Plavix, 75 mg, film-coated tablets, 28 pcs.

Plavix is ​​a prodrug with antiplatelet properties. Clopidogrel prevents platelet aggregation by inhibiting the interaction of adenosine diphosphate with receptors located on the platelet membrane and stimulating glycoprotein IIb/IIIa receptors. Plavix also reduces platelet aggregation provoked by other antagonists and stops their activation by released adenosine diphosphate.

The medicine is used to prevent the appearance of atherothrombosis after suffering an ischemic cerebrovascular accident or myocardial necrosis in the presence of obliterating endarteritis. Clopidogrel is used in acute coronary syndrome and is prescribed to prevent the development of atrial fibrillation, atherothrombotic or thromboembiolic disorders.

Analogues of the drug according to ATC codes:

AGREGAL DETROMB ZYLT LISTAB 75 LOPIREL PLAVIX PLAGRIL PLOGREL EGITROMB All

You should consult your doctor before using PLAVIX. These instructions for use are for informational purposes only. For more complete information, please refer to the manufacturer's instructions.

Release form, composition and packaging

The film-coated tablets are pink, round, slightly biconvex, engraved with “75” on one side and “II 7I” on the other.

Excipients: mannitol, macrogol 6000, microcrystalline cellulose (low water content, 90 microns), low-substituted hyprolose, hydrogenated castor oil, opadry pink (lactose monohydrate, hypromellose, titanium dioxide (E171), triacetin, red iron oxide dye (E172) ), carnauba wax.

7 pcs. - blisters (1) - cardboard packs. 7 pcs. - blisters (2) - cardboard packs. 7 pcs. - blisters (3) - cardboard packs. 10 pcs. - blisters (1) - cardboard packs. 10 pcs. - blisters (2) - cardboard packs. 10 pcs. - blisters (3) - cardboard packs. 14 pcs. - blisters (1) - cardboard packs. 14 pcs. - blisters (2) - cardboard packs. 14 pcs. - blisters (3) - cardboard packs.

pharmachologic effect

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 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.

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.

When taking clopidogrel daily at a dose of 75 mg, from the first day of administration, a significant suppression of ADP-induced platelet aggregation is observed, 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.

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 events), the incidence of clinical outcomes, other adverse reactions and abnormal clinical laboratory parameters was similar in both men and women.

Pharmacodynamics of the drug

Clopidogrel is considered a prodrug. The active metabolite of the substance helps inhibit platelet aggregation.

The metabolite selectively inhibits the connection of adenosine diphosphate (ADP) with P2Y12 platelet receptors, suppresses the subsequent activation of the GPIIb/IIIa complex, stopping the process of platelet union.

Due to irreversible binding, platelets do not react by activating ADP until 10 days (the remaining life time of blood elements). The restoration of their natural function is carried out as the formed components of the blood are renewed.

Thrombus aggregation induced by liganads other than adenosine diphosphate is also suppressed by blocking the increased activation of platelets that have been released by ADP.

Due to the fact that the formation of the active metabolite occurs with the participation of cytochrome P450 isoenzymes, some of which are inhibited by other drugs or are multiform, not every patient is likely to adequately suppress thrombus aggregation.

With daily use of Plavix at a dosage of 75 mg, from the moment of first taking the tablets, there is a significant inhibition of ADP-induced platelet aggregation, which slowly increases over 3-7 days, and then reaches a stable level.

At steady state, platelet aggregation is inhibited by 40% to 60%.

After the last use of the tablets, platelet aggregation and hemorrhage period are slowly restored to the initial level over 5 days.

Clopidogrel prevents the appearance of atherothrombosis in any concentration of atherosclerosis, including damage to peripheral, coronary or cerebral blood vessels.

The ACTIVE-A trial showed that in people with atrial fibrillation who had even one risk factor for vascular events and are intolerant to indirect anticoagulants, Plavix together with Acetylsalicylic acid reduces the likelihood of cardiac necrosis, cerebral hemorrhage, systemic thromboembolism or vascular death , by reducing the risk of stroke.

The effect of using clopidogrel together with Acetylsalicylic acid appears quickly and lasts about five years.

A reduction in the risk of complications affecting large vessels in patients taking clopidogrel in combination with acetylsalicylic acid was noted by reducing the likelihood of developing cerebral blood flow disorders.

