Instruction for use: Plavix

Dosage form: film-coated tablets

Active substance: Clopidogrelum

ATX

B01AC04 Clopidogrel

Pharmacological groups

Antiaggregants

The nosological classification (ICD-10)

I20.0 Unstable angina: heberden disease; Angina pectoris; The attack of angina pectoris; recurrent angina; Spontaneous angina; Stable angina pectoris; Angina rest; Angina progressing; Angina mixed; Angina spontaneous; stable angina; Chronic stable angina; Angina Syndrome X

I21 Acute myocardial infarction: Myocardial infarction in the acute phase; Acute Myocardial Infarction; Myocardial infarction with pathologic Q wave and without; Myocardial infarction complicated by cardiogenic shock; Infarction left ventricular; Transmural myocardial infarction; Myocardial infarction netransmuralny (subendocardial); Netransmuralny myocardial infarction; Subendocardial myocardial infarction; The acute phase of myocardial infarction; Acute myocardial infarction;Sub-acute phase of myocardial infarction; Subacute phase of myocardial infarction; Thrombosis of the coronary arteries (the arteries); Threatened myocardial infarction; Myocardial infarction without Q wave

I74 Embolism and arterial thrombosis: Thrombosis of effort (stress); Arterial thrombosis; Arteriothrombosis; Subacute and chronic arterial thrombosis; Subacute thrombosis of peripheral arteries; Postoperative thrombosis; Vascular thrombosis; Vascular embolism; Thrombosis of aortocoronary shunt; Arterial thrombosis; Thrombosis of arteries; Coronary artery thrombosis; Coronary thrombosis; Thrombosis of blood vessels; Thrombosis with ischemic stroke; Thrombosis with general surgical operations; Thrombosis in Oncology Operations; Vascular thrombosis; Thrombus formation in the postoperative period; Thrombotic complications; Thromboembolic diseases; Thromboembolic syndrome; Thromboembolic complication in the postoperative period; Thromboembolism of arteries; Partial vascular thrombosis; Embolism; Embolism of arteries

Z100 * CLASS XXII Surgical practice: Abdominal surgery; adenomectomy; Amputation; Coronary angioplasty; Angioplasty of the carotid arteries; Antiseptic skin treatment for wounds; Antiseptic Hand; Appendectomy; atherectomy; Balloon coronary angioplasty; Vaginal hysterectomy; The coronary bypass; Interventions in the vagina and cervix; Interventions on the bladder; Intervention in the mouth; Restoration and reconstructive surgery; Hand hygiene of medical personnel; Gynecologic surgery; Gynecological intervention; Gynecological surgery; Hypovolemic shock during operations; Disinfection of purulent wounds; Disinfection of wounds edges; Diagnostic intervention; Diagnostic procedures; Cervical Diathermocoagulation; Long-surgery; Replacing the fistula catheters; Infection in orthopedic surgery; Artificial heart valve; cystectomy; Short-term outpatient surgery; Short-term operation; Short surgical procedures; Krikotireotomiya; Blood loss during surgery; Bleeding during surgery and in the postoperative period; Kuldotsentez; laser photocoagulation; laser coagulation; retinal laser coagulation; Laparoscopy; Laparoscopy in Gynecology; CSF fistula; Small gynecological operations; Small surgical procedures; Mastectomy and subsequent plastic; mediastinotomy; Microsurgical operations on the ear; Mukogingivalnye operation; suturing; Minor surgery; neurosurgical operation; Immobilization of the eyeball in ophthalmic surgery; testectomy; pancreatectomy; Perikardektomiya; The period of rehabilitation after surgery; The period of convalescence after surgery; Percutaneous transluminal coronary angioplasty; Pleural thoracentesis; Pneumonia postoperative and posttraumatic; Preparation for surgical procedures; Preparation for surgery; Preparation of the surgeon's hands before surgery; Preparation of the colon for surgical procedures; Postoperative aspiration pneumonia in neurosurgical and thoracic surgery; Postoperative nausea; Postoperative bleeding; postoperative granuloma; postoperative shock; The early postoperative period; myocardial revascularization; Radiectomy; gastric Resection; bowel resection; uterine Resection; liver Resection; enterectomy; Resection of part of the stomach; Reocclusion of the operated vessel; Bonding tissues during surgical procedures; Removal of sutures; Condition after eye surgery; Condition after surgery; Condition after surgery in the nasal cavity; Condition after gastrectomy; Status after resection of the small intestine; Condition after tonsillectomy; Condition after removal of the duodenum; Condition after phlebectomy; Vascular surgery; Splenectomy; Sterilization of surgical instruments; Sterilization of surgical instruments; sternotomy; Dental surgery; Dental intervention in periodontal tissues; strumectomy; Tonsillectomy; Thoracic surgery; Thoracic surgery; total gastrectomy; Transdermal intravascular coronary angioplasty; Transurethral resection; Turbinektomiya; Removal of a tooth; cataract surgery; Removal of cysts; tonsillectomy; Removal of fibroids; Removing the mobile primary teeth; Removing polyps; Removing broken tooth; Removal of the uterus body; Removal of sutures; Fistula likvoroprovodyaschih ways; Frontoetmoidogaymorotomiya; Surgical infection; Surgical treatment of chronic limb ulcers; Surgery; The surgery in the anal area; The surgery on the colon; Surgical practice; The surgical procedure; Surgical interventions; Surgery on the gastrointestinal tract; Surgical procedures on the urinary tract; Surgical procedures on the urinary system; Surgical intervention of the genitourinary system; Surgical procedures on the heart; Surgical manipulation; surgery; Surgery on the veins; Surgical intervention; Vascular surgery; Surgical treatment of thrombosis; Surgery; cholecystectomy; Partial gastric resection; hysterectomy; Percutaneous transluminal coronary angioplasty; Percutaneous transluminal angioplasty; Coronary artery bypass; tooth Extirpation; Extirpation of milk teeth; pulpectomy; pulsative cardiopulmonary bypass; tooth Extraction; teeth Extraction; cataract extraction; Electrocoagulation; endourological intervention; episiotomy; Etmoidotomiya; Complications after tooth extraction

