300 mg, the Cmax of the active metabolite is 2 times higher than the Cmax when taking Plavix ® at a maintenance dose of 75 mg for 4 days. C max of the active metabolite is achieved 30-60 minutes after taking Plavix ® .

Removal

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

Pharmacokinetics in special clinical situations

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

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

The pharmacokinetics of clopidogrel in children has not been studied.

In patients with severe kidney damage (creatinine clearance 5-15 ml/min) after repeated doses of clopidogrel at a dose of 75 mg/day, the initiation of ADP-induced platelet aggregation was lower (25%) compared to that in healthy volunteers, but bleeding time was prolonged similar to that in healthy volunteers receiving clopidogrel at a dose of 75 mg/day.

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

The prevalence of alleles of the CYP2C9 isoenzyme genes responsible for intermediate and reduced metabolism differs among representatives of different racial groups. There are very few literary data among representatives of the Mongoloid race, which does not allow us to assess the significance of genotyping the CYP2C19 isoenzyme for the development of ischemic complications.

Pharmacogenetics

With the help of the CYP2C19 isoenzyme, both the active metabolite and the intermediate metabolite - 2-oxoclopidogrel - are formed. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel, when studying platelet aggregation ex 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*2 and CYP2C19*3 genes are non-functional. Alleles of the CYP2C19*2 and CYP2C19*3 genes are the cause of decreased metabolism in the majority of representatives of the Caucasian (85%) and Mongoloid races (99%). Other alleles associated with absent or decreased metabolism are less common and include, but are not limited to, the CYP2C19*4, *5, *6, *7, and *8 alleles. Patients who are poor metabolizers must have the two loss-of-function gene alleles listed above. Published frequencies of CYP2C19 poor metabolizer phenotypes are 2% in Caucasians, 4% in Blacks, and 14% in Chinese.

In a crossover study conducted on 40 volunteers, 10 people in each group (ultrarapid metabolizers, extensive metabolizers, intermediate metabolizers, poor metabolizers), the pharmacokinetics and antiplatelet effects of clopidogrel were assessed at a dose of 300 mg followed by 75 mg/day and when taking clopidogrel at a dose of 600 mg followed by 150 mg/day for 5 days (reaching an equilibrium state). There were no significant differences in active metabolite exposure and mean platelet aggregation inhibition (API) (ADP-induced) values ​​between ultrarapid, extensive, and intermediate metabolizers. In poor metabolizers, exposure to the active metabolite was reduced by 63-71% compared to extensive metabolizers. When using the 300 mg/75 mg treatment regimen in poor metabolizers, the antiplatelet effect was reduced with average IAT values ​​of 24% (at 24 hours) and 37% (at 5 days of treatment) compared with IAT of 39% (at 24 hours). and 58% (on day 5 of treatment) in extensive metabolizers and 37% (after 24 hours) and 60% (on day 5 of treatment) in intermediate metabolizers. When poor metabolizers received the 600 mg/150 mg regimen, exposure to the active metabolite was higher than when receiving the 300 mg/75 mg regimen. In addition, the IAT was 32% (at 24 hours) and 61% (at day 5 of treatment), which was greater than that of poor metabolizers receiving the 300 mg/75 mg regimen and was similar to that in the groups of patients with higher intensity CYP2C19 -metabolism, receiving a treatment regimen of 300 mg/75 mg. However, clinical outcome studies have not yet established a clopidogrel dosing regimen for patients in this group.

Consistent with the results of this study, a meta-analysis of six studies that included data from 335 volunteers treated with clopidogrel at steady state found that intermediate metabolizers had a 28% reduction in active metabolite exposure and a 28% reduction in poor metabolizers. 72%, although IAT was reduced compared to extensive metabolizers with differences in IAT being 5.9% and 21.4%, respectively.

The effect of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been assessed in prospective, randomized, controlled studies. However, few retrospective analyzes are currently available. Genotyping results are available from the following clinical studies: CURE, CHARISMA, CLARITY-TIMI 28, TRITON-TIMI 38 and ACTIVE-A, as well as several published cohort studies.

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

In the CHARISMA study and one cohort study (Simon), an increase in the incidence of cardiovascular events was observed only in poor metabolizers (when compared with extensive metabolizers).

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

Indications

Prevention of atherothrombotic complications (in combination with acetylsalicylic acid) in patients with acute coronary syndrome:

- without ST segment elevation (unstable angina or non-Q wave myocardial infarction), including patients who underwent stenting during percutaneous coronary intervention;

- with ST segment elevation (acute myocardial infarction).

Dosage regimen

Adults and elderly patients should take Plavix ® orally, regardless of meals. The drug in a dose of 300 mg is intended for use as a loading dose in patients with acute coronary syndrome.

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

Treatment with clopidogrel should begin with a single loading dose of 300 mg, and then continue with a dose of 75 mg 1 time / day (in combination with acetylsalicylic acid in doses of 75-325 mg / day). Since the use of acetylsalicylic acid in higher doses 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 is observed by the third month of treatment. The course of treatment is up to 1 year.

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

Clopidogrel is prescribed as a single dose of 75 mg 1 time/day with an initial single dose of 300 mg in combination with acetylsalicylic acid and thrombolytics (or without thrombolytics). Combination therapy is started as soon as possible after the onset of symptoms and continued for at least 4 weeks. U patients over 75 years old

For a maintenance dose of clopidogrel (75 mg), Plavix ® 75 mg tablets are used.

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

The status of a weak CYP2C19 metabolizer is associated with a decrease in the antiplatelet effect of clopidogrel. The regimen of high doses (600 mg loading dose, then 150 mg 1 time/day daily) in poor metabolizers increases the antiplatelet effect of clopidogrel. However, the optimal dosing regimen for patients with reduced metabolism by the CYP2C19 isoenzyme in clinical trials for clinical outcomes has not yet been established.

Side effect

Side effects observed in clinical studies

The safety of clopidogrel has been studied in more than 44,000 patients, incl. in more than 1200 patients treated for a year or more. The tolerability of clopidogrel at a dose of 75 mg/day in the CAPRIE study corresponded to the tolerability of acetylsalicylic acid at a dose of 325 mg/day. The overall tolerability of clopidogrel was similar to that of acetylsalicylic acid, regardless of the age, gender and race of the patients. The following are clinically significant adverse effects observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A.

Bleeding

The overall incidence of all bleeding in patients receiving either clopidogrel or acetylsalicylic acid was 9.3%. The incidence of severe bleeding with clopidogrel was 1.4%, and with acetylsalicylic acid - 1.6%.

In patients receiving clopidogrel and in patients receiving acetylsalicylic acid, gastrointestinal bleeding occurred in 2% and 2.7% of cases, respectively, and hospitalization was required in 0.7% and 1.1% of cases.

The incidence of other bleeding events was higher in patients receiving clopidogrel than in patients receiving acetylsalicylic acid (7.3% versus 6.5%, respectively). However, the incidence of major bleeding was similar in both groups (0.6% vs 0.4%). The most common symptoms observed in both groups were purpura/bruising and epistaxis. Hematomas, hematuria and ocular hemorrhages (mainly conjunctival) were less common. The incidence of intracranial hemorrhage was 0.4% in patients receiving clopidogrel and 0.5% in patients receiving acetylsalicylic acid.

In the CURE clinical trial

There was an increase in the incidence of major and minor bleeding in the clopidogrel + acetylsalicylic acid group compared with the placebo + acetylsalicylic acid group (incidence rate 3.7% versus 2.7% for major bleeding and 5.1% versus 2.4% for minor bleeding). The main locations of major bleeding were gastrointestinal bleeding and bleeding at the site of arterial puncture.

The use of a combination of clopidogrel with acetylsalicylic acid compared with the use of a combination of placebo with acetylsalicylic acid did not lead to a statistically significant increase in the incidence of life-threatening bleeding (2.2% and 1.8%), respectively) and fatal bleeding (0.2% in both groups). The incidence of non-life-threatening major bleeding was significantly higher in the clopidogrel + acetylsalicylic acid group compared with the placebo + acetylsalicylic acid group (1.6% versus 1%), and the incidence of intracranial hemorrhage in both groups was 0.1%.

The incidence of major bleeding when using the combination of clopidogrel + acetylsalicylic acid depended on the dose of the latter (<100 мг - 2.6%; 100-200 мг - 3.5%, >200 mg - 4.9%), the same as their frequency when using acetylsalicylic acid alone (<100 мг - 2%, 100-200 мг - 2.3%, >200 mg - 4%). In patients who stopped taking the drug more than 5 days before coronary artery bypass surgery, there was no increase in the incidence of major bleeding within 7 days after this procedure (4.4% when taking clopidogrel + acetylsalicylic acid versus 5.3% when taking acetylsalicylic acid alone). In patients who remained on antiplatelet therapy during the last five days before coronary artery bypass surgery, the incidence of these complications after the intervention was 9.6% (clopidogrel + acetylsalicylic acid) and 6.3% (acetylsalicylic acid alone).

