Instruction for use: ClopidogrelI want this, give me price
Trade name of the drug – Deplatt, Cardogrel, Kardutol, Klopidex, Clopigrant, Clopidogrel, Clopidogrel-LEKSVM, Clopidogrel-Nanolek, Clopidogrel-Richter, Clopidogrel-SZ, Clopidogrel-TAD, Clopidogrel-Teva, Clopidogrel hydrogensulfate, Clopidogrel hydrogensulfate, Clopidogrel Bisulfate, Clopilet, Lirta, Agregal, Detromb, Klopidex, Listab 75, Zyllt, Lopirel, Pidogrel, Plavix, Plagril, Plogrel, Targetek, Troken, Trombex, Tromborel, Fluder, Egitromb.
The Latin name of the substance Clopidogrel
Clopidogrelum (genus. Clopidogreli)
Methyl - (+) - (S) -alpha- (o-chlorophenyl) -6,7-dihydrothieno [3.2-c] pyridin-5 (4H) -acetate
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
I24.9 Acute ischemic heart disease, unspecified: Coronary heart disease; Coronary insufficiency; Acute coronary insufficiency; Acute coronary syndrome
I25.2 Transferred last myocardial infarction: Cardiac syndrome; Myocardial infarction; post-MI; Rehabilitation after myocardial infarction; Reocclusion of the operated vessel; Angina postinfarctnaya; Status after myocardial infarction; Status after myocardial infarction; myocardial infarction
I48 Atrial fibrillation and flutter: Permanent atrial tachyarrhythmias; Relief frequent ventricular rate during atrial flutter or blink; atrial fibrillation; Paroxysm of atrial fibrillation and flutter; Paroxysm of atrial fibrillation; Paroxysmal atrial fibrillation; Atrial premature beats; Tahiaritmicheskoy atrial fibrillation; Tahisistolicheskoy atrial fibrillation; auricular flutter; Life-threatening ventricular fibrillation; Atrial fibrillation; Chronic atrial fibrillation; supraventricular arrhythmia; Paroxysmal atrial fibrillation and flutter; Paroxysmal fibrilloflutter; Atrial premature beats
I49.8 Other specified cardiac arrhythmias: atrial fibrillation; Arrhythmia Paroxysmal atrial; Atrial arrhythmia tachysystolic; sinus arrhythmia; Asynergia ventricular; Asynergia left ventricle; Corrigan's pulse; atrial fibrillation; atrial tachyarrhythmia; The migration of supraventricular pacemaker; Orthostatic changes in pulse; Disclaimer sinoatrial node; The paradoxical pulse; Paroxysm of atrial fibrillation; Paroxysmal atrial fibrillation; Paroxysmal dysrhythmia; Paroxysmal atrial-ventricular rhythm; Romano-Ward syndrome; trigemini; bigeminy
I63 Cerebral infarction: ischemic Stroke; Ischemic brain disease; Ischemic stroke; Ischemic stroke and its consequences; Ischemic cerebral stroke; Ischemic cerebrovascular accident; Ischemic brain damage; Ischemic brain damage; ischemic conditions; Cerebral ischemia; Acute hypoxia brain; Acute cerebral ischemia; Acute ischemic cerebrovascular accident; Acute cerebral infarction; Acute ischemic stroke; Acute period of ischemic stroke; Focal cerebral ischemia; Ischemic stroke; recurrent stroke; The syndrome of Morgagni-Adams-Stokes; Chronic cerebral ischemia; cerebrovascular stroke; embolic stroke; Ischemic brain damage
I70 Atherosclerosis: Atherosclerosis; Atherosclerosis of peripheral vessels; Atherosclerotic changes; Atherosclerotic vascular changes; Atherosclerotic disorders; spontaneous; Trombangioz obliterans; Frinlendera disease
I73.9 Peripheral vascular disease, unspecified: angiospasm; Vasospasm / vasoconstriction; vasospastic disorders; Violation of venous microcirculation; Violation of circulation; Violation of peripheral blood circulation; Lack of peripheral blood circulation in the lower and upper limbs; Peripheral arterial occlusive disease; Peripheral arterial occlusive disease in stages III-IV on Fontaine; Peripheral vascular insufficiency; Peripheral vascular lesions; Peripheral vascular disorders; Peripheral circulatory disorder; spasm of artery; angiospasm; Functional peripheral arterial disease; Chronic occlusive disease; Chronic obliterating diseases of the lower limbs; Chronic arterial occlusive disease
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
I77.1 arteriostenosis: Occlusive arterial disease; Peripheral arterial occlusive disease;Peripheral arterial occlusive disease in stages III-IV on Fontaine
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
Characteristics of the substance Clopidogrel
Oral antiplatelet agent.
Mode of action - antiaggregational.
Clopidogrel 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 P2Y12-receptor 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 during the rest of their life (about 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the rate of platelet pool renewal. Aggregation of platelets caused by agonists other than ADP is also inhibited by blocking platelet stimulation with released ADP. Since the formation of the active metabolite occurs with the enzymes of the cytochrome P450 system, some of which may differ in polymorphism or inhibited by other drugs, not all patients can adequately suppress platelet aggregation.
Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, particularly in the lesions of the cerebral, coronary or peripheral arteries.