Composition

active substance: Clopidogrel hydrogen sulfate in the form II 391.5 mg

(In terms of clopidogrel 300 mg)

Excipients

Core tablet: mannitol - 275.7 mg; Macrogol 6000 - 136 mg; MCC (low water content, 90 microns) - 124 mg; Giprolose low-substituted - 51.6 mg; Castor oil hydrogenated - 13.2 mg

Film sheath: Opadry® pink * - 30 mg; Wax carnauba - traces

* Opadry® pink contains: lactose monohydrate, hypromellose, titanium dioxide (E171), triacetin, iron dye red oxide (E172)

Description of dosage form

Oblong tablets covered with a pink film shell, engraved with the number "300" on one side and number "1332" on the other.

Pharmachologic effect

Mode of action - antiaggregational.

Pharmacodynamics

Clopidogrel is a prodrug, one of its metabolites is active and inhibits the aggregation of platelets. The active metabolite of clopidogrel selectively inhibits the binding of ADP to the P2Y12 receptor of platelets and the subsequent ADP-mediated activation of the glycoprotein IIb / IIIa complex, leading to suppression of platelet aggregation. Due to irreversible binding, platelets remain immune to stimulation of ADP for the rest of their life (about 7-10 days), and the restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal. Aggregation of platelets caused by agonists other than ADP is also inhibited by blockade of enhanced platelet activation by the released ADP.

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

With a daily intake of clopidogrel at a dose of 75 mg, a significant inhibition of ADP-induced platelet aggregation is noted from the first day of administration, which gradually increases for 3-7 days and then reaches a constant level (when the equilibrium state is reached). In the equilibrium state, platelet aggregation is suppressed on average by 40-60%. After stopping the use of clopidogrel, platelet aggregation and bleeding time gradually return to the baseline, on average for 5 days.

When comparing the pharmacodynamic properties of clopidogrel in men and women, a smaller inhibition of ADP-induced platelet aggregation is observed in women, but no sex differences in lengthening of bleeding time are revealed.

In patients with recent myocardial infarction (MI), stroke and peripheral arterial occlusive disease, Plavix® at a dose of 75 mg / day significantly reduces the risk of developing ischemic complications (combined MI, stroke and cardiovascular death), and he Has the greatest efficacy in patients with peripheral arterial occlusive disease, especially in combination with MI in a history, and is also more effective in patients younger than 75 years.

In patients with acute coronary syndrome without ST segment elevation (unstable angina, MI), Plavix® (loading dose 300 mg, then 75 mg / day) in combination with acetylsalicylic acid (ASA) (75-325 mg 1 time (Heparin therapy, glycoprotein IIb / IIIa blockers, lipid-lowering drugs, beta-blockers, ACE inhibitors) and doses of ASA, significantly reduces the overall risk of developing ischemic complications: acute myocardial infarction, stroke and Cardiovascular death with a decrease in relative risk in conservative treatment - by 17%; After percutaneous transluminal coronary angioplasty (PTCA) with stenting or without stenting - by 29% and after aortocoronary bypass - by 10%.

In patients with acute myocardial infarction with elevation of the ST segment, taking Plavix® (during the first 12 hours, the MI loading dose was 300 mg, then at 75 mg / day) in combination with ASA (loading dose 150-325 mg, then 75 -162 mg once a day) and fibrinolytic, and (according to indications) with heparin reduces the combined rate of angiography detected at the time of discharge from the hospital coronary artery occlusion related to the infarction zone, or fatal outcomes, or the development of repeated MI; And for patients who have not undergone angiography at discharge, the incidence of death or recurrent MI until the 8th day of myocardial infarction or until discharge from the hospital, mainly by decreasing the incidence of coronary artery occlusion related to the infarction zone. In patients with acute myocardial infarction with ST-segment elevation, ST-segment reduction or left bundle branch blockade, taking Plavix® 75 mg / day in combination with ASC at 162 mg once daily leads to a reduction in the incidence of fatalities for any of the reasons and The total frequency of the first repeated myocardial infarction, stroke, and death.