In the CLARITY clinical trial

The incidence of major bleeding (defined as intracranial bleeding or bleeding associated with a decrease in hemoglobin of more than 5 g/dL) was similar in the clopidogrel + acetylsalicylic acid and placebo + acetylsalicylic acid groups (1.3% versus 1.1%) and was essentially independent of baseline patient characteristics and type of fibrinolytic therapy or heparin therapy. The incidence of fatal bleeding (0.8% and 0.6% in the clopidogrel + acetylsalicylic acid and placebo + acetylsalicylic acid groups, respectively) and intracranial hemorrhage (0.5% and 0.7% in the clopidogrel + acetylsalicylic acid and placebo + acetylsalicylic acid groups, respectively) was low and did not differ significantly in both treatment groups.

In the COMMIT clinical trial

The overall incidence of non-cerebral major bleeding or cerebral bleeding was low and did not differ significantly between the two groups (0.6% and 0.5% in the clopidogrel + acetylsalicylic acid and placebo + acetylsalicylic acid groups, respectively).

In the ACTIVE A study, the incidence of major bleeding in the clopidogrel + acetylsalicylic acid group was higher than in the placebo + acetylsalicylic acid group (6.7% versus 4.3%). Major bleeding was mainly extracranial in both groups (5.3% in the clopidogrel + acetylsalicylic acid group; 3.5% in the placebo + acetylsalicylic acid group), and gastrointestinal bleeding was mainly observed (3.5% vs 1.8%). There were more intracranial hemorrhages in the clopidegrel + acetylsalicylic acid group (1.4% versus 0.8%, respectively).

There were no statistically significant differences between treatment groups in the incidence of fatal bleeding and hemorrhagic stroke (0.8% and 0.6%, respectively).

Hematological disorders

In the CAPRIE clinical trial

Severe neutropenia (<0.45×10 9 /л) наблюдалась у 4 больных (0.04%), получавших клопидогрел, и у 2 больных (0.02%), получавших ацетилсалициловую кислоту. У двух из 9599 пациентов, получавших клопидогрел, число нейтрофилов было равно нулю, а ни у одного из 9586 пациентов, получавших ацетилсалициловую кислоту, такой степени снижения количества нейтрофилов не отмечалось. В ходе лечения клопидогрелом наблюдался один случай апластической анемии.

Incidence of severe thrombocytopenia (<80×10 9 /л) составляла 0.2% в группе клопидогрела и 0.1% в группе ацетилсалициловой кислоты.

In the CURE and CLARITY clinical studies

The number of patients with thrombocytopenia or neutropenia was similar in both groups.

Other clinically significant side effects

Side effects observed in clinical studies CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A with a frequency of ≥ 0.1%, as well as all serious side effects are presented below, according to the following classification: very common (≥ 10%); often (≥1% and<10%); нечасто (≥0.1% и <1%); редко (≥0.01% и <0.1%), очень редко (<0.01%).

From the nervous system: uncommon - headache, dizziness and paresthesia; rarely - vertigo.

often - diarrhea, abdominal pain, dyspepsia; uncommon - gastric and duodenal ulcers, gastritis, vomiting, nausea, constipation, flatulence.

infrequently - prolongation of bleeding time.

uncommon - thrombocytopenia; leukopenia, neutropenia and eosinophilia.

For the skin and subcutaneous tissues: infrequently - rash, itching.

Side effects observed in the post-marketing period

From the blood coagulation system: very rarely - cases of serious bleeding, mainly in the subcutaneous fat, muscles and joints, ocular hemorrhages (conjunctival, in the tissue and retina of the eye), bleeding from the respiratory system, nosebleeds, hematuria, bleeding from a postoperative wound; cases of fatal bleeding (mainly intracranial, gastrointestinal and retroperitoneal).

From the hematopoietic system: very rarely - agranulocytosis, aplastic anemia/pancytopenia, thrombocytopenic thrombohemolytic purpura.

From the immune system: very rarely - anaphylactoid reactions, serum sickness.

From the mental side: very rarely - confusion, hallucinations.

From the nervous system: very rarely - changes in taste sensations.

From the cardiovascular system: very rarely - vasculitis, decreased blood pressure.

From the respiratory system: very rarely - bronchospasm, interstitial pneumonitis.

From the digestive system: very rarely - pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis, changes in liver tests, hepatitis (non-infectious), acute liver failure.

Allergic reactions: very rarely - urticaria, angioedema.

Dermatological reactions: very rarely - maculopapular or erythematous rash, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), eczema and lichen planus.

From the musculoskeletal system: very rarely - arthralgia, arthritis, myalgia.

From the urinary system: very rarely - glomerulopathy, increased serum creatinine.

Others: very rarely - fever.

Contraindications for use

- severe liver failure;

- acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage;

- rare hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome;

- pregnancy;

- lactation period;

- children under 18 years of age (safety and effectiveness of use have not been established);

- hypersensitivity to the components of the drug.

WITH caution

- with moderate liver failure, in which there may be a predisposition to bleeding (limited clinical experience);

- for renal failure (limited clinical experience);

- in case of injuries, surgical interventions (risk of increased bleeding);

- for diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal or intraocular);

- while taking NSAIDs, incl. and selective COX-2 inhibitors;

- with simultaneous administration of warfarin, heparin, glycoprotein IIb/IIIa inhibitors;

- in patients with a genetically determined decrease in the function of the CYP2C19 isoenzyme (in patients who are weak CYP2C19 metabolizers, when clopidogrel is used in recommended doses, less of the active metabolite of clopidogrel is formed and its antiplatelet effect is less pronounced; weak metabolizers receiving clopidogrel in recommended doses in acute coronary heart disease syndrome or percutaneous coronary intervention, may have a higher incidence of cardiovascular complications than patients with normal CYP2C19 function).

Use during pregnancy and breastfeeding

As a precautionary measure, the use of clopidogrel during pregnancy is not recommended 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 pregnancy, embryonic development, childbirth and postnatal development.

Breastfeeding should be discontinued when treated with clopidogrel, because Clopidogrel and/or its metabolites have been shown to be excreted in breast milk.

Use in children

Contraindicated in children and adolescents under 18 years of age.

Overdose

Symptoms: An overdose of clopidogrel can lead to an increase in bleeding time with subsequent complications in the form of bleeding.

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

Drug interactions

Warfarin: simultaneous use with clopidogrel may increase the intensity of bleeding, so the use of this combination is not recommended.

Glycoprotein IIb/IIIa blockers: Prescribing glycoprotein IIb/IIIa blockers together with clopidogrel requires caution in patients with an increased risk of bleeding (in cases of trauma and surgery or other pathological conditions).

Acetylsalicylic acid: acetylsalicylic acid does not change the effect of clopidogrel, which inhibits ADP-induced platelet aggregation, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, simultaneous administration of acetylsalicylic acid 500 mg 2 times a day with clopidogrel for 1 day did not cause a significant increase in the bleeding time caused by taking clopidogrel. There may be a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid, which 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 acetylsalicylic acid for up to one year.

Heparin: According to a clinical trial conducted in healthy subjects, when taking clopidogrel, no change in the dose of heparin was required and its anticoagulant effect did not change. Concomitant use of heparin did not change 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 these drugs requires caution.

Thrombolytics: The safety of combined use of clopidogrel, fibrin-specific or fibrin-nonspecific thrombolytic drugs and heparin has been studied in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed in the case of combined use of thrombolytic agents and heparin with acetylsalicylic acid.

NSAIDs: in a clinical study conducted in healthy volunteers, co-administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies between clopidogrel and other NSAIDs, it is currently not known whether there is an increased risk of gastrointestinal bleeding when clopidogrel is taken with other NSAIDs. Therefore, the prescription of NSAIDs, incl. COX-2 inhibitors should be used with caution in combination with clopidogrel.

Other combination therapy

Because Clopidogrel is metabolized to the formation of its active metabolite in part by the isoenzyme CYP2C19; the use of drugs that inhibit this system may lead to a decrease in the concentration of the active metabolite of clopidogrel. The clinical significance of this interaction has not been established. Concomitant use of strong or moderate CYP2C19 inhibitors (eg, omeprazole) with clopidogrel should be avoided. If proton pump inhibitors must be co-administered with clopidogrel, the proton pump inhibitor with the least CYP2C19 inhibitory activity, such as pantoprazole, should be used.

Proton pump inhibitors

In clinical studies, it was shown that simultaneous administration of clopidogrel in a standard regimen (300 mg loading dose / 75 mg maintenance dose) and omeprazole 80 mg led to a significant decrease in the formation of the active metabolite of clopidogrel and its antiplatelet effect, regardless of whether these drugs were taken simultaneously or at intervals of 12 hours. However, when using a high-dose regimen of clopidogrel (600 mg loading dose/150 mg maintenance dose), the formation of the active metabolite and platelet aggregation were the same as when taking clopidogrel alone with a standard dosage regimen.

