Plavix tablets analogue. Plavix analogue. Which is better is the eternal question.

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 remedy is prescribed by a cardiologist, less often by a therapist after the studies. Released by prescription.

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

According to the instructions for use, the drug contains the active substance clopidogrel and belongs to antiplatelet agents. Provided therapeutic actions:

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

Plavix indications for use

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

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

The medicine is available by prescription and is taken strictly according to the doctor's prescription after blood tests for clotting.

Plavix - instructions for use

The medication is taken once a day, mostly in the morning. The dosage depends on the indications and the patient's condition - from 75 to 600 mg. In the first days of admission, 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 the cardiologist. It depends on additionally prescribed medications, therapy with acetylsalicylic acid or drugs containing it.

Plavix's analogs

The drug for thinning 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 is relevant, which drugs are better, the features of the reception.

Prices for analogues of Plavix 75 mgand producing countries

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

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

Aspirin Cardio

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

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 the convenient use and replacement of the reception of individual funds. As a result, improved indicators of platelet functionality are observed, and the risk of vascular complications is reduced. Structural analogues of Coplavix are Plagril A (75 mg of clopidogrel and 75 mg of 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 tablet is taken at 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 negatively affects the lining of the stomach and intestines, can lead to erosions, ulcers and bleeding. The disadvantage of the drug is the need for division, it is possible to exceed or shorten the required amount of ASA.

Lopirel

A cheaper analogue of Plavix is ​​Lopirel. It also contains clopidogrel at a dosage of 75 mg. It has the same indications, contraindications, adverse reactions. It is possible to use it together with acetylsalicylic acid to enhance the effect or use the complex preparation 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 prosthetics of the knee and hip joints. Released by prescription. Frequency of appointment - twice a day for a long time.

Thrombo ASS

The Austrian equivalent of Thrombo ACC is an over-the-counter source of acetylsalicylic acid. 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. It is taken once a day.

Xarelto

The German drug Xarelto is available in dosages of 2.5, 10, 15 and 20 mg and belongs to anticoagulants. Medicinal properties are provided by the active ingredient in the composition - rivaroxaban. It is used after surgical interventions on the lower extremities to prevent thromboembolism once a day. Which is better - Plavix or Xarelto, depends on the indications and the patient's condition.

Substitute for Plavix Pradax is the original, clinically studied anticoagulant in patients. It 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.

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

Which is better - Plavix or Pradaxa, depends on the indications and the 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, 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 medicines.

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 drug is from 400 to 750 rubles. The difference is that it is produced in a dosage of 75 mg or with the 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 relapses. Whether it is possible to replace Brilinta with Plavix is ​​determined by the cardiologist based on the history.

Plavix or Clopidogrel - which is better after stenting

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

Buyers are concerned about the difference between Clopidogrel and Plavix. It contains the same substance - clopidogrel, which provides uniform 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 the cardiologist which company to choose the analogue.

Zilt or Plavix - which is better

Zilt and Plavix are analogues in terms of the 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 of high quality and effective. It is possible to replace one with another.

The difference is the dosage of the drugs. If you need additional load, 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 at once per dose to achieve the desired dose.

The choice of analogues must be agreed with the cardiologist, listening to the recommendations regarding the manufacturer, time of admission and duration. Drugs are dispensed by prescription and are taken for a long time. If necessary, you should regularly donate blood to determine clotting factors.

Preparations containing Clopidogrel (Clopidogrel, ATC code (ATC) B01AC04):

Commercial names abroad - Apolets, Cardogrel, Ceruvin, Clavix, Clodian, Clodrel, Clopact, Clopicard, Clopivas, Clopilet, Clopitab, Cloplat, Clotiz, Deplatt, Freeclo, Noklot, Nugrel, Pidolap, Orawis, Placta, Plagerine, Platloc, Torplatt .

The website author's responses to typical requests from page visitors:

Which is better - Plavix or Clopidogrel Teva?

Plavix is ​​the original drug, and Clopidogrel Teva is a copy, although produced by a very serious Israeli company. A copy, by definition, cannot be better than the original.

Which is better to take - Plavix or Coplavix?

Coplavix is ​​a combination of Plavix and aspirin. One tablet combines two drugs that increase the risk of bleeding, so Coplavix can be taken only on the clear recommendation of the attending physician.

Comparison of the quality of Clopidogrel from different manufacturers.

The best of the Clopidogrels is the original Plavix, and the quality of the copies is determined by the manufacturer. A comparison of generic manufacturers is written in the article "Which generic is better?" . See the table and analyze.

Plavix (original Clopidogrel) - official instructions for use. Prescription drug, information intended for healthcare professionals only!

Clinico-pharmacological group:

Antiplatelet agent

pharmachologic effect

Antiaggregant. 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 rest of their lives (approximately 7-10 days), and the recovery of normal platelet function occurs at a rate corresponding to the rate of platelet turnover.