Pharmacokinetics

Suction

Suction data were obtained with ingestion of 75 mg clopidogrel. After a single dose and with oral administration at a dose of 75 mg / day clopidogrel quickly absorbed.

The mean Cmax of unchanged clopidogrel in plasma (approximately 2.2-2.5 ng / ml after ingestion of a single dose of 75 mg) is reached approximately 45 minutes after administration. According to the deducing of metabolites of clopidogrel through the kidneys, its absorption is approximately 50%.

Distribution

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

Metabolism

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo clopidogrel is metabolized in two ways: the first through esterases and subsequent hydrolysis with the formation of an inactive derivative of carboxylic acid (85% of circulating metabolites in the systemic bloodstream), and the second through the cytochrome P450 system. Initially clopidogrel is metabolized to 2-oxoklopidogrel, which is an intermediate metabolite. The subsequent metabolism of 2-oxoklopidogrel leads to the formation of an active metabolite of the clopidogrel-thiol clopidogrel derivative. In vitro, this active metabolite is formed mainly by the CYP2C19 isoenzyme, but some other isoenzymes also participate in its formation, including CYP1A2, CYP2B6 and CYP3A4. The active thiol clopidogrel metabolite, which was isolated in in vitro studies, quickly and irreversibly binds to platelet receptors, thus inhibiting their aggregation.

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

Excretion

Within 120 hours after ingestion of 14C-labeled clopidogrel in person, about 50% of the radioactivity is released through the kidneys with urine and about 46% of the radioactivity - through the intestine with the fecal masses. After a single oral dose of 75 mg of T1 / 2 clopidogrel is approximately 6 hours. After a single administration and taking repeated doses of T1 / 2, the main circulating inactive blood metabolite is 8 hours.

Pharmacogenetics

With the help of the CYP2C19 isoenzyme, both an active metabolite and an intermediate metabolite, 2-oxoclopidogrel, are formed. The pharmacokinetics and antiplatelet effect of the active metabolite clopidogrel, when examining platelet aggregation ex vivo, vary depending on the genotype of the isoenzyme CYP2C19. The allele of the CYP2C19 * 1 gene corresponds to a fully functional metabolism, while the CYP2C19 * 2 and CYP2C19 * 3 gene alleles are non-functional. Alleles of CYP2C19 * 2 and CYP2C19 * 3 genes cause a decrease in metabolism in the majority of representatives of Caucasoid (85%) and Mongoloid races (99%). Other alleles that are associated with a lack or decrease in metabolism are less common and include, but are not limited to, the alleles of the CYP2C19 * 4, * 5, * 6, * 7, and * 8 genes. Patients with a low activity of the CYP2C19 isoenzyme should have the two alleles of the gene with loss of function indicated above. Published frequency of occurrence of phenotypes of people with low activity of the isoenzyme CYP2C19 is 2% for Caucasians, 4% for Negro people and 14% for Chinese. There are special tests to determine the patient's genotype of the isoenzyme CYP2C19.

In a cross-sectional study of 40 volunteers, 10 patients in each group (individuals with very high, high, intermediate, and low activity of the CYP2C19 isoenzyme) evaluated the pharmacokinetics and antiplatelet effect when taking 300 mg clopidogrel followed by 75 mg / day And when 600 mg of clopidogrel is taken and then taken 150 mg / day for 5 days (reaching the Css state). There were no significant differences in the exposure of the active metabolite and the mean platelet aggregation inhibition (IAT) (induced by ADP) in individuals with very high, high and intermediate activity of the CYP2C19 isoenzyme. In volunteers with a low activity of the CYP2C19 isoenzyme, the exposure of the active metabolite decreased by 63-71% compared to individuals with a high activity of the CYP2C19 isoenzyme.

When the treatment regimen was used, 300 mg-loading dose / 75 mg-maintenance dose (300/75 mg) in volunteers with a low activity of the CYP2C19 isoenzyme, the antiplatelet effect was reduced with a mean of 24% (24 h) and 37% (5 (After 24 hours) and 58% (on the 5th day of treatment) in volunteers with a high activity of the isoenzyme CYP2C19 and 37% (after 24 hours) and 60% (for 5 days) Day of treatment) in volunteers with intermediate activity of the isoenzyme CYP2C19. When volunteers with a low activity of the CYP2C19 isoenzyme received a treatment regimen of 600 mg - loading dose / 150 mg - maintenance dose (600/150 mg), the exposure of the active metabolite was higher than with the 300/75 mg regimen. In addition, the IAT was 32% (after 24 hours) and 61% (on the 5th day of treatment), which was more than that of people with a low activity of the isoenzyme CYP2C19 who received the 300/75 mg treatment regimen and was similar to that in the groups Patients with a higher intensity of CYP2C19 metabolism who received a 300/75 mg treatment regimen.