With simultaneous use of clopidogrel (300 mg loading dose, then 75 mg/day maintenance dose) and pantoprazole 80 mg, exposure to the active metabolite of clopidogrel was reduced by 20% (day 1) and 14% (day 5). The mean platelet aggregation inhibition was reduced by 15% (at 24 hours) and 11% (at 5 days). These minor changes suggest that clopidogrel can be taken in combination with pantoprazole.

The CURRENT trial showed no interaction between clopidogrel and proton pump inhibitors (mainly omeprazole and pantoprazole) for the primary endpoints (cardiovascular death, myocardial infarction, or stroke) and some secondary endpoints, including stent thrombosis.

Warfarin

Although clopidogrel 75 mg/day did not alter the pharmacokinetics of warfarin (a CYP2C19 substrate) or MHO in patients receiving long-term warfarin treatment, concomitant use of clopidogrel increases the risk of bleeding due to its independent additive effect on hemostasis. However, at high concentrations in vitro, clopidogrel inhibited CYP2C19 activity.

A number of clinical studies have been conducted with clopidogrel and other concomitantly prescribed drugs to study possible pharmacodynamic and pharmacokinetic interactions, which showed that:

- when clopidogrel was used together with atenolol, nifedipine, or with both drugs at the same time, no clinically significant pharmacodynamic interaction was observed;

- simultaneous use of phenobarbital and estrogens did not have a significant effect on the pharmacodynamics of clopidogrel;

— the pharmacokinetic parameters of digoxin and theophylline did not change when they were used together with clopidogrel;

- antacids did not reduce the absorption of clopidogrel;

- Phenytoin and tolbutamide can be safely used concomitantly with clopidogrel (CAPRIE study), although data obtained from studies with human liver microsomes indicate that the carboxyl metabolite of clopidogrel may inhibit the activity of the CYP2C9 isoenzyme of the cytochrome P450 family, which may lead to increased plasma concentrations of certain drugs (phenytoin, tolbutamide and some NSAIDs), which are metabolized by the CYP2C9 isoenzyme,

- ACE inhibitors, diuretics, beta-blockers, slow calcium channel blockers, lipid-lowering agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, hormone replacement therapy and glycoprotein IIb/IIIa blockers: not identified in clinical studies clinically significant adverse interaction.

Conditions for dispensing from pharmacies

The drug is available with a prescription.

Storage conditions and periods

The drug should be stored out of the reach of children at a temperature not exceeding 30°C. Shelf life - 3 years.

Use for liver dysfunction

Contraindicated in severe liver failure.

Use with caution in moderate hepatic impairment, which may predispose to bleeding (limited clinical experience).

Use for renal impairment

Use with caution in renal failure (limited clinical experience).

Use in elderly patients

U patients over 75 years old Treatment with clopidogrel should be started without taking a loading dose.

special instructions

When treating with clopidogrel, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients must be carefully monitored to exclude signs of bleeding, incl. and hidden.

Due to the risk of bleeding and hematological undesirable effects, if clinical symptoms suspicious for bleeding appear during treatment, you should urgently do a clinical blood test, determine APTT, platelet count, indicators of platelet functional activity and conduct other necessary studies.

Clopidogrel, as well as other antiplatelet drugs, should be used with caution in patients with trauma, surgery or other pathological conditions, due to the risk of increased bleeding, as well as in patients receiving acetylsalicylic acid, NSAIDs, incl. COX-2 inhibitors, heparin or glycoprotein IIb/IIIa inhibitors due to an increased risk of bleeding.

The combined use of clopidogrel with warfarin may increase the intensity of bleeding, therefore, with the exception of very rare clinical situations (such as the presence of a floating thrombus in the left ventricle, stenting in patients with atrial fibrillation), the combined use of clopidogrel and warfarin is not recommended.

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

Patients should be warned that when taking clopidogrel (alone or in combination with acetylsalicylic acid) it may take longer to stop bleeding, and that if they experience unusual bleeding (in location or duration) they should be informed talk to your doctor about this. Before any upcoming surgery and before starting any new drug, patients should tell their doctor (including their dentist) that they are taking clopidogrel.

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

During treatment, it is necessary to monitor the functional activity of the liver. In case of severe liver damage, one should remember the risk of developing hemorrhagic diathesis.

Taking clopidogrel is not recommended for acute stroke less than 7 days old (as there is no data on its use in this condition). Plavix ® should not be taken by patients with rare hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome.

In patients who are weak CYP2C19 metabolizers of clopidogrel at recommended doses, less of the active metabolite of clopidogrel is formed and its effect on platelet function is less pronounced. Patients with acute coronary syndrome or undergoing percutaneous coronary intervention who are poor CYP2C19 metabolizers receiving clopidogrel at recommended doses may have a higher incidence of cardiovascular events than patients with normal CYP2C19 function. Tests are available for genotyping the CYP2C19 isoenzyme; these tests can be used to help determine therapeutic strategy. The use of higher doses of clopidogrel in patients with an established weak CYP2C19 metabolizer genotype may be discussed.

Impact on the ability to drive vehicles and operate machinery

Plavix ® does not significantly affect the abilities required to drive a car or operate machinery.

In this article you can read the instructions for use of the drug Plavix. Reviews of site visitors - consumers of this medicine, as well as the opinions of specialist doctors on the use of Plavix in their practice are presented. We kindly ask you to actively add your reviews about the drug: whether the medicine helped or did not help get rid of the disease, what complications and side effects were observed, perhaps not stated by the manufacturer in the annotation. Analogues of Plavix in the presence of existing structural analogues. Use for the treatment and prevention of thrombosis and thromboembolism in patients with heart attack and angina in adults, children, as well as during pregnancy and lactation. Composition of the drug.

Plavix- antiplatelet agent. It 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 ADP to the platelet P2Y12 receptor and subsequent ADP-mediated activation of the glycoprotein 2b/3a complex, leading to suppression of platelet aggregation. Due to irreversible binding, platelets remain immune to ADP stimulation for the remainder of their life (approximately 7-10 days), and restoration of normal platelet function occurs at a rate consistent with platelet turnover.

Platelet aggregation induced by agonists other than ADP is also inhibited by blocking enhanced platelet activation by released ADP.

Because the formation of the active metabolite occurs with the participation of isoenzymes of the P450 system, some of which differ in polymorphism or are inhibited by other drugs; not all patients have adequate platelet suppression.

When taking clopidogrel daily 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 (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 levels within an average of 5 days.

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

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 plus acetylsalicylic acid (compared with acetylsalicylic acid alone) ) reduced the combined incidence of stroke, myocardial infarction, non-central nervous system (CNS) systemic thromboembolism, or vascular death, largely due to a reduction in the risk of stroke. The effectiveness of taking clopidogrel in combination with acetylsalicylic acid was detected early and persisted for up to 5 years. The reduction in the risk of major vascular complications in the group of patients taking clopidogrel in combination with acetylsalicylic acid was mainly due to a greater reduction in the incidence of strokes. The risk of stroke of any severity was reduced when taking clopidogrel in combination with acetylsalicylic acid, and there was a trend towards a decrease in the incidence of myocardial infarction in the group treated with clopidogrel in combination with acetylsalicylic acid, but there was no difference in the incidence of non-CNS thromboembolism or vascular death. In addition, taking clopidogrel in combination with acetylsalicylic acid reduced the total number of days of hospitalization for cardiovascular reasons.

Compound

Clopidogrel hydrosulfate + excipients.

Pharmacokinetics

With a single or repeated oral dose of 75 mg per day, Plavix is ​​quickly absorbed. Based on the excretion of clopidogrel metabolites in urine, its absorption is approximately 50%.

Clopidogrel is extensively metabolized in the liver. Clopidogrel is metabolized in two ways: the first - through esterases and subsequent hydrolysis with the formation of an inactive carboxylic acid derivative (85% of circulating metabolites), the second - through isoenzymes of the cytochrome P450 system.

Within 120 hours after human ingestion of 14C-labeled clopidogrel, about 50% of the radioactivity is excreted in the urine and approximately 46% in the feces.

Indications

Prevention of atherothrombotic complications:

• in adult patients with myocardial infarction (with duration from several days to 35 days), with ischemic stroke (with duration from 7 days to 6 months), with diagnosed occlusive disease of peripheral arteries;
• in adult patients with acute coronary syndrome without ST segment elevation (unstable angina or non-Q wave myocardial infarction), including patients who underwent stenting during percutaneous coronary intervention (in combination with acetylsalicylic acid);
• in adult patients with acute coronary syndrome with ST segment elevation (acute myocardial infarction) with drug treatment and the possibility of thrombolysis (in combination with acetylsalicylic acid).

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

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

Release forms

Film-coated tablets 75 mg and 300 mg.

Instructions for use and dosage regimen

Tablets 75 mg

The drug is taken orally, regardless of food intake.

Adults and elderly patients with normal CYP2C19 isoenzyme activity

Myocardial infarction, ischemic stroke and diagnosed peripheral arterial occlusive disease

The drug is prescribed in a dose of 75 mg 1 time per day.