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

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

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

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

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 study CAPRIE (clopidogrel versus acetylsalicylic acid in patients at risk of ischemic events), the incidence of clinical outcomes, other adverse reactions and abnormal clinical and laboratory parameters was the same in both men and women.

Pharmacokinetics

Suction and distribution

With a course inside at a dose of 75 mg per day, clopidogrel is rapidly absorbed.

After oral administration in a single dose of 75 mg, the average values ​​of Cmax of unchanged clopidogrel in blood plasma are reached after about 45 minutes. According to the excretion of clopidogrel metabolites in the urine, its absorption is approximately 50%.

In vitro, clopidogrel and its major circulating inactive metabolite bind reversibly to plasma proteins (98% and 94%, respectively). This bond is unsaturable 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% 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. The 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 CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite of clopidogrel, which has been isolated in in vitro studies, rapidly and irreversibly binds to platelet receptors, thus blocking platelet aggregation.

breeding

Within 120 hours of oral 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.

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, no differences were obtained in terms of platelet aggregation and bleeding time. Dose adjustment is not required in elderly patients.

The pharmacokinetics of clopidogrel in children has not been studied.

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

In patients with severe liver damage, after daily administration of clopidogrel at a dose of 75 mg per day for 10 days, 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 is different in representatives of different ethnic groups. There are very few literature data among representatives of the Mongoloid race, which does not allow us to evaluate the effect of CYP2C19 isoenzyme genotyping on the clinical outcome of events.

Pharmacogenetics

Several polymorphic isoenzymes of the cytochrome P450 system are involved in the activation of clopidogrel. The CYP2C19 isoenzyme is involved in the formation of both the active metabolite and the intermediate metabolite, 2-oxoclopidogrel. The pharmacokinetics and antiplatelet effects of the active metabolite of clopidogrel, as measured by ex vivo platelet aggregation, differ depending on the genotype of the CYP2C19 isoenzyme. The allele of the CYP2C19*1 gene is responsible for a normally functioning metabolism, while the alleles of the CYP2C19*2 isoenzyme gene and the CYP2C19*3 isoenzyme are responsible for a reduced metabolism. These alleles are responsible for decreased metabolism in approximately 85% of Caucasians and 99% of Mongoloids. Other alleles associated with decreased metabolism are CYP2C19*4, *5, *6, *7, and *8, but they are rare in the general population. Published data on the frequency of occurrence of the phenotype and genotype of the CYP2C19 isoenzyme are presented in the table.

The influence of the CYP2C19 isoenzyme genotype on the pharmacokinetics of the active metabolite of clopidogrel was investigated in 227 people in 7 published studies. In individuals with reduced metabolism of the CYP2C19 isoenzyme, a decrease in Cmax and AUC of the active metabolite by 30-50% was observed after taking a loading dose of 300 mg or 600 mg and a subsequent maintenance dose of 75 mg. Decreased activity of the clopidogrel metabolite may result in less platelet inhibition or increased platelet reactivity. To date, an attenuated antiplatelet response to clopidogrel has been described in intermediate and reduced metabolisers in 21 studies in 4520 subjects. The relative difference in antiplatelet response between groups with different genotypes differed between studies due to the use of different methods for assessing the response, but was more than 30%.

The association between CYP2C19 genotype and outcome of clopidogrel therapy was evaluated in two post-marketing clinical trials (CLARITY-TIMI 28 (n=465) and TRITON-TIMI 38 (n=1477) and 5 cohort studies (n=6489). TIMI 28 and one cohort study (Trenk, n=765), CV events were not significantly different by genotype.In TRITON-TIMI 38 and three cohort studies (Collet, Sibbing, Giusti, n=3516), patients with an intermediate and reduced metabolism had a higher incidence of cardiovascular events (death, myocardial infarction, stroke) or stent thrombosis, compared with patients with a good metabolism.In the fifth cohort study (Simon, n=2208), an increase in the frequency of cardiovascular events observed only in patients with reduced metabolism.

Pharmacogenetic testing allows you to determine the genotype with variability in the activity of the CYP2C19 isoenzyme.

Genetic variants of other enzymes of the P450 system with effects on the ability to form active metabolites of clopidogrel are also possible.

Indications for use of PLAVIX®

Prevention of atherothrombotic events in patients with myocardial infarction, ischemic stroke or with diagnosed peripheral arterial occlusive disease.

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

• non-ST segment elevation (unstable angina or non-Q wave myocardial infarction), including patients who underwent stenting for percutaneous coronary intervention;
• with ST segment elevation (acute myocardial infarction) with drug treatment and the possibility of thrombolysis.

Dosing regimen

Plavix® is prescribed for adults and elderly patients.

The drug is taken orally, regardless of the meal.