However, in studies with clinical outcomes, the dosage regimen of clopidogrel for patients in this group has not yet been established. Similarly to the results of this study, a meta-analysis of six studies, which included data from 335 volunteers who received clopidogrel and were in the Css-achieving state, showed that, in comparison with volunteers with high CYP2C19 isoenzyme activity, volunteers with an intermediate activity of the CYP2C19 isoenzyme exhibited an active metabolite Decreased by 28%, and in volunteers with a low activity of the isoenzyme CYP2C19 - by 72%, while the IAB was reduced with differences in the AITs of 5.9 and 21.4%, respectively.

There was no evaluation of the effect of the CYP2C19 genotype on clinical outcomes in patients receiving clopidogrel in prospective, randomized, controlled trials.

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

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

In the CHARISMA study and one cohort study (Simon), an increase in the incidence of cardiovascular complications was observed only in patients with a low activity of the isoenzyme CYP2C19 (when compared with patients with high activity of the isoenzyme CYP2C19).

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

Individual patient groups

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

Patients of advanced age. In elderly volunteers (over 75 years), when compared with young volunteers, there was no difference in platelet aggregation and bleeding time. Do not require dose adjustment in the elderly.

Children. No data available.

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

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

Race affiliation. The prevalence of the alleles of the CYP2C19 isoenzyme genes, which cause intermediate and low activity of this isoenzyme, differs among representatives of different racial groups. There are limited literature data on their prevalence in representatives of the Mongoloid race, which makes it impossible to assess their genotyping values for the isoenzyme CYP2C19 for the development of ischemic complications.

Indications

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

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

- with the rise of the ST segment (acute myocardial infarction).

Contraindications

Hypersensitivity to clopidogrel or any of the excipients of the drug;

Severe hepatic impairment;

Acute bleeding, eg bleeding from peptic ulcers or intracranial hemorrhage;

Rare hereditary intolerance to galactose, lactase deficiency and glucose-galactose malabsorption;

pregnancy;

The period of breastfeeding (see "Application in pregnancy and lactation");

Children under 18 years of age (safety and efficacy not established).

With caution: moderate hepatic insufficiency, which may predispose to bleeding (limited clinical experience of use); Renal failure (limited clinical experience); Trauma, surgery (see "Special instructions"); Diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal or intraocular); Simultaneous administration of drugs that can cause damage to the mucous membrane of the gastrointestinal tract (such as acetylsalicylic acid (ASA) and NSAIDs, including selective inhibitors of COX-2); In patients treated with ASA, heparin, warfarin inhibitors of glycoprotein IIb / IIIa, NSAIDs, including selective inhibitors of COX-2, as well as other drugs whose use is associated with the risk of bleeding, SSRIs (see "Interaction" , "Special instructions"); In patients with low activity of the isoenzyme CYP2C19 (see "Pharmacokinetics" subsection "Pharmacogenetics", "Method of administration and dose", "Special instructions"); History of allergic reactions to thienopyridines (for example, ticlopidine, prasugrel - the possibility of cross-allergic and hematological reactions, see section "Special instructions"); Recent transient impairment of cerebral circulation or ischemic stroke (when combined with ASA, see "Special instructions").

Pregnancy and breast-feeding

Studies in animals showed no direct or indirect adverse effects on the course of pregnancy, embryonic development, childbirth and postnatal development. Since it is not always possible to predict the reaction in humans from the results of animal studies and due to the absence of data from controlled clinical trials on the use of clopidogrel by pregnant women, clopidogrel during pregnancy is not recommended as a precautionary measure, unless, in the opinion of the doctor, Its application is urgently needed.

In studies on rats, it has been shown that clopidogrel and / or its metabolites are excreted into breast milk. Whether clopidogrel penetrates human milk is unknown. Since many drugs can be excreted into breast milk and have an adverse effect on the infant, the treating physician, based on the importance of taking Plavix® for the mother, should recommend to her or stop taking the drug, or take the drug, but refuse to breast-feed.

Side effects

Data obtained in clinical trials

The safety of clopidogrel has been studied in more than 44,000 patients, incl. More than 12,000 patients who received treatment for a year or more. In general, the tolerability of clopidogrel at a dose of 75 mg / day in the CAPRIE trial corresponded to the tolerability of ASA at a dose of 325 mg / day, regardless of the age, gender and race of patients. The following are clinically significant adverse effects observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE A.

Bleeding and hemorrhage

Comparison of monotherapy with clopidogrel and ASA. In the CAPRIE clinical trial, the total incidence of all bleeding in patients taking clopidogrel and in patients taking ASA was 9.3%.

The incidence of severe bleeding with clopidogrel and ASA was comparable: 1.4 and 1.6%, respectively.