Treatment with Plavix should begin with a single dose of 300 mg loading dose, and then continue at a dose of 75 mg once a day (in combination with acetylsalicylic acid in doses of 75-325 mg per day). Since the use of acetylsalicylic acid in higher doses is associated with an increased risk of bleeding, the recommended dose of acetylsalicylic acid for this indication does not exceed 100 mg. The optimal duration of treatment has not been formally determined. Data from clinical studies support taking the drug for up to 12 months, and the maximum beneficial effect was observed by the 3rd month of treatment

Plavix is ​​prescribed as a single dose of 75 mg 1 time per day with an initial single dose of a loading dose in combination with acetylsalicylic acid and thrombolytics or without combination with thrombolytics. In patients over 75 years of age, treatment with Plavix should be started without taking a loading dose. Combination therapy is started as soon as possible after the onset of symptoms and continued for at least 4 weeks. The effectiveness of the combination of clopidogrel and acetylsalicylic acid for this indication for more than 4 weeks has not been studied.

Atrial fibrillation (atrial fibrillation)

Plavix is ​​prescribed 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 per day).

Skipping a dose

If less than 12 hours have passed since you missed the next dose, you should immediately take the missed dose of the drug, and then take the next doses at the usual time.

If more than 12 hours have passed since the next dose was missed, the patient should take the next dose at the usual time (do not take a double dose).

Special patient groups

In elderly volunteers (over 75 years of age), when compared with young volunteers, there were no differences in platelet aggregation and bleeding time. Elderly patients do not require dose adjustment.

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

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

Patients of different ethnic backgrounds. 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 only limited data for representatives of the Mongoloid race to assess the effect of CYP2C19 isoenzyme genotype on clinical manifestations.

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

Tablets 300 mg

Adults and elderly patients should take Plavix orally, regardless of meals. The drug in a dose of 300 mg is intended for use as a loading dose in patients with acute coronary syndrome.

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

Treatment with clopidogrel should begin with a single loading dose of 300 mg, and then continue with a dose of 75 mg once a day (in combination with acetylsalicylic acid in doses of 75-325 mg per day). Since the use of acetylsalicylic acid in higher doses 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 is observed by the third month of treatment. The course of treatment is up to 1 year.

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

Clopidogrel is prescribed as a single dose of 75 mg 1 time per day with an initial single dose of 300 mg in combination with acetylsalicylic acid and thrombolytics (or without thrombolytics). Combination therapy is started as soon as possible after the onset of symptoms and continued for at least 4 weeks. In patients over 75 years of age, treatment with clopidogrel should be started without taking a loading dose.

For a maintenance dose of clopidogrel (75 mg), Plavix 75 mg tablets are used.

Side effect

• thrombocytopenia, leukopenia, eosinophilia, neutropenia, thrombotic thrombocytopenic purpura, aplastic anemia, pancytopenia, agranulocytosis, granulocytopenia, anemia;
• serum sickness;
• anaphylactoid reactions;
• intracranial hemorrhage (several fatal cases have been reported);
• headache;
• paresthesia;
• dizziness;
• taste disturbances;
• hallucinations;
• confusion;
• ocular hemorrhages (conjunctival, in the tissue and retina of the eye);
• hematoma;
• serious bleeding from the surgical wound;
• vasculitis;
• decrease in blood pressure;
• nose bleed;
• bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage);
• bronchospasm;
• interstitial pneumonia;
• gastrointestinal bleeding;
• diarrhea;
• stomach ache;
• dyspepsia;
• stomach and duodenal ulcers;
• vomiting, nausea;
• constipation;
• bloating;
• retroperitoneal hemorrhage;
• gastrointestinal bleeding and retroperitoneal hemorrhage with fatal outcome;
• colitis (including nonspecific ulcerative colitis or lymphocytic colitis);
• stomatitis;
• acute liver failure;
• hepatitis;
• subcutaneous bruising;
• rash;
• purpura (subcutaneous hemorrhage);
• bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme);
• hives;
• eczema;
• lichen planus;
• hemorrhages in muscles and joints;
• arthritis;
• arthralgia;
• myalgia;
• hematuria;
• glomerulonephritis;
• increased concentration of creatine in the blood;
• fever;
• bleeding from the site of vascular puncture;
• increased bleeding time;
• decrease in the number of neutrophils;
• decrease in the number of platelets in peripheral blood.

Contraindications

• severe liver failure;
• acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage;
• rare hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome;
• pregnancy;
• lactation period (breastfeeding);
• children under 18 years of age (safety and effectiveness of use have not been established);
• hypersensitivity to the components of the drug.

Use during pregnancy and breastfeeding

The use of Plavix is ​​contraindicated during pregnancy and lactation (breastfeeding) due to the lack of data on the clinical use of the drug during pregnancy. Experimental studies have revealed no direct or indirect adverse effects on pregnancy, embryonic development, childbirth and postnatal development.

It is not known whether clopidogrel is excreted into breast milk in humans. Breastfeeding should be discontinued during treatment with clopidogrel, because Clopidogrel and/or its metabolites have been shown to be excreted in breast milk in lactating rats.

Use in children

Contraindicated in children under 18 years of age (safety and effectiveness have not been established).

special instructions

When using Plavix, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients must be carefully monitored to exclude signs of bleeding, incl. and hidden.

Due to the risk of bleeding and hematological side effects, if clinical symptoms suspicious for bleeding appear during treatment, you should urgently do a clinical blood test, determine APTT, platelet count, indicators of platelet functional activity and conduct other necessary studies.

Plavix, as well as other antiplatelet drugs, should be used with caution in patients who have an increased risk of bleeding associated with trauma, surgery or other pathological conditions, as well as in combination therapy with acetylsalicylic acid, NSAIDs (including inhibitors COX-2), heparin or glycoprotein 2b/3a inhibitors.

Concomitant use of clopidogrel with warfarin may increase the risk of bleeding, therefore, caution should be exercised when using clopidogrel and warfarin together.

For planned surgical interventions and if there is no need for an antiplatelet effect, the course of treatment with Plavix should be discontinued 7 days before surgery.

Clopidogrel prolongs bleeding time, so the drug should be used with caution in patients with diseases predisposing to the development of bleeding (especially gastrointestinal and intraocular).

Drugs that can cause damage to the gastrointestinal mucosa (such as acetylsalicylic acid, NSAIDs) should be used with caution in patients receiving clopidogrel. Patients should be warned that it may take longer to stop bleeding when taking clopidogrel (alone or in combination with acetylsalicylic acid) and that if they experience unusual bleeding (in location or duration), they should be advised talk to your doctor about this. Before any upcoming surgery and before starting any new drug, patients should tell their doctor (including their dentist) that they are taking clopidogrel.

Very rarely, after taking clopidogrel (sometimes even for short periods), cases of thrombotic thrombocytopenic purpura (TTP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia in combination with either neurological symptoms, renal dysfunction or fever, have been reported. The development of TTP can be life-threatening and require urgent measures, including plasmapheresis.

During treatment, it is necessary to monitor the functional activity of the liver. In case of severe liver damage, the risk of developing hemorrhagic diathesis should be taken into account.

Plavix should not be prescribed to patients with rare hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome.

Impact on the ability to drive vehicles and operate machinery

Plavix does not have a significant effect on the ability to drive vehicles or engage in other potentially hazardous activities.

Drug interactions

Although clopidogrel 75 mg daily did not alter the pharmacokinetics of warfarin (a CYP2C9 substrate) or MHO in patients receiving long-term warfarin treatment, concomitant use of clopidogrel increases the risk of bleeding due to its independent additive effect on blood clotting. Therefore, caution should be exercised when taking warfarin and clopidogrel simultaneously.

Prescribing glycoprotein 2b/3a receptor blockers together with clopidogrel requires caution, especially in patients with an increased risk of bleeding (in cases of trauma and surgery or other pathological conditions).

Acetylsalicylic acid does not change the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, simultaneous administration of acetylsalicylic acid 500 mg 2 times a day for 1 day with clopidogrel did not cause a significant increase in the bleeding time caused by taking clopidogrel. There may be a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid, which 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 acetylsalicylic acid for up to 1 year.

When used simultaneously with heparin, according to a clinical study conducted on healthy volunteers, when taking clopidogrel, no change in the dose of heparin was required and its anticoagulant effect did not change. Concomitant use of heparin did not change the antiplatelet effect of clopidogrel. There may be a pharmacodynamic interaction between Plavix and heparin, which may increase the risk of bleeding (caution is required with this combination).

The safety of combined use of Plavix, fibrin-specific or fibrin-nonspecific thrombolytic drugs and heparin has been studied in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed in the case of combined use of thrombolytic agents and heparin with acetylsalicylic acid.

In a clinical study conducted in healthy volunteers, coadministration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of studies on the interaction of clopidogrel with other non-steroidal anti-inflammatory drugs (NSAIDs), it is currently unknown whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel together with other NSAIDs (prescribing NSAIDs, including COX-2 inhibitors , together with Plavix requires caution).