The possibility of a stroke when using clopidogrel with acetylsalicylic acid is reduced. There is also a reduced risk of myocardial necrosis in patients taking Plavix, but there is no difference in the risk of thrombus embolism outside of vascular death or CNS death.

There was also a reduction in hospitalization time due to cardiovascular disorders.

Pharmacokinetics

Suction and distribution

When taken orally at a dose of 75 mg/day, clopidogrel is rapidly absorbed.

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

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% 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, a 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 was isolated in in vitro studies, rapidly and irreversibly binds to platelet receptors, thereby blocking platelet aggregation.

Removal

Within 120 hours after human ingestion of 14C-labeled clopidogrel, approximately 50% of the radioactivity is excreted in urine and approximately 46% in 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, 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 ethnic groups. There are very few literary data among representatives of the Mongoloid race, which does not allow us to assess the effect of genotyping of the CYP2C19 isoenzyme 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, studied by ex vivo platelet aggregation, differ depending on the genotype of the CYP2C19 isoenzyme. The allele of the CYP2C19*1 gene is responsible for normally functioning metabolism, while the alleles of the CYP2C19*2 isoenzyme gene and the CYP2C19*3 isoenzyme are responsible for reduced metabolism. These alleles are responsible for a decrease in metabolism in approximately 85% of Caucasians and 99% of Mongoloids. Other alleles associated with reduced metabolism are the CYP2C19*4, *5, *6, *7 and *8 isoenzymes, but these 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.

Frequency of occurrence of the phenotype and genotype of the CYP2C19 isoenzyme in patients of different races

The effect of CYP2C19 genotype on the pharmacokinetics of the active metabolite of clopidogrel was studied 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. Reduced 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 poor metabolizers in 21 studies involving 4520 subjects. The relative difference in antiplatelet response between genotype groups varied across studies due to different methods used to assess response, but was greater than 30%.

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

Pharmacogenetic testing makes it possible to determine the genotype with variability in the activity of the CYP2C19 isoenzyme.

There may also be genetic variants of other enzymes of the P450 system with effects on the ability to form active metabolites of clopidogrel.

Nature of isoenzyme metabolism Frequency (%) Caucasians (n=1356) Negroids (n=966) Mongoloids (n=573) Intensive metabolism of the CYP2C19 isoenzyme*1/*1 74 66 38 Intermediate metabolism of the CYP2C19 isoenzyme*1/*2 or *1/ *3 26 29 50 Reduced metabolism of the CYP2C19 isoenzyme*2/*2 or *2/*3 or *3/*3 2 4 14

PLAVIX: DOSAGE

Plavix® is prescribed to adults and elderly patients.

The drug is taken orally, regardless of food intake.

Myocardial infarction, ischemic stroke and diagnosed peripheral arterial occlusive disease

The drug is prescribed in a dose of 75 mg 1 time/day. Treatment can begin from the first days to 35 days after myocardial infarction; within a period of 7 days to 6 months - for ischemic stroke.

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 maximum beneficial effect is observed by the 3rd 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)

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 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 Plavix should be started without taking a loading dose.

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

Drug interactions

When clopidogrel is used simultaneously with warfarin, the intensity of bleeding may increase (this combination is not recommended).

Prescribing glycoprotein IIb/IIIa 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 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 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. 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 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 and a decrease in its clinical effectiveness. Concomitant 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 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 clopidogrel.

Phenytoin and tolbutamide can be used safely concomitantly with clopidogrel (CAPRIE study), although data from studies with human liver microsomes suggest 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, β-blockers, calcium channel blockers, lipid-lowering drugs, coronary vasodilators, hypoglycemic drugs (including insulin), antiepileptic drugs, drugs for hormone replacement therapy, with blockers of glycoprotein IIb/IIIa receptors.

Side effects

Studies regarding the safety level of Plavix were conducted on 44,000 patients. In 12,000 patients, therapy lasted more than 1 year. Clinical trial results showed that hemorrhage became a common side effect in the first 30 days of therapy.

From the lymph and blood side, patients rarely developed eosinophilia, leukopenia or thrombocytopenia. Neutropenia appeared occasionally. Occasionally, patients experienced severe throbocytopenia, occlusive thrombotic microangiopathy, acquired hemophilia A, agranulocytosis, a sharp decrease in the number of all blood cells was noted, and aplastic anemia developed.