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

The drug is prescribed at a dose of 75 mg 1 time per day. Treatment can be started from the first days to 35 days after myocardial infarction; in terms of 7 days to 6 months - with ischemic stroke.

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

Treatment with Plavix should be started with a single dose of a loading dose of 300 mg, and then continued at a dose of 75 mg 1 time per day (in combination with acetylsalicylic acid at 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 dose of acetylsalicylic acid recommended for this indication does not exceed 100 mg. The maximum beneficial effect is observed by 3 months of treatment. The course of treatment is up to 1 year.

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

Plavix® is administered as a single dose of 75 mg once daily with an initial single loading dose in combination with acetylsalicylic acid and thrombolytics (or without thrombolytics). Combination therapy is started as early as possible after the onset of symptoms and continued for at least 4 weeks.

In patients over 75 years of age, treatment with Plavix should be initiated without a loading dose.

In patients with a genetically determined decrease in the function of the CYP2C19 isoenzyme, a decrease in the intensity of metabolism with the help of the CYP2C19 isoenzyme may lead to a decrease in the effectiveness of clopidogrel. The optimal dosing regimen for patients with weakened metabolism using the CYP2C19 isoenzyme has not yet been established.

Side effect

The safety of clopidogrel has been studied in clinical studies in more than 42,000 patients, including over 9,000 patients who took the drug for a year or more. Listed below are clinically significant side effects observed in the CAPRIE, CURE, CLARITY and COMMIT clinical trials. The tolerability of clopidogrel at a dose of 75 mg per day in the CAPRIE study corresponded to the tolerability of acetylsalicylic acid at a dose of 325 mg per day. The overall tolerability of the drug was similar to that of acetylsalicylic acid, regardless of age, gender and race of patients.

On the part of the blood coagulation system: in the CAPRIE study, the overall frequency of bleeding in patients receiving clopidogrel or acetylsalicylic acid was 9.3%; the frequency of severe cases with clopidogrel was 1.4%, and with acetylsalicylic acid - 1.6%. In patients treated with clopidogrel, gastrointestinal bleeding occurred in 2.0% of cases, and in 0.7% of cases required hospitalization. In patients treated with clopidogrel and in patients treated with 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 frequency of other bleeding was higher in patients treated with clopidogrel than in patients treated with acetylsalicylic acid (7.3% vs. 6.5%, respectively). However, the frequency of major bleeding in both groups was the same (0.6% vs. 0.4%). Purpura/bruising and nosebleeds were observed most frequently in both groups. Less common were hematomas, hematuria, and ocular hemorrhages (mainly in the conjunctiva). The frequency of intracranial hemorrhage was 0.4% in patients treated with clopidogrel, and 0.5% in patients treated with acetylsalicylic acid.

In the CURE study, the combination of clopidogrel + acetylsalicylic acid compared with the combination of placebo + acetylsalicylic acid did not lead to a statistically significant increase in life-threatening bleeding (2.2% vs. 1.8%) or fatal bleeding (0.2% vs. 0.2% frequency). respectively). However, the risk of major, minor and other bleeding was significantly higher when using a combination of clopidogrel + acetylsalicylic acid: major bleeding that does not pose a threat to life (1.6% - clopidogrel + acetylsalicylic acid, 1.0% - placebo + acetylsalicylic acid), primarily gastrointestinal bleeding and bleeding at the injection site, as well as minor bleeding (5.1% - clopidogrel + acetylsalicylic acid, 2.4% - placebo + acetylsalicylic acid). The frequency of intracranial bleeding was 0.1% in both groups. The frequency of major bleeding when using a 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%), as well as when using a combination of acetylsalicylic acid with placebo (<100 мг - 2%; 100-200 мг - 2.3%; >200 mg - 4%). During the study, the risk of bleeding (life-threatening, major, minor, other) decreased: 0-1 month of treatment [clopidogrel: 599/6259 (9.6%); placebo: 413/6303 (6.6%)], 1-3 months of treatment [clopidogrel: 276/6123 (4.5%); placebo: 144/6168 (2.3%)], 3-6 months of treatment [clopidogrel: 228/6037 (3.8%); placebo: 99/6048 (1.6%)], 6-9 months of treatment [clopidogrel: 162/5005 (3.2%); placebo: 74/4972 (1.5%)], 9-12 months of treatment [clopidogrel: 73/3841 (1.9%); placebo: 40/3844 (1.0%)].

In patients who stopped taking the drug more than 5 days before coronary artery bypass surgery, there was no increase in the frequency of major bleeding within 7 days after coronary bypass surgery (4.4% in the case of clopidogrel + acetylsalicylic acid and 5.3% in the case of placebo + acetylsalicylic acid). In patients who continued to take the drug for five days before coronary bypass surgery, the frequency was 9.6% in the case of clopidogrel + acetylsalicylic acid and 6.3% in the case of taking acetylsalicylic acid alone.