Because Clopidogrel is metabolized to form an active metabolite, partly with the participation of 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. The simultaneous use of strong or moderate inhibitors of the CYP2C19 isoenzyme (for example, omeprazole) with clopidogrel should be avoided. If concomitant use of a proton pump inhibitor and clopidrrel is necessary, a proton pump inhibitor with the least inhibition of the CYP2C19 isoenzyme, such as pantoprazole, should be prescribed.

A number of clinical studies have been conducted with clopidogrel and other concomitantly prescribed drugs to study possible pharmacodynamic and pharmacokinetic interactions, which showed the following.

When clopidogrel was used in combination with atenolol, nifedipine, or both drugs simultaneously, no clinically significant pharmacodynamic interaction was observed.

The simultaneous use of phenobarbital, cimetidine and estrogens did not have a significant effect on the pharmacodynamics of clopidogrel.

The pharmacokinetic parameters of digoxin and theophylline did not change when they were used together with clopidogrel.

Antacids did not reduce the absorption of Plavix.

Phenytoin and tolbutamide can be safely used concomitantly with clopidogrel (CAPRIE study). It is unlikely that clopidogrel can affect the metabolism of other drugs, such as phenytoin and tolbutamide, as well as NSAIDs, which are metabolized by the CYP2C9 isoenzyme.

In clinical studies, no clinically significant adverse interactions of clopidogrel with ACE inhibitors, diuretics, beta-blockers, slow calcium channel blockers, lipid-lowering drugs, coronary vasodilators, hypoglycemic drugs (including insulin), antiepileptic drugs, drugs for hormone replacement therapy were identified , with blockers of glycoprotein 2b/3a receptors.

Analogues of the drug Plavix

Structural analogues of the active substance:

• Aggregal;
• Deplatt 75;
• Dethromb;
• Sylt;
• Cardutol;
• Clopigrant;
• Clopidex;
• Clopidogrel;
• Clopidogrel hydrosulfate;
• Clopidogrel bisulfate;
• Clopylet;
• Listab;
• Lopirel;
• Plagril;
• Plogrel;
• Targetek;
• Trocken;
• Aegitromb.

If there are no analogues of the drug for the active substance, you can follow the links below to the diseases for which the corresponding drug helps, and look at the available analogues for the therapeutic effect.

INSTRUCTIONS
on medical use of the drug
PLAVIX 75 mg

pharmachologic effect
The active ingredient in Plavix is ​​clopidogrel. Clopidogrel is an antiplatelet agent that selectively inhibits the binding of ADP (adenosine diphosphate) to platelet surface receptors. Due to this, ADP-mediated activation of the GP IIb/IIIa complex occurs, which leads to inhibition of platelet aggregation. The drug also causes other reactions that help suppress platelet aggregation. The effect of the drug on platelets is irreversible, therefore such platelets will be unable to form aggregates throughout their lives. The restoration of platelet aggregation properties occurs with the formation of new cells.
After internal use of clopidogrel at a dose of 75 mg per day, rapid absorption occurs, but the content of the original substance in the blood plasma is small - only after 2 hours a concentration is observed that is within the measurement limit of 0.00025 mg/l. Absorption of the drug is within 50%, which can be monitored by the level of metabolites eliminated in the urine. The main metabolite, a carboxyl derivative, has no pharmacological effect and makes up 85% of the original substance that circulates in the blood. Metabolism of clopidogrel occurs in the liver. Cmax (approximately 3 ml/kg) of the carboxyl derivative in the blood plasma is observed after 60 minutes, subject to repeated administration of Plavix at a dose of 75 mg.
Clopidogrel is a prodrug. The active metabolite of the substance, a thiol derivative, is metabolized due to the oxidation of clopidogrel to 2-oxoclopidogrel. Subsequently, 2-oxyclopidogrel is hydrolyzed. The oxidation phase of clopidogrel is regulated mainly by cytochrome isoenzymes (ZA4 and P450 2B6) and slightly by enzymes 1A2, 1A1 and 2C19. The thiol derivative, isolated in vitro, irreversibly and quickly binds to platelet receptors, which leads to irreversible inhibition of platelet aggregation. Kinetic studies of the main metabolite showed a linear relationship at a dose of 50 to 150 mg of clopidogrel (increase in plasma metabolite content depending on the dosage).
In vitro, reversible binding of the main circulating thiol metabolite and clopidogrel to human plasma proteins was detected (94 and 98%, respectively).
The half-life of the thiol metabolite is 8 hours for both single and repeated use. Elimination: with urine – 50%, with intestines – 46%.

Indications for use
For the prevention of atherothrombosis in patients with:
· ischemic stroke – prescribed from 7 days to 6 months after an ischemic stroke;
Confirmed peripheral arterial disease;
· myocardial infarction - the prescription of the drug is justified after a few days (maximum - up to 35 days after myocardial infarction);
· acute coronary syndrome without S-T segment elevation in combination with acetylsalicylic acid (myocardial infarction in the absence of a pathological Q wave on the electrocardiogram, unstable angina).

Mode of application
Plavix is ​​taken orally. The dose for adults is 75 mg/day, regardless of food. In patients under 18 years of age, the effectiveness and safety of the drug have not been established.
Acute coronary syndrome without S-T segment elevation - starting dose - 300 mg once, after which maintenance treatment is prescribed at a dose of 75 mg / day in combination with acetylsalicylic acid from 75 to 325 mg per day. The optimal duration of therapy has not been established. The maximum effect was recorded after 3 months of taking Plavix. Sometimes therapy is indicated for up to 1 year.
Prevention of ischemia in patients after ischemic stroke, myocardial infarction and with confirmed occlusive syndrome of peripheral arteries - 75 mg/day from the first days of the disease to 35 days (with myocardial infarction) and from the 7th day to 6 months after an ischemic stroke.

Side effects
Gastrointestinal tract: abdominal pain, dyspeptic disorders, diarrhea (common - ≤1/10, 1/100); nausea, flatulence, gastritis, constipation, vomiting, peptic ulcer of the duodenum and stomach (uncommon - ≤1/100, 1/1000); pancreatitis, increased transaminase activity, hepatitis, colitis, including lymphocytic or ulcerative (very rare - ≤1/10,0000).
Central nervous system: dizziness, headache, paresthesia (uncommon); confusion, disturbance of taste sensations, hallucinations (very rare).
Hematopoietic system: decreased number of eosinophilic and neutrophilic granulocytes, leukopenia, decreased platelet count and increased bleeding time (uncommon); severe thrombocytopenia with platelet count ≤30x109/L, thrombohemolytic thrombocytopenic purpura (1 case in 200,000 taking Plavix), agranulocytosis, granulocytopenia, anemia and pancytopenia/aplastic anemia (very rare).
Skin: itching, rash (uncommon); erythema multiforme (bullous rash), urticaria, erythematous rash, angioedema, lichen planus (very rare).
Hypersensitivity reactions are very rare (anaphylactoid reactions).
Respiratory system: bronchospasm (very rare).
Musculoskeletal system: arthritis, joint pain (very rare).
Cardiovascular system: decreased blood pressure, vasculitis (very rare).
Urinary system: increased serum creatinine levels, glomerulonephritis (very rare).
Others: fever (very rare).
Most often, bleeding due to taking Plavix was observed during the first 30 days of therapy. Several cases of death have been reported - gastrointestinal, intracranial retroperitoneal bleeding. Cases of hemorrhages in the joints have also been recorded - hematoma, hemarthrosis, eye bleeding (retinal, conjunctival, ocular), from the respiratory tract (pulmonary hemorrhage, hemoptysis), nosebleeds, bleeding from a surgical wound and hematuria.

Contraindications
· Anaphylactoid reactions to the active substance or other components of Plavix;
· under 18 years of age;
· pregnancy and breastfeeding;
lactase deficiency, rare hereditary galactose intolerance, glucose-galactose malabsorption syndrome;
· acute bleeding;
· severe liver diseases.

Pregnancy
Pregnancy and lactation are a contraindication for taking Plavix.