Other negative reactions:

• Immune system – anaphylactic shock, serum sickness, hypersensitivity to thienopyridines.
• Auditory organs – dizziness.
• Mental disorders - twilight confusion, delirium.
• Visual organs – hemorrhage often occurs in the eye (retinal, ocular, conjunctival).
• Nervous system - intracranial bleeding is sometimes observed, which can be fatal. It is also possible to develop vertigo, headaches, or numbness in the limbs.
• Vessels – frequent occurrence of hematomas. Occasionally, hypotension, rheumatic purpura, bleeding from the wound in the postoperative period, and severe hemorrhage develop.
• Hepatobiliary system – changes in liver parameters, acute form of liver dysfunction, hepatitis.
• Mammary glands – gynecomastia.
• Respiratory system, chest - frequent nosebleeds. Less commonly, bronchospasm, interstitial pneumonia occurs, and eosinophilic pneumonia develops. Bleeding from the respiratory organs, accompanied by hemoptysis, is also possible.
• Connective tissue and locomotor system - occasionally muscle weakness, hemarthrosis, joint pain, arthritis occur.
• Common disorders are fever.
• Urinary organs and kidneys - increased creatinine levels, presence of blood in urine, glomerular nephritis.
• Changes in laboratory parameters - a decrease in the concentration of platelets or neutrophils, prolonged bleeding.

Bruises often form on the skin. Sometimes purpura, rashes, and itching appear on the skin. It is extremely rare to develop bullous dermatitis (Lyell's syndrome, erythema multiforme), nettle fever, Quincke's edema, lichen planus, various forms of rash, DRESS syndrome, hypersensitivity reactions.

Regarding the gastrointestinal tract, after taking Plavix, retroperitoneal hemorrhage may occur, leading to death, or bleeding from the gastrointestinal tract. Other symptoms: stomatitis, pancreatitis, disorder, colitis, dyspepsia, bloating, gastritis, vomiting, stool disorder, nausea, abdominal pain, constipation, ulcerative lesions.

Pregnancy and lactation

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. 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 during pregnancy and breastfeeding

There are no clinical data regarding the effect of Plavix on the fetus during gestation. But for safety reasons, pregnant women should not take the pills.

Large-scale studies have also not been conducted on whether clopidogrel passes into breast milk. But the results of preclinical trials using rats showed that Plavix passes into breast milk. Therefore, it is advisable to avoid taking the medication during breastfeeding.

Preclinical trials have confirmed that clopidogrel has a negative effect on fertility. During the period of conception, it is also forbidden to take pills.

PLAVIX: SIDE EFFECTS

The safety of clopidogrel has been studied in clinical studies of more than 42,000 patients, including more than 9,000 patients who took the drug for a year or more. The following are clinically significant side effects observed in the CAPRIE, CURE, CLARITY, and COMMIT clinical studies. 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 the drug was similar to the tolerability of acetylsalicylic acid, regardless of the age, gender and race of patients.

From the blood coagulation system: in the CAPRIE study, the overall incidence of bleeding in patients receiving clopidogrel or acetylsalicylic acid was 9.3%; the incidence of severe cases with clopidogrel was 1.4%, and with acetylsalicylic acid - 1.6%. In patients receiving clopidogrel, gastrointestinal bleeding occurred in 2.0% of cases and required hospitalization in 0.7% of cases. 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 in the conjunctiva) 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 study, the use of 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 (incidence 2.2% versus 1.8%) or fatal bleeding (incidence 0.2% versus 0.2%). respectively). However, the risk of major, minor and other bleedings was significantly higher when using the combination of clopidogrel + acetylsalicylic acid: major bleedings that are not life-threatening (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 incidence of intracranial bleeding was 0.1% in both groups. The incidence of major bleeding when using the combination of clopidogrel + acetylsalicylic acid depended on the dose of the latter (200 mg - 4.9%), as well as when using the combination of acetylsalicylic acid with placebo (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 incidence of major bleeding within 7 days after coronary artery 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 taking the drug for five days before coronary artery bypass surgery, the incidence was 9.6% in the case of clopidogrel + acetylsalicylic acid and 6.3% in the case of acetylsalicylic acid alone.