In general, the incidence of gastrointestinal hemorrhage in patients taking clopidogrel and those taking ASA was 2% and 2.7%, respectively. The incidence of gastrointestinal bleeding requiring hospitalization was 0.7% and 1.1%, respectively.

The overall frequency of bleeding from another site with clopidogrel in comparison with ASA was higher (7.3% vs. 6.5%, respectively). However, the incidence of severe bleeding with clopidogrel and ASA was comparable (0.6% or 0.4%, respectively). The most frequently reported development of the following bleeding: purpura / bruising, epistaxis. Less commonly reported on the development of hematomas, hematuria and ocular hemorrhage (mainly conjunctival). The incidence of intracranial hemorrhages with clopidogrel and ASA was comparable (0.4% or 0.5%, respectively).

Comparison of the combined therapy of clopidogrel + ASA and placebo + ASA. In the CURE clinical trial, patients with clopidogrel + ASA experienced an increase in the incidence of major bleeding (3.7 vs. 2.7%) and small bleeding (5.1 versus 2.4% ). Basically, the sources of large bleeding were the gastrointestinal tract and the puncture site of the arteries. The incidence of life-threatening hemorrhage in patients taking clopidogrel + ASA was not significantly different (2.2% and 1.8%, respectively) compared to patients taking placebo + ASA, the frequency of fatal bleeding was the same (0.2% With both types of therapy).

The incidence of non-life-threatening large bleeding was significantly higher in patients taking clopidogrel + ASA than in patients taking placebo + ASA (1.6% and 1%, respectively), but the incidence of intracranial hemorrhage was similar (0.1% With both types of therapy). The incidence of major bleeding in the clopidogrel + ASA group depended on the dose of ASA (<100 mg: 2.6%, 100-200 mg: 3.5%,> 200 mg: 4.9%), as well as the incidence of major bleeding in Placebo + ASA group (<100 mg: 2%, 100-200 mg: 2.3%,> 200 mg: 4%).

Patients who stopped antiplatelet therapy more than 5 days before coronary artery bypass grafting did not show a higher incidence of major bleeding within 7 days after the intervention (4.4% in the clopidogrel + ASA group and 5.3% in the placebo + ASA group).

Patients who continued antiplatelet therapy for the last five days before aortocoronary bypass surgery, the incidence of these events after intervention was 9.6% (clopidogrel + ASA) and 6.3% (placebo + ASA).

In the CLARITY clinical trial, the frequency of major bleeding (defined as intracranial hemorrhage or bleeding with a hemoglobin decrease of> 5 g / dl) was comparable in both treatment groups (1.3 vs. 1.1% in the clopidogrel + ASA group and placebo + ASA group, respectively) . It was the same in subgroups of patients, divided by baseline characteristics and by types of fibrinolytic therapy or heparin therapy.

The incidence of fatal bleeding (0.8% vs. 0.6%) and intracranial hemorrhage (0.5% vs 0.7%) in the treatment of clopidogrel + ASA and placebo + ASA, respectively, was low and comparable in both treatment groups.

In the COMMIT clinical trial, the overall incidence of non-cerebral large bleeding or cerebral bleeding was low and the same in both treatment groups (clopidogrel + ASA group and placebo + ASA group).

In the clinical study ACTIVE-A, the incidence of major bleeding in the clopidogrel + ASA group was higher than in the placebo + ASA group (6.7% vs. 4.3%, respectively). Large bleeding was mainly extracranial in both groups (5.3% vs. 3.5%), mainly gastrointestinal bleeding (3.5% vs. 1.8%). In the clopidogrel + ASK group, intracranial hemorrhage was greater than in the placebo + ASA group (1.4 vs. 0.8%, respectively).

There were no statistically significant differences between these treatment groups in the frequency of fatal bleeding (1.1 versus 0.7%) and hemorrhagic stroke (0.8% vs. 0.6%).

Blood disorders

In the CAPRIE study, severe neutropenia (<0.45 · 109 / L) was observed in 4 patients (0.04%) taking clopidogrel and 2 patients (0.02%) taking ASA.

In two of the 9599 patients taking clopidogrel, there was a complete absence of neutrophils in the peripheral blood, which was not observed in any of the 9586 patients taking ASA. Although the risk of developing myelotoxic effects with clopidogrel is low, if a patient who takes clopidogrel has a fever or other signs of infection, the patient should be examined for possible neutropenia. In the treatment of clopidogrel in one case, development of aplastic anemia was observed.

The incidence of severe thrombocytopenia (<80 · 109 / L) was 0.2% of patients taking clopidogrel and 0.1% of patients taking ASA reported very rare cases of platelet count decrease <30 · 109 / L.

In the CURE and CLARITY studies, there was a comparable number of patients with thrombocytopenia or neutropenia in both treatment groups.

Other clinically relevant adverse reactions observed during clinical trials of CAPRIE, CURE, CLARITY COMMIT, and ACTIVE-A

The frequency of adverse reactions that were observed during the above clinical trials is presented in accordance with the WHO classification: very often ≥10%; Often ≥1% and <10%; Infrequently ≥0.1% and <1%; Rarely ≥0.01% and <0.1%; Very rarely <0.01%; The frequency is unknown - it is not possible to determine the frequency of occurrence of an undesired reaction from the available data.