Drug interactions
It is not recommended to use Plavix in combination with warfarin, since there is a high likelihood of increased bleeding.
Clopidogrel potentiates the effect of aspirin on collagen-induced reduction in platelet aggregation. Aspirin does not affect the inhibitory effect of clopilogrel on platelet aggregation. The use of aspirin at a dose of 0.5 g 2 times / day does not cause a clinically significant increase in bleeding time, which is prolonged due to the action of Plavix. The safety of long-term use of Plavix in combination with aspirin has not been established. However, taking a combination of both drugs did not cause any negative effects when taken for no more than 1 year.
Clinical trials on healthy volunteers showed that no dose adjustment of heparin is required when taking Plavix. However, the safety of combining Plavix with heparin has not been established, so the simultaneous administration of these drugs is carried out with caution. The use of heparin does not change the antiaggregation effect of clopidogrel.
Clinical trials in healthy volunteers showed that combining Plavix with naproxen increased the likelihood of developing occult gastrointestinal bleeding. Combinations of Plavix with other non-steroidal anti-inflammatory drugs have not been studied in terms of the risk of bleeding from the gastrointestinal tract. Prescribing non-steroidal anti-inflammatory drugs during Plavix therapy requires caution.
There was no clinically significant interaction between clopidogrel and nifedipine, or atenolol, or a combination of all three drugs.
The pharmacodynamics of clopidogrel are practically unchanged when combined with cimetidine, phenobarbital or estrogens.
When combined with Plavix, no pharmacokinetic changes were detected when taking theophylline and digoxin.
Antacids do not affect the absorption of clopidogrel.
Studies of clopidogrel with human liver microsomes have shown that Plavix can inhibit the activity of one of the cytochrome enzymes - CYP 2C9. Because of this, the concentration of tolbutamide and phenytoin in the blood may be increased (since these drugs are metabolized precisely through the cytochrome P450 enzyme CYP 2C9).
The CAPRIE study proved the safety of using the combination of Plavix with tolbutamide and phenytoin.
In addition to the above drugs, other clinical trials on the interaction of clopidogrel with drugs prescribed for the treatment of atherothrombosis have not been conducted. Patients participating in the Plavix clinical trial most commonly received beta-adrenergic blockers, diuretics, angiotensin-converting factor inhibitors, antiepileptic drugs, lipid-lowering drugs, calcium channel antagonists, coronary lytics, antidiabetic drugs (including insulin), hormonal drugs, GP IIb antagonists/ IIIa and other means. No clinically significant interactions have been identified with these combinations.

Overdose
In case of overdose, an increase in bleeding time may be observed. To quickly restore bleeding time, platelet transfusion is used. There is no specific antidote.

Release form
75 mg film-coated tablets. The shell is filmy, pink. The tablets are slightly convex, round, with a white core visible on the break of the tablet, engraved “75” on one side and “1175” on the other. The blister contains 14 tablets.

Storage conditions
Temperature no more than 25°C.

Compound
Active substance: clopidogrel sulfate (as base).
Excipients: microcrystalline cellulose 90 microns, macrogol 6000, mannitol, low-substituted hydroxypropylcellulose, hydrogenated castor oil, carnauba wax.
Shell: Opadry 32K14834 (hypromellose, lactose, titanium dioxide, red iron oxide, triacetin).

Pharmacological group
Agents that primarily affect tissue metabolic processes
Medicines that affect blood clotting
Medicines that inhibit blood clotting
Antiplatelet agents

Active substance: Clopidogrel

Additionally
In the presence of an elevated S-T segment on the ECG of patients with acute myocardial infarction, Plavix therapy is not recommended for the first few days after the onset of the disease.
It is not recommended to take Plavix in patients with acute ischemic stroke, since there are no clinical data on the use of the drug in such cases. Plavix can be used no earlier than 7 days after the development of an ischemic stroke.
If bleeding develops while taking Plavix, it is recommended to immediately examine the blood (clinical blood test) to determine the cellular composition.
With caution, Plavix, like other antithrombotic drugs, should be prescribed to patients with a high risk of bleeding due to injury, pathological conditions and during surgical interventions. Plavix is ​​prescribed with caution to patients taking non-steroidal anti-inflammatory drugs, acetylsalicylic acid, heparin, thrombolytics or glycoprotein IIb/IIIa inhibitors.
Severe cases of bleeding have been reported in patients who took acetylsalicylic acid, heparin, heparin and acetylsalicylic acid together with Plavix.
When planning surgical interventions, if there is a risk of bleeding, treatment with clopidogrel is canceled a week before surgery.
It is recommended to carefully monitor the condition of patients for timely detection of signs of bleeding, including hidden ones. Bleeding is most common at the beginning of Plavix therapy (1-2 weeks of use), as well as during surgical operations and (or) invasive cardiac examinations.
Prescribed with caution in case of increased risk of eye bleeding and bleeding from the gastrointestinal tract. A patient taking Plavix is ​​warned that the drug prolongs bleeding time, so he must inform the doctor of any unusual symptoms accompanying the use of the drug, especially in cases of even minor bleeding or bleeding.
The patient is obliged to inform other doctors (dentist, surgeon) that he is taking Plavix, especially if he is scheduled for surgery or additional treatment with other medications.
In patients with impaired renal function, clinical experience with the drug is limited. In case of renal failure, Plavix is ​​prescribed with caution. In patients with impaired liver function, clinical experience with the drug is limited. In case of liver failure while taking clopidogrel, hemorrhagic diathesis may occur, so Plavix is ​​prescribed to such patients with caution.
Plavix does not affect the speed of psychomotor reaction, so it can be used by drivers and people working with complex equipment.

Name:

Plavix

Pharmacological
action:

Antiplatelet agent. It 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 ADP to the platelet P2Y12 receptor and subsequent ADP-mediated activation of the glycoprotein IIb/IIIa complex, leading to suppression of platelet aggregation.
Due to irreversible binding, platelets remain immune to ADP stimulation for the remainder of their life (approximately 7-10 days), and restoration of normal platelet function occurs at a rate consistent with platelet turnover.
Platelet aggregation induced by agonists other than ADP also inhibited by blockade of enhanced platelet activation by released ADP.
Because the formation of the active metabolite occurs with the participation of isoenzymes of the P450 system, some of which differ in polymorphism or are inhibited by other drugs; not all patients have adequate platelet suppression.

When taking clopidogrel daily 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 (when an equilibrium state is reached).
In equilibrium platelet aggregation is suppressed by an average of 40-60% After discontinuation of clopidogrel, platelet aggregation and bleeding time gradually returned to baseline levels within an average of 5 days.
Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular in lesions of the cerebral, coronary or peripheral arteries.

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 plus acetylsalicylic acid (compared with acetylsalicylic acid alone) ) reduced the combined incidence of stroke, myocardial infarction, non-central nervous system (CNS) systemic thromboembolism, or vascular death, largely due to a reduction in the risk of stroke.
The effectiveness of taking clopidogrel in combination with acetylsalicylic acid was detected early and persisted for up to 5 years. The reduction in the risk of major vascular complications in the group of patients taking clopidogrel in combination with acetylsalicylic acid was mainly due to a greater reduction in the incidence of stroke.
The risk of stroke of any severity was reduced when taking clopidogrel in combination with acetylsalicylic acid, and there was a trend towards a decrease in the incidence of myocardial infarction in the group treated with clopidogrel in combination with acetylsalicylic acid, but there was no difference in the incidence of non-CNS thromboembolism or vascular death.
In addition, taking clopidogrel in combination with acetylsalicylic acid reduced the total number of days of hospitalization for cardiovascular reasons.

Pharmacokinetics
Suction
With a single or repeated oral dose of 75 mg/day, clopidogrel is rapidly absorbed.
After oral administration in a single dose of 75 mg, the average Cmax of unchanged clopidogrel in the blood plasma is reached after approximately 45 minutes and is approximately 2.2-2.5 ng/ml. Based on the excretion of clopidogrel metabolites in urine, its absorption is approximately 50%.
Distribution
In vitro, clopidogrel and its main inactive metabolite circulating in the blood are reversibly bound to plasma proteins (98% and 94%, respectively). This bond is unsaturable over a wide range of concentrations.
Metabolism
Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, clopidogrel is metabolized in two ways: the first - through esterases and subsequent hydrolysis with the formation of an inactive carboxylic acid derivative (85% of circulating metabolites), the second - through isoenzymes of the cytochrome P450 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 metabolism along this pathway is carried out with the participation of isoenzymes CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite of clopidogrel, which was isolated in in vitro studies, rapidly and irreversibly binds to platelet receptors, thereby blocking platelet aggregation.
The Cmax of the active metabolite of clopidogrel after taking a loading dose of 300 mg is 2 times higher than the Cmax after 4 days of taking a maintenance dose of 75 mg clopidogrel. In this case, when taking 300 mg of clopidogrel, Cmax is achieved within approximately 30-60 minutes.

Removal
Within 120 hours after human ingestion of 14C-labeled clopidogrel, about 50% of the radioactivity is excreted in the urine and approximately 46% in the feces. After a single oral dose of 75 mg, T1/2 of clopidogrel is approximately 6 hours. After a single dose and repeated doses, T1/2 of the main circulating inactive metabolite is 8 hours.
Pharmacogenetics
With the help of the CYP2C19 isoenzyme, both the active metabolite and the intermediate metabolite - 2-oxo-clopidogrel - are formed. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel, when studying platelet aggregation ex 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*2 and CYP2C19*3 genes are non-functional. Alleles of the CYP2C19*2 and CYP2C19*3 genes are the cause of decreased metabolism in the majority of representatives of the Caucasian (85%) and Mongoloid races (99%).
Other alleles associated with absent or decreased metabolism are less common and include, but are not limited to, the CYP2C19*4, *5, *6, *7, and *8 alleles. Patients with low CYP2C19 activity must have the two loss-of-function alleles listed above. Published frequencies of occurrence of phenotypes in individuals with low CYP2C19 activity are 2% in Caucasians, 4% in Blacks, and 14% in Chinese. To determine the patient's genotype of the CYP2C19 isoenzyme, there are appropriate tests.