In the CLARITY study, an overall increase in the incidence of bleeding was observed in the clopidogrel + acetylsalicylic acid group (17.4%) compared with the placebo + acetylsalicylic acid group (12.9%). The incidence 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 was practically independent of the baseline 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 noncerebral 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).

From the hematopoietic system: in the CAPRIE study - severe neutropenia (

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

Other clinically significant side effects observed in the CAPRIE, CURE, CLARITY and COMMIT studies with an incidence of ≥ 0.1%, as well as all severe side effects, are presented below, according to the WHO classification. Their frequency is defined as follows: often (> 1/100, 1/1000, 1/10,000,

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

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

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

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

Dermatological reactions: uncommon - rash and itching.

Post-marketing data

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

In addition to clinical trial data, the following adverse events have been spontaneously reported. In each organ system class (according to the MedDRA classification), they are given with an indication of frequency. The term "very rarely" corresponds to the frequency

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

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

From the digestive system: very rarely - colitis (including ulcerative or lymphocytic colitis), pancreatitis, changes in taste, 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, increased 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.

Instructions for use PLAVIX®

Platelet aggregation inhibitor.

Clopidogrel is a prodrug and must be metabolized by CYP2C19 enzymes to form its active metabolite. The active metabolite of clopidogrel selectively blocks platelet P2Y12 receptors, inhibiting the binding of ADP to these receptors and the subsequent ADP-mediated activation of the GPIIb/IIIa glycoprotein complex, thereby preventing platelet aggregation. The irreversibility of blockade of P2Y12 receptors persists for the entire remaining life of platelets (approximately 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the platelet cycle. Platelet aggregation induced by agonists other than ADP is also suppressed by blocking the increased platelet activation induced by released ADP.

Since the active metabolite is formed by the CYP2C19 isoenzyme, some of which are polymorphic or suppressed by other drug compounds, platelet suppression is not sufficient in all patients.

Regular use of the drug in a daily dose of 75 mg from the first day of use leads to significant inhibition of platelet aggregation caused by ADP. The inhibitory effect increases progressively and an equilibrium state is achieved after 3-7 days. At the same time, the average level of inhibition under the influence of a daily dose of 75 mg was from 40 to 60%. Platelet aggregation and bleeding time gradually returned to baseline levels, on average 5 days after cessation of treatment.

The safety and effectiveness of clopidogrel were assessed in a double-blind study in five clinical programs involving a total of over 80,000 patients:

• CAPRIE, comparing clopidogrel with acetylsalicylic acid (ASA), and CURE, CLARITY and COMMIT and ACTIVE-A, which compared clopidogrel with placebo (comparison groups with ASA and other standard therapy).

Recent myocardial infarction, recent stroke, or diagnosed peripheral arterial occlusive disease

The CAPRIE study included 19,185 patients with atherothrombosis, manifested as recent myocardial infarction (less than 35 days), recent ischemic stroke (7 days to 6 months), or diagnosed peripheral arterial occlusive disease (PAD). Patients were randomized to receive 75 mg clopidogrel or 325 mg ASA/day and remained under observation for 1 to 3 years. In the subgroup of patients who had myocardial infarction, most patients received ASA from the first days after myocardial infarction.

Clopidogrel led to a statistically significant reduction in the incidence of new ischemic disorders (myocardial infarction, ischemic stroke and sudden death) compared with ASA: the number of ischemic disorders among patients who received at least one dose of the drug was 939 in the group receiving clopidogrel and 1020 in the ASA group. The percentage relative risk reduction was 8.7% in the ASA group [95% CI:

• 0.2-16.4];
• (p=0.045), which corresponds to 10 [CI: 0-20] additional patients with success in preventing new ischemic events for every 1000 patients treated for 2 years. Analysis of overall mortality did not demonstrate a significant difference between clopidogrel (5.8%) and ASA (6%).