In the CLARITY study, an overall increase in bleeding rates was observed in the clopidogrel + acetylsalicylic acid group (17.4%) compared with the placebo + acetylsalicylic acid group (12.9%). The frequency of major bleeding was similar in both groups (1.3% and 1.1% in the clopidogrel + acetylsalicylic acid and placebo + acetylsalicylic acid groups, respectively) and practically did not depend on the initial characteristics of the patients and the type of fibrinolytic 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 bleeding (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 groups.

In the COMMIT study, the overall incidence of non-cerebral major bleeding or cerebral bleeding was low and similar in both groups (0.6% and 0.5% in the clopidogrel + acetylsalicylic acid and placebo + acetylsalicylic acid groups, respectively).

On the part of the hematopoietic system: in the CAPRIE study - severe neutropenia (<0.45х109/л) наблюдалась у 4 больных (0.04%), получавших клопидогрел, и у 2 больных (0.02%), получавших ацетилсалициловую кислоту. У 2 пациентов из 9599, получавших клопидогрел, число нейтрофилов было равно нулю, и ни у одного из 9586, получавших ацетилсалициловую кислоту, такого значения не отмечалось. В ходе лечения клопидогрелом наблюдался один случай апластической анемии. Частота тяжелой тромбопитопении (<80 000/мкл) составляла 0.2% в группе клопидогрела и 0.1% в группе ацетилсалициловой кислоты.

In the CURE and CLARITY studies, the number of patients with thrombocytopenia or neutropenia was similar in both groups.

Other clinically significant side effects noted in the CAPRIE, CURE, CLARITY and COMMIT studies with a frequency of not more than 0.1%, as well as all severe side effects, are presented below, in accordance with the WHO classification. Their frequency is defined as follows: often (> 1/100,<1/10); нечасто (> 1/1000, < 1/100); редко (>1/10 000, < 1/1000).

From the side of the central nervous system and peripheral nervous system: infrequently - headache, dizziness, paresthesia; rarely - vertigo.

From the digestive system: often - dyspepsia, diarrhea, abdominal pain; infrequently - nausea, gastritis, flatulence, constipation, vomiting, peptic ulcer of the stomach and duodenum.

From the blood coagulation system: infrequently - prolongation of bleeding time.

From the hemopoietic system: infrequently - leukopenia, neutropenia, eosinophilia, thrombocytopenia.

Dermatological reactions: infrequently - rash and itching.

Post marketing data

From the blood coagulation system: most often - bleeding (in most cases - during the first month of treatment). Several fatal cases are known (intracranial, gastrointestinal and retroperitoneal bleeding); there are reports of severe cases of skin hemorrhages (purpura), musculoskeletal bleeding (hemarthrosis, hematoma), ocular hemorrhages (conjunctival, ocular, retinal), epistaxis, hemoptysis, pulmonary hemorrhages, hematuria and bleeding from the surgical wound; in patients taking clopidogrel simultaneously with acetylsalicylic acid or with acetylsalicylic acid and heparin, there have also been cases of severe bleeding.

In addition to clinical trial data, the following side effects have been spontaneously reported. In each class of the organ system (according to the MedDRA classification), they are given with an indication of the frequency. The term "very rarely" corresponds to the frequency<1/10 000. В рамках каждой группы частота побочных эффектов представлена в порядке убывания тяжести.

On the part of the hematopoietic system: very rarely - thrombocytopenic thrombohemolytic purpura (1 in 200,000 patients), severe thrombocytopenia (platelet count? 30,000 / μl), granulocytopenia, agranulocytosis, anemia and aplastic anemia / pancytopenia.

From the side of the central nervous system: very rarely - confusion, hallucinations.

From the side of the cardiovascular system: very rarely - vasculitis, arterial hypotension.

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

On the part of the digestive system: very rarely - colitis (including ulcerative or lymphocytic colitis), pancreatitis, changes in taste sensations, stomatitis, hepatitis, acute liver failure, increased activity of liver enzymes.

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

From the urinary system: very rarely - glomerulonephritis, an increase in serum creatinine.

Dermatological reactions: very rarely - bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), erythematous rash (associated with clopidogrel or acetylsalicylic acid), eczema, lichen planus.

Allergic reactions: very rarely - angioedema, urticaria, anaphylactoid reactions, serum sickness.

Other: very rarely - fever.

Contraindications to the use of PLAVIX®

• 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 efficacy have not been established);
• hypersensitivity to the components of the drug.