According to a crossover study (40 volunteers) and a meta-analysis of six studies (335 volunteers) that included subjects with very high, high, intermediate and low CYP2C19 activity, there were no significant differences in exposure to the active metabolite and in mean values ​​of inhibition of platelet aggregation (IAT) (induced by ADP) in volunteers with very high, high and intermediate activity of the CYP2C19 isoenzyme were not detected.
In volunteers with low CYP2C19 isoenzyme activity, exposure to the active metabolite was reduced compared to volunteers with high CYP2C19 isoenzyme activity.
When volunteers with low CYP2C19 activity received the 600 mg loading dose/150 mg maintenance dose regimen (600 mg/150 mg), exposure to the active metabolite was higher than when taking the 300 mg/75 mg regimen.
In addition, IAT was similar to that in groups of patients with higher rates of metabolism by the isoenzyme CYP2C19 receiving the 300 mg/75 mg treatment regimen. However, in studies taking into account clinical outcomes, the dosage regimen of clopidogrel for patients in this group (patients with low CYP2C19 isoenzyme activity) has not yet been established.
Clinical studies to date have not had a sufficient sample size to detect differences in clinical outcome in patients with low CYP2C19 activity.
Pharmacokinetics in special clinical situations
The pharmacokinetics of the active metabolite of clopidogrel in elderly patients, children, and patients with kidney and liver diseases has not been studied.

Indications for
application:

Prevention of atherothrombotic complications:
- in adult patients with myocardial infarction (with duration from several days to 35 days), with ischemic stroke (with duration from 7 days to 6 months), with diagnosed occlusive disease of peripheral arteries;
- in adult patients with acute coronary syndrome without ST segment elevation (unstable angina or non-Q wave myocardial infarction), including patients who underwent stenting during percutaneous coronary intervention (in combination with acetylsalicylic acid);
- in adult patients with acute coronary syndrome with ST segment elevation (acute myocardial infarction) with drug treatment and the possibility of thrombolysis (in combination with acetylsalicylic acid).
Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation (atrial fibrillation):
- in patients with atrial fibrillation (atrial fibrillation), who have at least one risk factor for the development of vascular complications, cannot take indirect anticoagulants and have a low risk of bleeding (in combination with acetylsalicylic acid).

Mode of application:

The drug is taken orally, regardless of food intake.
Adults and elderly patients with normal CYP2C19 isoenzyme activity
Myocardial infarction, ischemic stroke and diagnosed peripheral arterial occlusive disease
The drug is prescribed in a dose of 75 mg 1 time/day.
Acute coronary syndrome without ST segment elevation (unstable angina, non-Q wave myocardial infarction)
Treatment with Plavix should begin with a single dose of 300 mg loading dose, and then continue at a dose of 75 mg 1 time / day (in combination with acetylsalicylic acid in doses of 75-325 mg / day).
Since the use of acetylsalicylic acid in higher doses is associated with an increased risk of bleeding, the recommended dose of acetylsalicylic acid for this indication does not exceed 100 mg.

The optimal duration of treatment has not been formally determined. Data from clinical studies support taking the drug for up to 12 months, and the maximum beneficial effect was observed by the 3rd month of treatment
Acute coronary syndrome with ST segment elevation (acute myocardial infarction with ST segment elevation)
Plavix is ​​prescribed as a single dose of 75 mg 1 time/day with an initial single dose of a loading dose in combination with acetylsalicylic acid and thrombolytics or without combination with thrombolytics.
In patients over 75 years of age, treatment with Plavix should be started without taking a loading dose. Combination therapy is started as soon as possible after the onset of symptoms and continued for at least 4 weeks.
The effectiveness of the combination of clopidogrel and acetylsalicylic acid for this indication for more than 4 weeks has not been studied.
Atrial fibrillation (atrial fibrillation)
Plavix is ​​prescribed once a day at a dose of 75 mg. In combination with clopidogrel, acetylsalicylic acid (75-100 mg/day) should be started and then continued.

Skipping a dose
If less than 12 hours have passed since you missed the next dose, you should immediately take the missed dose of the drug, and then take the next doses at the usual time.
If more than 12 hours have passed since the next dose was missed, the patient should take the next dose at the usual time (do not take a double dose).
Patients with genetically determined reduced activity of the CYP2C19 isoenzyme
Low activity of the CYP2C19 isoenzyme is associated with a decrease in the antiplatelet effect of clopidogrel.
The regimen of using the drug in higher doses (600 mg - loading dose, then 150 mg 1 time / day daily) in patients with low activity of the CYP2C19 isoenzyme increases the antiplatelet effect of clopidogrel.
However, at the moment, in clinical studies that take into account clinical outcomes, the optimal dosage regimen of clopidogrel for patients with its reduced metabolism due to genetically determined low activity of the CYP2C19 isoenzyme has not been established.

Special patient groups
In elderly volunteers (over 75 years of age), when compared with young volunteers, there were no differences in platelet aggregation and bleeding time.
Elderly patients do not require dose adjustment.
After repeated doses of clopidogrel at a dose of 75 mg/day in patients with severe kidney damage (creatinine clearance from 5 to 15 ml/min), inhibition of ADP-induced platelet aggregation (25%) was lower compared to that in healthy volunteers, but bleeding time was prolonged was similar to that in healthy volunteers receiving clopidogrel at a dose of 75 mg/day. In addition, all patients had good tolerability of the drug.
After administration of clopidogrel at a daily dose of 75 mg daily for 10 days in patients with severe liver damage, the inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers.
The mean bleeding time was also comparable in both groups.

Patients of different ethnic backgrounds. 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 only limited data for representatives of the Mongoloid race to assess the effect of CYP2C19 isoenzyme genotype on clinical manifestations.
Female and male patients.
In a small comparative study of the pharmacodynamic properties of clopidogrel in men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in prolongation of bleeding time.
In the large controlled trial CAPRIE (clopidogrel versus acetylsalicylic acid in patients at risk of ischemic complications), the incidence of clinical outcomes, other adverse events and abnormal clinical laboratory parameters was the same in both men and women.

Side effects:

The safety of clopidogrel has been studied in more than 44,000 patients, incl. in more than 12,000 patients treated for a year or more. In general, the tolerability of clopidogrel at a dose of 75 mg/day in the CAPRIE study corresponded to the tolerability of acetylsalicylic acid at a dose of 325 mg/day, regardless of age, gender and race of patients. Clinically significant adverse effects observed in five large clinical trials are listed below: CAPRIE, CURE , CLARITY, COMMIT and ACTIVE-A. In addition to the experience of adverse reactions in clinical studies, there were spontaneous reports of adverse reactions.
From the blood coagulation system: In clinical studies and during use of the drug after its release to the market, bleeding was most often reported, mainly during the first month of use of the drug.
In the CAPRIE clinical trial, the overall incidence of all bleeding in patients receiving either clopidogrel or acetylsalicylic acid was 9.3%. The incidence of severe bleeding with clopidogrel and acetylsalicylic acid was the same.
In the CURE clinical trial, patients who stopped taking the drug more than 5 days before coronary artery bypass surgery did not experience an increased incidence of major bleeding within 7 days after the procedure. In patients who continued antiplatelet therapy during the last five days before coronary artery bypass surgery, the incidence of these events after surgery was 9.6% (clopidogrel + acetylsalicylic acid) and 6.3% (placebo + acetylsalicylic acid).

In the CLARITY clinical trial, there was an overall increase in bleeding rates in the clopidogrel + acetylsalicylic acid group compared with the placebo + acetylsalicylic acid group. The incidence of major bleeding was similar in both groups. It was the same in subgroups of patients, separated by baseline characteristics and by type of fibrinolytic or heparin therapy.
In the COMMIT clinical trial, the overall incidence of non-cerebral major bleeding or cerebral bleeding was low and similar in both groups (clopidogrel + acetylsalicylic acid group and placebo + acetylsalicylic acid group).
In the ACTIVE-A clinical trial, the incidence of major bleeding in the clopidogrel + acetylsalicylic acid group was higher than in the placebo + acetylsalicylic acid group (6.7% versus 4.3%). Major bleeding was mostly extracranial in both groups (5.3% vs. 3.5%), and gastrointestinal bleeding was mainly observed (3.5% vs. 1.8%). There were more intracranial hemorrhages in the clopidogrel + acetylsalicylic acid group compared to the placebo + acetylsalicylic acid group (1.4% versus 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%).