When analyzing subgroups using qualitative assessment of the condition (myocardial infarction, stroke and PAAD), the greatest beneficial effect (achieved statistical significance at p = 0.003) was in patients with PAAD (especially those with a history of myocardial infarction) (RRR = 23.7% ;CI:

• 8.9-36.2) and weaker (insignificant difference with ASA) in patients who had a stroke (RRR=7.3%;
• CI: -5.7-18.7). In patients enrolled only on the basis of recent myocardial infarction, the outcome in the clopidogrel group was numerically better, but not statistically different from ASA (RRR= -4%;
• CI: -22.5-11.7). In addition, subgroup analysis by age suggests that the success of clopidogrel in patients over 75 years of age was less than in patients under 75 years of age.

Because the CAPRIE study was not designed to evaluate the effectiveness of specific subgroups, it is unclear whether the difference in relative risk reduction between the qualifying conditions actually exists or is due to chance.

Acute coronary syndrome

The CURE study included 12,562 patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q wave myocardial infarction) within 24 hours of the last episode of chest pain or symptoms suggestive of ischemia. To be included in the study, patients were required to have either ECG changes indicating new ischemic events or elevated cardiac enzyme levels of at least 2 times the normal level:

• troponin I or T. Patients were assigned to groups of clopidogrel (300 mg loading dose, followed by a dose of 75 mg/day, n=6259) or placebo (n=6303), both in combination with ASA (75-325 mg once a day). days) and other standard appointments. The course of therapy was carried out for up to one year. In this study, 823 (6.6%) patients were simultaneously treated with GPIIb/IIIa receptor antagonists. Heparins were prescribed to more than 90% of patients, and heparin therapy did not have a significant effect on the relative percentages of bleeding between clopidogrel and placebo.

The number of patients with new cardiovascular events (cardiovascular death, myocardial infarction or stroke) was 582 (9.3%) in the clopidogrel group and 719 (11.4%) in the placebo group, with a 20% reduction in relative risk (95% CI 10-28%; p=0.00009) in the group receiving clopidogrel (17% relative risk reduction in patients receiving conservative treatment, 29% in patients after PLCA (percutaneous luminal coronary angioplasty) with or without stenting , and 10% after coronary artery bypass grafting.New cardiovascular events were prevented with the following relative risk reduction (RRR): 22% (CI: 8.6, 33.4), 32% (CI: 12.8, 46.4), 4% (CI : -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI:

• -31.6, 44.2) for intervals of 0-1, 1-3, 3-6, 6-9 and 9-12 months, respectively. Thus, after 3 months of treatment, the benefit observed in the clopidogrel + ASA group no longer increased, while the risk of bleeding remained.

The use of clopidogrel in the CURE study was associated with a reduction in the need for thrombolytic therapy (relative risk reduction 43.3%; CI:

• 24.3%, 57.5%) and in GPIIb/IIIa inhibitors (RRR=18.2%;
• CI: 6.5%, 28.3%).

The number of patients with overall cardiovascular events (cardiovascular death, myocardial infarction, stroke or refractory ischemia) was 1035 (16.5%) in the clopidogrel group and 1187 (18.8%) in the placebo group, with a relative risk reduction in the clopidogrel group of 14% (95% CI 6-21%, p=0.0005). This benefit is mainly explained by a statistically significant reduction in the incidence of myocardial infarction [287 (4.6%) in the clopidogrel group and 363 (5.8%) in the placebo group]. There was no effect on readmission rates for unstable angina.

The results obtained in the treatment of different groups of patients (unstable angina, non-Q wave myocardial infarction, low and high risk, diabetes mellitus, need for revascularization, age, gender) are consistent with the results of the primary analyses. Specifically, in a post-hoc analysis of 2172 patients (17% of the total treated population of the CURE study) undergoing stent placement (Stent-CURE), the results showed that clopidogrel compared with placebo clearly demonstrated a significant relative risk reduction of 26.2% in favor of clopidogrel for the primary endpoint (cardiovascular death, myocardial infarction, stroke), and a significant relative risk reduction of 23.9% for the second primary endpoint (cardiovascular death, myocardial infarction, stroke or refractory ischemia ). Moreover, the safety profile of clopidogrel in this subgroup of patients did not raise any particular concerns. Thus, the results in this subgroup are consistent with the overall results of the study.

Treatment benefits with clopidogrel were independent of other short- or long-term cardiovascular treatments (such as low molecular weight heparins or unfractionated heparin, GPIIb/IIIa receptor antagonists, lipid-lowering agents, beta-blockers and ACE inhibitors). The effectiveness of clopidogrel did not depend on the dose of acetylsalicylic acid (75-325 mg 1 time / day).