With caution, the drug is prescribed for moderate hepatic insufficiency, in which a predisposition to bleeding is possible (limited clinical experience with use); renal failure (limited clinical experience); with injuries, surgical interventions; in 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 the simultaneous appointment of warfarin, heparin, inhibitors of glycoprotein IIb / IIIa; in patients with a genetically determined decrease in the function of the CYP2C19 isoenzyme (there are literature data indicating that patients with a genetically determined decrease in the activity of the CYP2C19 isoenzyme are subject to less systemic exposure to the active metabolite of clopidogrel and have a less pronounced antiplatelet effect of the drug, in addition, they may experience a higher frequency cardiovascular complications after myocardial infarction, compared with patients with normal activity of the isoenzyme CYP2C19).

Use of PLAVIX® during pregnancy and breastfeeding

The use of Plavix® during pregnancy and lactation (breastfeeding) is contraindicated due to the lack of data on the clinical use of the drug during pregnancy. In experimental studies, neither direct nor indirect adverse effects on the course of pregnancy, embryonic development, childbirth and postnatal development have been identified.

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

Application for violations of liver function

With caution, the drug should be prescribed for liver diseases (including with moderate liver failure).

Use is contraindicated in severe liver failure.

Application for violations of kidney function

With caution, the drug should be prescribed for kidney diseases (including moderate renal failure).

special instructions

When using Plavix, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgical intervention, it is necessary to carefully monitor patients for signs of bleeding, incl. and hidden.

Due to the risk of bleeding and hematological side effects, if clinical symptoms appear during treatment that are suspicious of bleeding, an urgent blood test should be done to determine the APTT, platelet count, platelet functional activity and other necessary studies.

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

The co-administration of clopidogrel with warfarin may increase bleeding intensity, therefore, except for special rare clinical situations (such as the presence of a floating thrombus in the left ventricle, stenting in patients with atrial fibrillation), the co-administration of Plavix and warfarin is not recommended.

For planned surgical interventions and in the absence of a need for an antiplatelet effect, treatment with Plavix should be discontinued 7 days before surgery.

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

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

Very rarely, there have been cases of development of thrombotic thrombocytopenic purpura (TTP) after taking clopidogrel (sometimes even for a short time). This was characterized by thrombocytopenia and microangiopathic hemolytic anemia associated with either neurological symptoms, renal dysfunction, or fever. The development of TTP may be life-threatening and require urgent measures, including plasmapheresis.

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

Influence on the ability to drive vehicles and control mechanisms

Plavix® does not significantly affect the ability to drive or use machines.

Overdose

Symptoms: prolonged bleeding time and subsequent complications in the form of bleeding.

Treatment: if bleeding occurs, appropriate therapy should be carried out. If rapid correction of prolonged bleeding time is needed, platelet transfusion is recommended. There is no specific antidote.

drug interaction

With the simultaneous use of clopidogrel with warfarin, an increase in the intensity of bleeding is possible (this combination is not recommended).

The appointment of glycoprotein IIb / IIIa receptor blockers in conjunction with clopidogrel requires caution, especially in patients with an increased risk of bleeding (with injuries and surgical interventions 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 did not cause a significant increase in bleeding time caused by clopidogrel. Between clopidogrel and acetylsalicylic acid, a pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, with their simultaneous use, care should be taken, 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. The simultaneous use of heparin did not change the antiplatelet effect of clopidogrel. Between the drug Plavix® and heparin, a pharmacodynamic interaction is possible, which may increase the risk of bleeding (with this combination, caution is required).

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

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

Because clopidogrel is metabolized with the formation of 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 and a decrease in its clinical efficacy. The simultaneous use of drugs that inhibit CYP2C19 (for example, omeprazole) is not recommended.

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

When using clopidogrel in conjunction with atenolol, nifedipine, or both drugs at the same time, clinically significant pharmacodynamic interaction was not observed.

The simultaneous use of phenobarbital, cimetidine and estrogens did not significantly affect 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 co-administered with clopidogrel (the CAPRIE study), although evidence from human liver microsome studies suggests that the carboxyl metabolite of clopidogrel may inhibit CYP2C9 activity, which may lead to increased plasma concentrations of certain drugs (phenytoin, tolbutamide and some NSAIDs) that are metabolized by the CYP2C9 isoenzyme.

In clinical studies, no clinically significant adverse interactions of clopidogrel with ACE inhibitors, diuretics, ?-blockers, calcium channel blockers, lipid-lowering agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, drugs for hormone replacement therapy, with blockers of glycoprotein IIb / IIIa receptors.

Terms of dispensing from pharmacies

The drug is dispensed by prescription.

Terms and conditions of storage

List B. The drug should be stored out of the reach of children at a temperature not exceeding 30°C. Shelf life - 3 years. Do not use after the expiry date stated on the packaging.

Name:

Plavix (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 rest of their lives (approximately 7-10 days), and the recovery of normal platelet function occurs at a rate corresponding to the rate of 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 an active metabolite occurs with the participation of isoenzymes of the P450 system, some of which are polymorphic or inhibited by other drugs, not all patients may have adequate platelet suppression.