From the nervous system: infrequently - headache, dizziness, paresthesia; Rarely - vertigo.

From the digestive tract: often - dyspepsia, abdominal pain, diarrhea; Infrequently - nausea, gastritis, bloating, constipation, vomiting, stomach ulcer, duodenal ulcer.

From the skin and subcutaneous tissue: infrequently - rash, itching.

On the part of the blood and lymphatic system: infrequently - an increase in bleeding time, a decrease in the number of platelets in the peripheral blood; Leukopenia, a decrease in the number of neutrophils in peripheral blood, eosinophilia.

Postmarketing experience with the drug

On the part of the blood and lymphatic system: the frequency is unknown - cases of serious bleeding, mainly subcutaneous, musculoskeletal, ocular hemorrhage (conjunctival, in the tissue and retina of the eye), bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage), nosebleeds, hematuria and bleeding From postoperative wounds; Cases of bleeding with a lethal outcome (especially intracranial hemorrhages, gastrointestinal bleeding and retroperitoneal hemorrhages), agranulocytosis, granulocytopenia, aplastic anemia / pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A.

On the part of the immune system: the frequency is unknown - anaphylactoid reactions, serum sickness; Cross-allergy with other thienopyridines (such as ticlopidine, prasugrel) (see "Special instructions").

Disorders of the psyche: the frequency is unknown - confusion, hallucinations.

From the side of the nervous system: the frequency is unknown - the violation of taste perception.

From the vessels: the frequency is unknown - vasculitis, lowering blood pressure.

From the respiratory system, chest and mediastinum: an unknown frequency - bronchospasm, interstitial pneumonia, eosinophilic pneumonia.

From the gastrointestinal tract: the frequency is unknown - colitis (including ulcerative or lymphocytic), pancreatitis, stomatitis.

From the side of the liver and bile ducts: the frequency is unknown - hepatitis (non-infectious), acute liver failure.

From the skin and subcutaneous tissues: frequency unknown - maculopapular or erythematous rash, urticaria, itching, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), acute generalized exanthematous pustules, drug hypersensitivity syndrome, drug Rash with eosinophilia and systemic manifestations (DRESS-syndrome), eczema, flat lichen.

From the musculoskeletal and connective tissue: the frequency is unknown - arthralgia (joint pain), arthritis, myalgia.

From the side of the kidneys and urinary tract: the frequency is unknown - glomerulonephritis.

General disorders and disorders at the injection site: frequency unknown - fever.

From the genitals and the breast: the frequency is unknown - gynecomastia.

Laboratory and instrumental data: the frequency is unknown - the deviation from the norm of laboratory indicators of the functional state of the liver, increasing the concentration of creatinine in the blood.

Interaction

With drugs, the use of which is associated with a risk of bleeding: there is an increased risk of bleeding due to their potential additive effect with clopidogrel. Concurrent with clopidogrel, the use of drugs, the use of which is associated with a risk of bleeding, should be done with caution.

With warfarin: although taking clopidogrel 75 mg / day did not alter the pharmacokinetics of warfarin (the substrate of the isoenzyme CYP2C9) or INR in patients who are long-treated with warfarin, concurrent administration of clopidogrel increases the risk of bleeding due to its independent additional effect on blood coagulation.

Therefore, care should be taken while taking warfarin and clopidogrel.

With IIb / IIIa receptor blockers: due to the possibility of pharmacodynamic interaction between clopidogrel and IIb / IIIa receptor blockers, their joint use requires caution, especially in patients who have an increased risk of bleeding (with trauma and surgical interventions or other pathological conditions) ( See "Special instructions").

With ASA: does not alter the effect of clopidogrel inhibiting ADP-induced platelet aggregation, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. Nevertheless, simultaneous with clopidogrel administration of ASA 500 mg twice daily for one day did not cause a significant increase in bleeding time caused by the use of clopidogrel. Because Between clopidogrel and ASA is possible pharmacodynamic interaction, which leads to an increased risk of bleeding. Therefore, when using them together, care should be taken. Nevertheless, in clinical trials, patients received combination therapy with clopidogrel and ASA (75-325 mg once daily) for up to 1 year.

With heparin: according to a clinical study conducted with the participation of healthy individuals, when taking clopidogrel, there was no need to adjust the dose of heparin and its anticoagulant effect did not change. Simultaneous use of heparin was not affected by the antiplatelet effect of clopidogrel. Between clopidogrel and heparin, pharmacodynamic interaction is possible, which can increase the risk of bleeding, so the simultaneous use of clopidogrel and heparin requires caution.

With thrombolytics: the safety of the combined use of clopidogrel, fibrin-specific or fibrin-specific thrombolytic agents, and heparin has been studied in patients with acute myocardial infarction.