The safety and effectiveness of clopidogrel in patients with acute ST-segment elevation myocardial infarction was studied in two randomized, placebo-controlled, double-blind studies, CLARITY and COMMIT.

The CLARITY study included 3491 patients enrolled within 12 hours of ST-segment elevation myocardial infarction with thrombolytic therapy. Patients received clopidogrel (loading dose 300 mg, subsequently 75 mg/day, n=1752), or placebo (n=1739), both drugs in combination with ASA (150-325 mg as a loading dose, subsequently 75-162 mg /day), fibrinolytic drug and, if necessary, heparin. The patients were observed for 30 days. The primary endpoint was the presence of infarct-related artery occlusion on predischarge angiogram, or death or recurrent myocardial infarction occurring before coronary angiography (study day 30). For patients who did not undergo angiography, the primary end point was death or recurrent myocardial infarction up to 8 days or before discharge from the hospital. Among the patients, 19.7% were women and 29.2% of patients were over 65 years of age. A total of 99.7% of patients received fibrinolytics (fibrin-specific:

• 68.7%;
• non-fibrin-specific: 31.1%), 89.5% - heparin, 78.7% - beta-blockers, 54.7% - ACE inhibitors and 63% - statins.

15% of patients in the clopidogrel group and 21.7% of patients in the placebo group met the primary endpoint, representing an absolute reduction of 6.7% and a reduction difference of 36% in favor of clopidogrel (95% CI, 24.47%; P < 0.001), mainly due to a decrease in the percentage of occlusion of the infarct-related artery. This benefit remained consistent across subgroups of patients prespecified by age, sex, infarct location, and type of fibrinolytic or heparin used.

The COMMIT factorial study design included 45,852 patients within 24 hours of the onset of symptoms suggestive of myocardial infarction, incl. ECG abnormalities (ST segment elevation, ST segment depression, or left bundle branch block). Patients received clopidogrel (75 mg/day, n=22961) or placebo (n=22891), in combination with ASA (162 mg/day), for 28 days or until discharge. Primary endpoints were death from any cause, first recurrent infarction, stroke, or death. The group included 27.8% women, 58.4% patients aged 60 years or older (26% aged 70 years or older), and 54.5% patients receiving fibrinolytics.

Clopidogrel significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the relative risk of the combination of recurrent heart attack, stroke or death by 9% (p=0.002), representing an absolute reduction of 0.5% and 0.9%, respectively. . This advantage remained constant in all age and gender groups of patients, and did not depend on the use of fibrinolytics, and was observed already 24 hours after the start of the drug.

Atrial fibrillation

The ACTIVE-W and ACTIVE-A studies, separate studies of the ACTIVE program, included patients with atrial fibrillation (AF) who had at least one risk factor for vascular complications. Based on inclusion criteria, physicians enrolled patients in the ACTIVE-W study if patients were eligible for vitamin K antagonist (VKA) therapy (eg, warfarin). The ACTIVE-A study included patients who were not eligible for VKA therapy because they were unwilling or unable to receive such treatment.

The ACTIVE-W trial showed that treatment with vitamin K antagonists was more effective when combined with clopidogrel and ASA.

The ACTIVE-A study (n=7554) was a multicenter, randomized, double-blind, placebo-controlled study comparing the clopidogrel 75 mg/day + ASA group (n=3772) with the placebo + ASA group (n=3782). The recommended dose of ASA was 75-100 mg/day. Patients received treatment for the entire duration of treatment, up to 5 years.

Patients randomized to the ACTIVE study program had documented history of MA, i.e. or persistent AF or at least 2 episodes of intermittent AF in the past 6 months, and also had at least one of the following risk factors:

• age ≥75 years or age 55–74 years in combination with diabetes mellitus requiring drug therapy, documented myocardial infarction, or documented acute coronary disease;
• treatment for systemic hypertension;
• previous stroke, transient ischemic attack (TIA) or non-CNS systemic embolism;
• left ventricular dysfunction with left ventricular stroke volume <45%;
• or documented peripheral vascular disease. The mean CHADS2 score was 2 (range 0–6).