With daily intake of clopidogrel at a dose of 75 mg from the first day of administration, there is a significant suppression of ADP-induced platelet aggregation, which gradually increases over 3-7 days and then reaches a constant level (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 return to baseline over an average of 5 days.
Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular, with lesions of the cerebral, coronary or peripheral arteries.

The ACTIVE-A clinical study showed that in patients with atrial fibrillation who had at least one vascular risk factor but were unable to take indirect anticoagulants, clopidogrel in combination with acetylsalicylic acid (compared to taking acetylsalicylic acid alone ) reduced the combined incidence of stroke, myocardial infarction, systemic thromboembolism outside the central nervous system (CNS), or vascular death, largely by reducing the risk of stroke.
The effectiveness of taking clopidogrel in combination with acetylsalicylic acid was detected early and persisted up to 5 years. The reduction in the risk of major vascular events 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 when taking clopidogrel in combination with acetylsalicylic acid was reduced, and there was also 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 frequency of thromboembolism outside the CNS or vascular death.
In addition, clopidogrel in combination with acetylsalicylic acid reduced the total number of days of hospitalization for cardiovascular reasons.

Pharmacokinetics
Suction
With a single and repeated oral administration at a 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 plasma is reached after about 45 minutes and is approximately 2.2-2.5 ng / ml. According to the excretion of clopidogrel metabolites in the urine, its absorption is approximately 50%.
Distribution
In vitro, clopidogrel and its major circulating inactive metabolite bind reversibly 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. The 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 has been isolated in in vitro studies, rapidly and irreversibly binds to platelet receptors, thus blocking platelet aggregation.
Cmax of the active metabolite of clopidogrel after taking its loading dose of 300 mg is 2 times higher than Cmax after 4 days of taking a maintenance dose of clopidogrel 75 mg. At the same time, when taking 300 mg of clopidogrel, Cmax is achieved within approximately 30-60 minutes.

breeding
Within 120 hours of oral 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, in the study of ex vivo platelet aggregation, 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. The alleles of the CYP2C19*2 and CYP2C19*3 genes are the cause of a decrease in metabolism in the majority of Caucasians (85%) and Mongoloids (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 activity of the CYP2C19 isoenzyme should have two of the above alleles of the gene with loss of function. The published frequencies of the phenotypes of individuals with low activity of the CYP2C19 isoenzyme are 2% in Caucasians, 4% in Blacks, and 14% in Chinese. There are appropriate tests to determine the patient's CYP2C19 isoenzyme genotype.

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

Indications for
application:

Prevention of atherothrombotic complications:
- in adult patients with myocardial infarction (with a prescription of several days to 35 days), with ischemic stroke (with a prescription of 7 days to 6 months), with a diagnosed peripheral arterial occlusive disease;
- in adult patients with non-ST elevation acute coronary syndrome (unstable angina pectoris 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 the meal.
Adults and elderly patients with normal activity of the CYP2C19 isoenzyme
Myocardial infarction, ischemic stroke, and diagnosed peripheral arterial occlusive disease
The drug is prescribed at a dose of 75 mg 1 time / day.
Non-ST elevation acute coronary syndrome (unstable angina, non-Q wave myocardial infarction)
Treatment with Plavix should be started with a single dose of a loading dose of 300 mg, and then continued at a dose of 75 mg 1 time / day (in combination with acetylsalicylic acid at doses of 75-325 mg / day).
Since the use of acetylsalicylic acid in higher doses is associated with an increased risk of bleeding, the dose of acetylsalicylic acid recommended 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 up to 12 months, and the maximum beneficial effect was observed by the 3rd month of treatment.
ST-segment elevation acute coronary syndrome (ST-segment elevation acute myocardial infarction)
Plavix is ​​administered 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 initiated without a loading dose. Combination therapy is started as early as possible after the onset of symptoms and continued for at least 4 weeks.
The effectiveness of the combination of clopidogrel and acetylsalicylic acid in this indication for more than 4 weeks has not been studied.
Atrial fibrillation (atrial fibrillation)
Plavix is ​​prescribed 1 time / day at a dose of 75 mg. In combination with clopidogrel, you should start and then continue taking acetylsalicylic acid (75-100 mg / day).

Missing another dose
If less than 12 hours have passed after missing the next dose, then you should immediately take the missed dose of the drug, and then take the next dose at the usual time.
If more than 12 hours have passed since missing the next dose, 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 at 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 dosing 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, no differences were obtained in terms of 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 (CC from 5 to 15 ml / min), inhibition of ADP-induced platelet aggregation (25%) was lower compared to that in healthy volunteers, however, prolongation of bleeding time was similar to that in healthy volunteers who received clopidogrel at a dose of 75 mg/day. In addition, all patients had good tolerability of the drug.
After taking clopidogrel at a daily dose of 75 mg daily for 10 days in patients with severe liver damage, 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 ethnicity. The prevalence of alleles of the CYP2C19 isoenzyme genes responsible for the intermediate and reduced metabolism of clopidogrel to its active metabolite differs in representatives of different ethnic groups. There are only limited data for representatives of the Mongoloid race to assess the effect of the 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, women showed less inhibition of ADP-induced platelet aggregation, but there was no difference in prolongation of bleeding time.
In the large controlled study CAPRIE (clopidogrel versus acetylsalicylic acid in patients at risk of ischemic complications), the incidence of clinical outcomes, other side effects and clinical laboratory abnormalities was the same in both men and women.