The frequency of clinically significant bleeding was similar to that observed in the joint use of thrombolytic agents and heparin with ASA.

With NSAID: in a clinical study conducted with healthy volunteers, the combined use of clopidogrel and naproxen increased hidden blood loss through the gastrointestinal tract.

However, due to the lack of research 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. Therefore, the use of NSAIDs, incl. Inhibitors of COX-2 in combination with clopidogrel, should be performed with caution (see "Special instructions").

With SSRIs: since SSRIs interfere with platelet activation and increase the risk of bleeding, simultaneous use of SSRI with clopidogrel should be conducted with caution.

With another concurrent therapy

With strong and moderate inhibitors of the isoenzyme CYP2C9 Since clopidogrel is metabolized prior to the formation of its active metabolite in part by the CYP2C19 isoenzyme, the use of drugs that inhibit this isoenzyme can lead to a decrease in the formation of an active metabolite of clopidogrel. The clinical significance of this interaction is not established. As a precaution, simultaneous use of clopidogrel and strong or moderate inhibitors of the CYP2C9 isoenzyme should be avoided. Strong and moderate inhibitors of the CYP2C9 isoenzyme are omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol.

The simultaneous use of proton pump inhibitors with potent or moderate inhibitors of the CYP2C19 isoenzyme (eg omeprazole, esomeprazole) should be avoided with clopidogrel (see "Pharmacokinetics", subsection Pharmacogenetics, "Specific guidance"). If proton pump inhibitors are to be taken concomitantly with clopidogrel, a proton pump inhibitor should be taken with the least inhibition of the CYP2C19 isoenzyme, such as pantoprazole and lantoprazole. A number of clinical studies with clopidogrel and other concomitant drugs were used to study the possible pharmacodynamic and pharmacokinetic interactions that showed:

- that when using clopidogrel together with atenolol, nifedipine or a combination thereof, clinically significant pharmacodynamic interaction was not observed;

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

- pharmacokinetic indices of digoxin and theophylline did not change when they were used together with clopidogrel;

- antacids did not reduce the absorption of clopidogrel;

- Phenytoin and tolbutamide can be safely used simultaneously with clopidogrel (CAPRIE study). It is unlikely that clopidogrel may affect the metabolism of other drugs, such as phenytoin and tolbutamide, as well as NSAIDs that are metabolized by the CYP2C9 isoenzyme of the cytochrome P450 family;

- ACE inhibitors, diuretics, beta-blockers, CCB, lipid-lowering drugs, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptics, hormone replacement therapy and blockers of GPIIb / IIIa receptors: clinical studies have not revealed clinically significant Unwanted interactions.

With drugs that are substrates of the isoenzyme CYP2C8. It was shown that clopidogrel increased the systemic exposure of repaglinide in healthy volunteers. In vitro studies have shown that an increase in systemic exposure of repaglinide is due to the inhibition of the CYP2C8 isoenzyme by the glucuronide metabolite clopidogrel. Caution should be exercised while using clopidogrel and medications that are primarily excreted by metabolism with the CYP2C8 isoenzyme (eg, repaglinide, paclitaxel) due to the risk of increasing their plasma concentrations.

Dosing and Administration

Inside, regardless of food intake.

Adults and elderly people

A tablet containing 300 mg of clopidogrel is intended for use as a loading dose for patients with acute coronary syndrome (see "Indications for Use").

Acute coronary syndrome without ST segment elevation (unstable angina, MI without Q wave). Treatment with clopidogrel should be started with a single dose of 300 mg, and then continued with a 75 mg dose once a day (in combination with ASA in doses of 75-325 mg / day). Since the use of higher doses of ASA is associated with an increased risk of bleeding, the recommended dosage for ASC should not exceed 100 mg. The maximum favorable effect is observed by the third month of treatment. The course of treatment is up to 1 year.

Acute coronary syndrome with ST segment elevation (acute MI with ST segment elevation). Clopidogrel is administered once in a dose of 75 mg once a day with an initial single dose 300 mg loading dose in combination with or without ASA and thrombolytics. Combination therapy is started as soon as possible after the onset of symptoms and lasts for at least 4 weeks.

In patients older than 75 years, treatment with clopidogrel should begin without taking its loading dose. As for the maintenance dose of clopidogrel, 75 mg, then Plavix® 75 mg tablets are taken for its administration.

Patients with a genetically determined decrease in the isoenzyme function of CYP2C19. The status of a weak CYP2C19 metabolizer is associated with a decrease in the antiplatelet effect of clopidogrel. The mode of application of high doses (600 mg - loading dose, then - 150 mg once a day daily) in weak metabolizers increases the antiaggregant effect of clopidogrel (see "Pharmacokinetics", Pharmacogenetics). However, the optimal dosage regimen for patients with reduced metabolism with the CYP2C19 isoenzyme in clinical trials for clinical outcomes has not yet been established (see Pharmacokinetics, Pharmacogenetics).