The frequency of adverse reactions that were observed either during clinical trials or were obtained from spontaneous reports of the development of adverse reactions is determined as follows: often (≥1/100 -<1/10); нечасто (≥1/1000 - <1/100); редко (≥1/10 000 - <1/1000), очень редко <1/10 000). B каждом системно-органном классе побочные реакции представлены в порядке убывания их тяжести.
From the hematopoietic system: uncommon - thrombocytopenia, leukopenia, eosinophilia; rarely - neutropenia, including severe neutropenia; very rarely - thrombotic thrombocytopenic purpura, aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anemia.
From the immune system: very rarely - serum sickness, anaphylactoid reactions.
From the nervous system: uncommon - intracranial hemorrhage (several fatal cases have been reported), headache, paresthesia, dizziness; very rarely - disturbances in taste perception.
From the mental side: very rarely - hallucinations, confusion.
From the side of the organ of vision: infrequently - ocular hemorrhages (conjunctival, in the tissue and retina of the eye).
Hearing and labyrinth disorders: rarely - vertigo.
From the cardiovascular system: often - hematoma; very rarely - serious bleeding from the surgical wound, vasculitis, decreased blood pressure.
From the respiratory system: often - nosebleeds; very rarely - bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonia.

From the digestive system: very often - gastrointestinal bleeding, diarrhea, abdominal pain, dyspepsia; uncommon - gastric and duodenal ulcers, vomiting, nausea, constipation, bloating; rarely - retroperitoneal hemorrhage; very rarely - gastrointestinal bleeding and retroperitoneal hemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative colitis or lymphocytic colitis), stomatitis, acute liver failure, hepatitis, abnormal liver function tests.
From the skin and subcutaneous tissues: often - subcutaneous bruising; uncommon - rash, itching, purpura (subcutaneous hemorrhage); very rarely - bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), angioedema, erythematous rash, urticaria, eczema, lichen planus.
From the musculoskeletal system: very rarely - hemorrhages in muscles and joints, arthritis, arthralgia, myalgia.
From the urinary system: infrequently - hematuria; very rarely - glomerulonephritis, increased concentration of creatine in the blood.
General reactions: very rarely - fever.
Local reactions: often - bleeding from the site of vascular puncture.
From laboratory research: uncommon - increased bleeding time, decreased number of neutrophils, decreased number of platelets in peripheral blood.

Contraindications:

Severe liver failure;
- acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage;
- rare hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome;
- pregnancy;
- lactation period (breastfeeding);
- children under 18 years of age (safety and effectiveness of use have not been established);
- hypersensitivity to the components of the drug.

Carefully the drug is prescribed for moderate liver failure, in which there may be a predisposition to bleeding (limited clinical experience with use); renal failure (limited clinical experience); for injuries, surgical interventions; for diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal or intraocular); while taking NSAIDs, incl. selective COX-2 inhibitors; with simultaneous administration of warfarin, heparin, glycoprotein IIb/IIIa inhibitors; in patients with low activity of the CYP2C19 isoenzyme (because when using clopidogrel in 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 CYP2C19 isoenzyme activity).

When using Plavix, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients must be carefully monitored to exclude signs of bleeding, incl. and hidden.
Due to the risk of bleeding and hematological side effects If clinical symptoms suspicious for bleeding appear during treatment, you should urgently do a clinical blood test, determine APTT, platelet count, indicators of platelet functional activity and conduct other necessary studies.
Plavix, as well as other antiplatelet drugs, should be used with caution in patients who have an increased risk of bleeding associated with trauma, surgery or other pathological conditions, as well as in combination therapy with acetylsalicylic acid, NSAIDs (including inhibitors COX-2), heparin or glycoprotein IIb/IIIa inhibitors.
Concomitant use of clopidogrel with warfarin may increase the risk of bleeding, therefore, caution should be exercised when using clopidogrel and warfarin together.

For planned surgical interventions and if there is no need for an antiplatelet effect, treatment with Plavix should be discontinued 7 days before surgery.
Clopidogrel prolongs bleeding time, so the drug should be used with caution in patients with diseases predisposing to the development of bleeding (especially gastrointestinal and intraocular).
Drugs that can cause damage to the gastrointestinal mucosa (such as acetylsalicylic acid, NSAIDs) should be used with caution in patients receiving clopidogrel.
Patients should be warned that it may take longer to stop bleeding when taking clopidogrel (alone or in combination with acetylsalicylic acid) and that if they experience unusual bleeding (in location or duration), they should be advised talk to your doctor about this.
Before any upcoming surgery and before starting any new drug, patients should tell their doctor (including their dentist) that they are taking clopidogrel.

Very rarely, after taking clopidogrel (sometimes even for short periods), cases of thrombotic thrombocytopenic purpura (TTP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia in combination with either neurological symptoms, renal dysfunction or fever, have been reported. The development of TTP can be life-threatening and require urgent measures, including plasmapheresis.
Clopidogrel is not recommended for acute stroke less than 7 days old, because There are no data on the use of the drug in this condition.
During treatment, it is necessary to monitor the functional activity of the liver. In case of severe liver damage, the risk of developing hemorrhagic diathesis should be taken into account.
Plavix should not be prescribed to patients with rare hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome.
Impact on the ability to drive vehicles and operate machinery
Plavix does not have a significant effect on the ability to drive vehicles or engage in other potentially hazardous activities.

Interaction
other medicinal
by other means:

Although clopidogrel 75 mg/day did not alter the pharmacokinetics of warfarin (a CYP2C9 substrate) or MHO in patients receiving long-term warfarin treatment, concomitant use of clopidogrel increases the risk of bleeding due to its independent additive effect on blood clotting. Therefore, caution should be exercised when taking warfarin and clopidogrel simultaneously.
Prescription of glycoprotein IIb/IIIa receptor blockers together with clopidogrel requires caution, especially in patients with an increased risk of bleeding (from trauma and surgery or other pathological conditions).
Acetylsalicylic acid does not change the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation.
However, simultaneous administration of acetylsalicylic acid 500 mg 2 times a day with clopidogrel for 1 day did not cause a significant increase in the bleeding time caused by taking clopidogrel. There may be a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid, which leads to an increased risk of bleeding. Therefore, when used simultaneously caution should be exercised, although in clinical studies patients received combination therapy with clopidogrel and acetylsalicylic acid for up to 1 year.

When used simultaneously with heparin, according to a clinical study conducted on healthy volunteers, when taking clopidogrel, no change in the dose of heparin was required and its anticoagulant effect did not change.
Concomitant use of heparin did not change the antiplatelet effect of clopidogrel. There may be a pharmacodynamic interaction between Plavix and heparin, which may increase the risk of bleeding (caution is required with this combination).
The safety of combined use of clopidogrel, fibrin-specific or fibrin-nonspecific thrombolytic drugs and heparin has been studied in patients with acute myocardial infarction. Rate of clinically significant bleeding was similar to that observed in the case of combined use of thrombolytic agents and heparin with acetylsalicylic acid.
In a clinical study conducted in healthy volunteers, coadministration of clopidogrel and naproxen increased occult gastrointestinal blood loss. 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 (prescribing NSAIDs, including COX-2 inhibitors, together with Plavix requires caution).

Because clopidogrel metabolized to form an active metabolite partially with the participation of 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. The simultaneous use of strong or moderate inhibitors of the CYP2C19 isoenzyme (for example, omeprazole) with clopidogrel should be avoided.
If concomitant use of a proton pump inhibitor and clopidrrel is necessary, a proton pump inhibitor with the least inhibition of the CYP2C19 isoenzyme, such as pantoprazole, should be prescribed.
A number of clinical studies have been conducted with clopidogrel and other concomitantly prescribed drugs to study possible pharmacodynamic and pharmacokinetic interactions, which showed the following.
When clopidogrel is used together with atenolol, nifedipine, or both drugs simultaneously, clinically no significant pharmacodynamic interaction was observed.
The simultaneous use of phenobarbital, cimetidine and estrogens did not have a significant effect on the pharmacodynamics of clopidogrel.

The pharmacokinetic parameters of digoxin and theophylline did not change when they were used together with clopidogrel.
Antacids did not reduce the absorption of clopidogrel.
Phenytoin and tolbutamide can be safely used concomitantly with clopidogrel (CAPRIE study). It is unlikely that clopidogrel can affect the metabolism of other drugs, such as phenytoin and tolbutamide, as well as NSAIDs, which are metabolized by the CYP2C9 isoenzyme.
In clinical studies, no clinically significant adverse interactions of clopidogrel with ACE inhibitors, diuretics, β-blockers, slow calcium channel blockers, lipid-lowering drugs, coronary vasodilators, hypoglycemic drugs (including insulin), antiepileptic drugs, drugs for hormone replacement therapy were identified , with blockers of glycoprotein IIb/IIIa receptors.

Pregnancy:

Contraindicated use of the drug Plavix during pregnancy and lactation (breastfeeding) due to the lack of data on the clinical use of the drug during pregnancy.
Experimental studies have revealed no direct or indirect adverse effects on pregnancy, embryonic development, childbirth and postnatal development.
It is not known whether clopidogrel is excreted into breast milk in humans. Breastfeeding should be discontinued during treatment with clopidogrel, because Clopidogrel and/or its metabolites have been shown to be excreted in breast milk in lactating rats.

Overdose:

Symptoms: prolongation of bleeding time and subsequent complications in the form of bleeding.
Treatment: If bleeding occurs, appropriate therapy should be administered. If rapid correction of prolonged bleeding time is necessary, platelet transfusion is recommended. There is no specific antidote.