The main criteria for excluding patients from the study were:

• gastric and duodenal ulcer within the previous 6 months, previous intracerebral hemorrhage, severe thrombocytopenia (platelet count <50 × 109/l), need for therapy with clopidogrel or anticoagulants, unresponsive to one of the two compounds.

73% of patients enrolled in the ACTIVE-A trial were unable to take vitamin K antagonists due to physician judgment, abnormal INR, fall or head injury, or specific bleeding risk; 26% of patients did not want to take vitamin K antagonists.

The patient group included 41.8% women. The average age of patients was 71 years, 41.6% of patients were over 75 years old. Overall, 23% of patients received antiarrhythmic drugs, 52.1% received beta-blockers, 54.6% received ACE inhibitors, and 25.4% received statins.

The number of patients who experienced the expected clinical outcome (first stroke, myocardial infarction, non-CNS systemic embolism, or death from vascular disease) was 832 (22.1%) in the clopidogrel+ASA group and 924 (24.4%) in the clopidogrel+ASA group. placebo+ASA group.

The beneficial effect of clopidogrel + ASA was observed in the early stages and persisted throughout the study period up to 5 years; The incidence of the primary outcome was consistently lower in the clopidogrel + ASA group than in the placebo + ASA group.

The reduction in the risk of major vascular complications in the clopidogrel + ASA treatment group was mainly due to a significant reduction in the incidence of stroke. Stroke was observed in 296 (7.8%) patients receiving clopidogrel + ASA and in 408 (10.8%) patients receiving placebo + ASA.

The incidence of ischemic stroke was significantly lower in the clopidogrel + ASA group than in the placebo + ASA group (6.2% and 9.1%, respectively; relative risk reduction, 32.4%; 95% confidence interval, 20.2-42.7%).

The risk of stroke of any severity decreased with the use of clopidogrel + ASA. In addition, it was reported that there were 46 fewer non-disabling strokes and 69 fewer disabling or fatal strokes in the clopidogrel + ASA group than in the placebo + ASA group.

There was a trend towards a reduction in the rate of myocardial infarction in the group receiving clopidogrel + ASA (relative risk reduction, 21.9%; 95% CI, -3% to 40.7%, p = 0.08). The incidence of vascular disease mortality was similar between the two groups.

The effectiveness of clopidogrel + ASA was maintained throughout the study period (5 years), the incidence of stroke was significantly lower in the clopidogrel + ASA group compared to the placebo + ASA group.

Pediatric patients

In a randomized, double-blind, parallel-group study (CLARINET), 906 pediatric patients (neonates and infants) with cyanotic congenital heart disease with systemic-pulmonary anastomosis received clopidogrel 0.2 mg/kg (n=467) or placebo (n =439) against the background of concomitant basic therapy before the second stage of the operation. The median time between palliative bypass surgery and study drug initiation was 20 days. About 88% of patients received concomitant ASA therapy (doses ranging from 1 to 23 mg/kg/day). There was no difference between the groups in the primary composite outcome measure, the sum of deaths, shunt thrombosis, or cardiac interventions up to 120 days after a thrombotic complication (relative risk reduction, 11.1%; 95% CI:

• -19.2, 33.6;
• p=0.43). The most commonly reported adverse reaction in both groups was hemorrhage;
• however, there was no significant difference between the groups in the incidence of hemorrhage. During long-term safety follow-up, 26 patients 1 year of age with a bypass were treated with clopidogrel until 18 months of age. No new security risks were identified during this monitoring.

Indications

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

Prevention of atherothrombotic events (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) with drug treatment and the possibility of thrombolysis.

Indications for use

The instructions for use indicate that Plavix is ​​indicated for the prevention of atherothrombosis after myocardial necrosis. Therapy is carried out no later than a month after a heart attack. The tablets are also prescribed to prevent the development of obliterating endarteritis and cerebral infarction. In the latter case, treatment is carried out after 7 days, but no later than six months after the hemorrhage.

Other indications:

• Acute coronary syndrome (myocardial necrosis without Q waves, unstable angina) without S-T segment enlargement, including patients who received a stent.
• Acute coronary syndrome.
• Acute myocardial necrosis with S-T segment elevation, in combination with acetylsalicylic acid (AA).