Overdose

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

Treatment: when bleeding occurs, appropriate treatment is required. The antidote of clopidogrel is not established. If it is necessary to quickly restore the prolonged bleeding time, then a transfusion of platelet mass is recommended.

Special instructions

In the treatment of clopidogrel, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgical intervention, careful monitoring of patients should be conducted to exclude signs of bleeding, incl. hidden.

In connection with the risk of bleeding and undesirable effects from the blood (see "Side effects"), if clinical symptoms appearing during treatment, suspicious for bleeding, it is urgent to make a general clinical blood test, determine APTT, the number of platelets, indicators of functional Activity of thrombocytes and conduct other necessary studies.

Clopidogrel, as well as other antiplatelet agents, should be used with caution in patients who have an increased risk of bleeding due to trauma, surgery or other pathological conditions, as well as in patients taking ASA, NSAIDs, incl. Inhibitors of COX-2, heparin or inhibitors of glycoprotein IIb / IIIa. Joint use of clopidogrel with warfarin may increase the risk of bleeding (see "Interaction"), so caution should be exercised when using clopidogrel and warfarin together.

If the patient is to have a planned surgical operation and there is no need for an antiplatelet effect, then for 5-7 days before the operation, the use of clopidogrel should be discontinued.

Clopidogrel prolongs bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (especially gastrointestinal and intraocular). Preparations that can cause damage to the gastrointestinal mucosa (such as ASA, NSAIDs) in patients taking clopidogrel should be used with caution.

Patients should be warned that taking clopidogrel (alone or in combination with ASA) to stop bleeding may take longer, and that if they have unusual bleeding (localization or duration), you should report This to your doctor. Before any upcoming operation and before starting any new drug, patients should inform the doctor (including the dentist) about taking clopidogrel.

Very rarely, after the use of clopidogrel (sometimes even briefly), there have been cases of TTP development, which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever. TTP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

It has been shown that in patients with recent transient cerebral infringement or stroke who have a high risk of developing recurrent ischemic complications, the combination of ASA and clopidogrel increases the risk of developing large bleeding. Therefore, such combination therapy should be conducted with caution and only in the case of clinical evidence of the benefits of its use.

The cases of development of acquired hemophilia with the use of clopidogrel were reported. With the confirmed isolated increase in APTT, accompanied or not accompanied by the development of bleeding, consideration should be given to the possibility of developing acquired hemophilia. Patients with a confirmed diagnosis of acquired hemophilia should be observed and treated by specialists in this disease and stop taking clopidogrel.

In patients with a low activity of the isoenzyme CYP2C19, clopidogrel at the recommended doses produces less active metabolite of clopidogrel and less pronounced its antiplatelet effect, and therefore, when taking the usually recommended doses of clopidogrel in acute coronary syndrome or percutaneous coronary intervention, a higher incidence of cardiovascular disease is possible, Vascular complications than in patients with normal activity of the isoenzyme CYP2C19. There are tests to determine the genotype of CYP2C19. These tests can be used to help in choosing a therapeutic strategy. The question of the use of higher doses of clopidogrel in patients with low activity of CYP2C19 is considered (see Pharmacokinetics, subsection Pharmacogenetics, Precautions, Dosage and Administration). Patients should collect anamnesis for any previously allergic and / or hematologic reactions to other thienopyridine (such as ticlopidine, prasugrel) because Reported the presence of cross-allergic and / or hematological reactions between thienopyridines (see "Side effects").

Tienopyridines can cause mild to severe allergic reactions (such as rash, angioedema) or hematologic reactions (such as thrombocytopenia and neutropenia). Patients who had previously experienced allergic and / or hematologic reactions to one of the drugs of the thienopyridine group may have an increased risk of developing similar reactions to another drug of the thienopyridine group. It is recommended to monitor cross-allergic and / or hematological reactions.

During the treatment it is necessary to monitor the functional state of the liver. With severe liver damage, one should remember about the risk of hemorrhagic diathesis. Taking clopidogrel is not recommended for an acute stroke less than 7 days old (because there are no data on its use in this condition).

Impact on the ability to drive vehicles and engage in other potentially hazardous activities. Plavix® does not significantly affect the abilities required to drive a car or to engage in other potentially hazardous activities.

Release Form

Film-coated tablets, 300 mg. For 10 tab. In a blister of aluminum foil / foil aluminum. For 1 or 3 blisters are placed in a cardboard box.

Manufacturer

Sanofi Winthrop Industry, France.

Sanofi Winthrop Industrie, France. 1, rue de la Vierge, Ambares et Lagrave, 33565, Carbon Blanc Sedex, France.

Legal entity in whose name the registration certificate was issued: Sanofi Pharma Bristol-Myers Squibb EsenSi, France.

Claims of consumers should be sent to the address: 125009, Moscow, ul. Tverskaya, 22.

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Plavix

At a temperature not higher 30 ° C.

Keep out of the reach of children.

The shelf life of the drug Plavix

3 years.

Do not use beyond the expiration date printed on the package.