Side effects:

The safety of clopidogrel has been studied in more than 44,000 patients, incl. 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 was consistent with the tolerability of acetylsalicylic acid at a dose of 325 mg / day, regardless of age, gender and race of patients. The following are clinically significant adverse effects observed in five large clinical studies: CAPRIE, CURE , CLARITY, COMMIT and ACTIVE-A. In addition to the experience of developing adverse reactions in clinical studies, there were spontaneous reports of the occurrence of adverse reactions.
From the blood coagulation system: in clinical studies and in the use of the drug after its introduction to the market, the development of bleeding was most often reported, mainly during the first month of using the drug.
In the CAPRIE clinical study, the overall incidence of all bleeding in patients treated with either clopidogrel or acetylsalicylic acid was 9.3%. The frequency of severe bleeding when using clopidogrel and acetylsalicylic acid was the same.
In the CURE clinical study, patients who discontinued the drug more than 5 days before coronary artery bypass grafting did not experience an increase in major bleeding events within 7 days after the intervention. In patients who continued antiplatelet therapy during the last five days before coronary artery bypass grafting, the frequency of these events after the intervention 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 frequency of major bleeding was the same in both groups. It was similar in subgroups of patients, distinguished by baseline characteristics and by type of fibrinolytic or heparin therapy.
In the COMMIT clinical study, 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 study, the incidence of major bleeding in the clopidogrel + acetylsalicylic acid group was higher than in the placebo + acetylsalicylic acid group (6.7% vs. 4.3%). Major bleeding was predominantly extracranial in both groups (5.3% vs 3.5%), with gastrointestinal bleeding predominant (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 defined 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: infrequently - thrombocytopenia, leukopenia, eosinophilia; rarely - neutropenia, including severe neutropenia; very rarely - thrombotic thrombocytopenic purpura, aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anemia.
From the side of the immune system: very rarely - serum sickness, anaphylactoid reactions.
From the side of the nervous system: infrequently - intracranial hemorrhage (several fatal cases have been reported), headache, paresthesia, dizziness; very rarely - a violation of taste perception.
From the side of the psyche: very rarely - hallucinations, confusion.
From the organ of vision: infrequently - ocular hemorrhages (conjunctival, in the tissues and retina of the eye).
On the part of the organ of hearing and labyrinth disorders: rarely - vertigo.
From the side of the cardiovascular system: often - hematoma; very rarely - serious bleeding from the surgical wound, vasculitis, lowering 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; infrequently - a stomach ulcer and duodenal ulcer, vomiting, nausea, constipation, bloating; rarely - retroperitoneal hemorrhage; very rarely - gastrointestinal bleeding and fatal retroperitoneal hemorrhage, pancreatitis, colitis (including ulcerative colitis or lymphocytic colitis), stomatitis, acute liver failure, hepatitis, abnormal liver function.
From the skin and subcutaneous tissues: often - subcutaneous bruising; infrequently - 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 the muscles and joints, arthritis, arthralgia, myalgia.
From the urinary system: infrequently - hematuria; very rarely - glomerulonephritis, an increase in the concentration of creatine in the blood.
General reactions: very rarely - fever.
Local reactions: often - bleeding from the place of vascular puncture.
From laboratory research: infrequently - an increase in bleeding time, a decrease in the number of neutrophils, a decrease in the number of platelets in peripheral blood.

Contraindications:

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

Carefully prescribe the drug for moderate hepatic insufficiency, in which a predisposition to bleeding is possible (limited clinical experience with use); renal failure (limited clinical experience); with injuries, surgical interventions; in 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 the simultaneous appointment of warfarin, heparin, inhibitors of glycoprotein IIb / IIIa; in patients with low activity of the CYP2C19 isoenzyme (because when they use clopidogrel at recommended doses, they form less active metabolite of clopidogrel and its antiplatelet effect is less pronounced, and therefore when taking the usually recommended doses of clopidogrel in acute coronary syndrome or percutaneous coronary intervention a higher incidence of cardiovascular complications is possible than in patients with normal activity of the CYP2C19 isoenzyme).