Plavix tablets are taken for atrial fibrillation to prevent thromboembolic or atherothrombotic disorders. Concomitant therapy with clopidogrel and AK is prescribed only to adults suffering from atrial fibrillation, who have risk factors for the occurrence of vascular disorders, have contraindications to taking VKAs (vitamin K antagonists) and there is no risk of hemorrhage, in order to prevent the occurrence of thromboembolic or atherothrombotic disorders , including stroke.

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 under 18 years of age (safety and effectiveness of use have not been established);
• hypersensitivity to the components of the drug.

The drug is prescribed with caution in case of 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 a genetically determined decrease in the function of the CYP2C19 isoenzyme (there is literature data indicating that patients with a genetically determined decrease in the activity of the CYP2C19 isoenzyme are exposed 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 CYP2C19 isoenzyme).

Compatibility with other drugs

Single-part use of Plavix with drugs, during the use of which the likelihood of bleeding increases, increases the risk of hemorrhagic complications. The combined use of clopidogrel and similar drugs requires extreme caution.

The simultaneous use of Plavix and AA does not change the inhibitory properties of the latter on ADP-induced platelet aggregation. But clopidogrel increases the effectiveness of AA in thrombus aggregation, which was induced by the proteinoid.

But the combined use of clopidogrel and AK 500 mg twice a day does not increase the bleeding time, which increases due to the use of clopidogrel. It is better not to use AK and Plavix in parallel. Although there is evidence when the drugs were taken simultaneously for a year. But some studies have confirmed that the simultaneous use of acetonic acid and clopidogrel increases the risk of mortality.

Interaction of Plavix with other drugs:

1. Oral anticoagulants. There is a risk of increased intensity of hemorrhage due to the significant impact on hemostasis. However, daily intake of 75 mg of clopidogrel does not change the pharmacokinetics of S-warfarin.
2. Heparin. There is a small chance of bleeding.
3. Blockers of glycoprotein IIb/IIIa platelet receptors. Shared use is permissible, but under strict medical supervision.
4. Thrombolytic drugs. Studies involving patients with acute heart attacks have shown that the risk of hemorrhage is similar to that which occurs when taking Aspirin and Plavix together.
5. Antidepressants (SSRIs). Parallel use requires caution, because selective serotonin reuptake inhibitors affect platelet aggregation and increase the likelihood of hemorrhage.
6. Anti-inflammatory non-steroidal drugs. Increased risk of hidden bleeding from the gastrointestinal tract.
7. Proton pump inhibitor. When Plavix is ​​used in parallel with Omeprazole or Esomeprazole, the content of the active metabolite in the blood decreases by 40–45%, which is accompanied by reduced inhibition of platelet adhesion (21–39%).
8. Antacids, Digoxin, Theopheline. Does not change the absorption of clopidogrel.
9. Drugs that inhibit CYP2C19 activity. There is a decreased content of the active metabolite of Plavix in the blood
10. Substrates of the CYP2C8 enzyme. Clopidogrel increases the exposure of Repaglinide.

The results of studies in which the liver was examined under a microscope showed that the carboxyl metabolites of Plavix inhibit cytochrome P450 2C9. This increases the blood levels of Tolbutamide, Phenytoin and some NSAIDs.

Using Plavix and ethanol together may cause a disulfiram-like reaction. The drug interacts with alcohol, which causes poisoning. Intoxication is manifested by the following symptoms:

• limb spasms;
• nausea;
• labored breathing;
• headache;
• heat;
• tachycardia.

Also, simultaneous use of Plavix and alcohol can reduce the effectiveness of treatment and increase the intensity of side symptoms of the drug. The load on the liver also increases and the risk of cardiovascular complications increases.

It is strictly forbidden to use clopidogrel with ethanol at the same time. Plavix tablets can be taken 24 hours before drinking alcohol for men and 48 hours for women. The drug is allowed to be used 20 hours after drinking alcohol for men and 48 hours for women.

special instructions

When using Plavix, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients should be closely monitored for 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 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 COX-2 inhibitors), heparin or glycoprotein IIb/IIIa inhibitors.

The combined use of clopidogrel with warfarin may increase the intensity of bleeding, therefore, with the exception of special 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 Plavix and warfarin is not recommended.

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.

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

Taking 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.

Impact on the ability to drive vehicles and operate machinery

Plavix® does not have a significant effect on the ability to drive vehicles or operate machinery.