When using the drug Plavix, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgical intervention, it is necessary to carefully monitor patients for signs of bleeding, incl. and hidden.
Due to the risk of bleeding and hematological side effects in the event of the appearance during treatment of clinical symptoms suspicious of the occurrence of bleeding, an urgent clinical blood test should be done, the APTT, platelet count, platelet functional activity indicators and other necessary studies should be carried out.
Plavix, as well as other antiplatelet drugs, should be used with caution in patients with 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.
Co-administration of clopidogrel with warfarin may increase the risk of bleeding, therefore, caution should be exercised when co-administering clopidogrel and warfarin.

For planned surgical interventions and if no antiplatelet effect is required, treatment with Plavix should be discontinued 7 days prior to 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) in patients receiving clopidogrel should be used with caution.
Patients should be warned that when taking clopidogrel (alone or in combination with acetylsalicylic acid), bleeding may take longer to stop, and that if they experience unusual (localization or duration) bleeding, they should be informed about it to your doctor.
Before any upcoming surgery and before starting any new drug, patients should tell their doctor (including a dentist) that they are taking clopidogrel.

Very rarely, after taking clopidogrel (sometimes even for a short time), there have been cases of the development of thrombotic thrombocytopenic purpura (TTP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia in combination with either neurological symptoms, impaired renal function or fever. The development of TTP may 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 the period of treatment, it is necessary to monitor the functional activity of the liver. In severe liver damage, the risk of developing hemorrhagic diathesis should be taken into account.
Plavix should not be administered to patients with rare hereditary problems of galactose intolerance, the lactase deficiency or glucose-galactose malabsorption syndrome.
Influence on the ability to drive vehicles and control mechanisms
Plavix does not significantly affect the ability to drive vehicles or engage in other potentially hazardous activities.

Interaction
other medicinal
by other means:

Although taking clopidogrel at a dose of 75 mg / day did not change the pharmacokinetics of warfarin (a substrate of the CYP2C9 isoenzyme) or MHO in patients receiving long-term treatment with warfarin, the simultaneous use of clopidogrel increases the risk of bleeding due to its independent additional effect on blood coagulation. Therefore, caution should be exercised when taking warfarin and clopidogrel at the same time.
Appointment of blockers of glycoprotein IIb / IIIa receptors together with clopidogrel requires caution, especially in patients with an increased risk of bleeding (with injuries and surgical interventions 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, the simultaneous administration of acetylsalicylic acid 500 mg 2 times / day for 1 day with clopidogrel did not cause a significant increase in bleeding time caused by taking clopidogrel. Between clopidogrel and acetylsalicylic acid, a pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, when used simultaneously care must be taken, 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.
Simultaneous use of heparin did not change the antiplatelet effect of clopidogrel. A pharmacodynamic interaction is possible between Plavix and heparin, which may increase the risk of bleeding (with this combination, caution is required).
The safety of the combined use of clopidogrel, fibrin-specific or fibrin-nonspecific thrombolytic drugs and heparin has been studied in patients with acute myocardial infarction. Frequency of clinically significant bleeding was similar to that observed in the case of the combined use of thrombolytic agents and heparin with acetylsalicylic acid.
In a clinical study conducted in healthy volunteers, the combined use of clopidogrel and naproxen increased occult blood loss through the gastrointestinal tract. However, due to the lack of studies on the interaction of clopidogrel with other NSAIDs, it is currently unknown whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel together with other NSAIDs (the appointment of NSAIDs, including COX-2 inhibitors, together with Plavix requires caution).

Because clopidogrel metabolized to 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 required, 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 in order to study the possible pharmacodynamic and pharmacokinetic interactions, which showed the following.
When using clopidogrel in conjunction with atenolol, nifedipine or both drugs at the same time clinically no significant pharmacodynamic interaction was observed.
The simultaneous use of phenobarbital, cimetidine and estrogens did not significantly affect 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 co-administered 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 with the participation of 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 agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, drugs for hormone replacement therapy have been identified. , with blockers of glycoprotein IIb / IIIa receptors.

Pregnancy:

Contraindicated the 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.
In experimental studies, neither direct nor indirect adverse effects on the course of pregnancy, embryonic development, childbirth and postnatal development have been identified.
It is not known whether clopidogrel is excreted in human breast milk. Breastfeeding during treatment with clopidogrel should be discontinued, 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 carried out. If rapid correction of prolonged bleeding time is needed, platelet transfusion is recommended. There is no specific antidote.

This table is built on the basis of data collected from the resources of pharmaceutical companies that produce these drugs. The average prices for drugs with a minimum dosage dispensed from Russian pharmacies in 2020 are indicated. Why analogues are cheaper than Plavix A lot of time and money is spent on the manufacture of the chemical formula of a new drug, tests are carried out. The pharmaceutical company then buys the patent, then spends the money on advertising and puts it on the market. The manufacturer puts a high price on the drug in order to quickly recoup the investment. Other medicines similar in composition, less well-known but time-tested remain many times cheaper. Share your experience

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