With a daily intake of clopidogrel at a dose of 75 mg from the first day of admission, there is a significant suppression of ADP-induced platelet aggregation, 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 level on average for 5 days.
In patients with recent myocardial infarction, ischemic stroke and / or diagnosed peripheral arterial occlusive disease, taking clopidogrel at a dose of 75 mg / day significantly reduces the risk of developing vascular complications (myocardial infarction, stroke, cardiovascular mortality).
In case of acute coronary syndrome without ST segment elevation on ECG (unstable angina, myocardial infarction), clopidogrel (loading dose 300 mg / day) in combination with acetylsalicylic acid (ACA) at a dose of 75-325 mg / day and other standard therapy is authentically and independently From other treatments reduces the risk of vascular complications.
With myocardial infarction with ST-segment elevation on the ECG, the use of clopidogrel (a loading dose of 300 mg once during the first 12 hours of the disease, then 75 mg / day) in combination with ASA (loading dose of 150-325 mg, then 75-162 mg / day ), Fibrinolytic therapy and, according to heparin indications, reduces the incidence of occlusion of the infarction-related coronary artery, repeated myocardial infarction and fatal outcomes.
In general, with myocardial infarction, regardless of ECG changes (elevation of the ST segment, depression of the ST segment, or the first complete blockage of the left bundle of the bundle), taking clopidogrel at a dose of 75 mg / day in combination with ASC 162 mg / day leads to a reduction in overall mortality and The total frequency of repeated myocardial infarction, ischemic stroke, and death.
A clinical study of ACTIVE-A showed that in patients with atrial fibrillation who had at least one risk factor for vascular complications but did not use indirect anticoagulants, clopidogrel in combination with ASA (compared with ASA and placebo) reduced the overall incidence of stroke, Myocardial infarction, systemic thromboembolism outside the central nervous system or vascular death in a greater degree by reducing the risk of stroke.
The effectiveness of taking clopidogrel in combination with ASA was detected early and persisted for up to 5 years. Reduction of the risk of major vascular complications in the group of patients taking clopidogrel in combination with ASA occurred mainly due to a greater decrease in the frequency of strokes. The risk of stroke of any severity with the use of clopidogrel in combination with ASA decreased, and there was a tendency to decrease the incidence of myocardial infarction in the group treated with clopidogrel in combination with ASA, but there was no difference in the frequency of thromboembolism outside the CNS or vascular death. In addition, the use of clopidogrel in combination with ASA reduced the total number of days of hospitalization for cardiovascular indications.
Suction. At a course of oral administration at a dose of 75 mg / day clopidogrel quickly absorbed. C max of unchanged clopidogrel in blood plasma (approximately 2.2-2.5 ng / ml after ingestion of a single dose of 75 mg) is achieved approximately 45 minutes after administration. According to the deducing of metabolites of clopidogrel with kidneys, its absorption is about 50%.
Distribution. In vitro clopidogrel and its basic circulating inactive inactive metabolite bind reversibly to plasma proteins (by 98 and 94%, respectively), and 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, carried out with the help of esterases, leads to hydrolysis of clopidogrel with the formation of an inactive derivative of carboxylic acid (85% of circulating metabolites); The second way is carried out with the help of cytochrome P450 isoenzymes. Initially, clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of an active metabolite of the clopidogrel-thiol derivative. In vitro this active metabolite is formed with the help of the CYP2C19 isoenzyme with the participation of some other isoenzymes, 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 blocking platelet aggregation.
Cmax of the active metabolite of clopidogrel after a single 300 mg loading dose is 2 times greater than that after 4 days of receiving a maintenance dose of clopidogrel 75 mg. C max is achieved within approximately 30-60 minutes.
After repeated use of clopidogrel inwards at a dose of 75 mg / day, Cmax of the basic inactive metabolite is about 3 mg / l, Tmax is reached after 1 hour.
Excretion. Within 120 hours after ingestion of 14C-labeled clopidogrel, approximately 50% of the dose was excreted through the kidneys (into the urine) and approximately 46% was excreted through the intestine. After a single oral dose of 75 mg of T1 / 2 is approximately 6 hours. After a single reception and taking repeated doses of T1 / 2 of the main circulating in the blood inactive metabolite is 8 hours.
Several polymorphic enzymes of the cytochrome P450 system are involved in the activation of clopidogrel. The CYP2C19 isozyme is involved in the formation of both an active metabolite and an intermediate metabolite, 2-oxo-clopidogrel. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel, studied through platelet aggregation ex vivo, differ depending on the genotype of the isoenzyme CYP2C19. The allele of the CYP2C19 * 1 gene corresponds to fully functional metabolism, whereas the alleles of the CYP2C19 * 2 and CYP2C19 * 3 isoenzymes are responsible for reduced metabolism. These alleles are responsible for a decrease in metabolism in about 85% of the representatives of the Caucasoid race and 99% of the representatives of the Mongoloid race. Other alleles associated with reduced metabolism are represented by CYP2C19 * 4, * 5, * 6, * 7 and * 8 isoenzymes, but they are rarely found in the general population. Patients with a low activity of the CYP2C19 isoenzyme should have the two alleles of the gene with loss of function indicated above. The incidence of phenotypes in individuals with low CYP2C19 isoenzyme activity is 2% in Caucasians, 4% in blacks and 14% in Chinese. Pharmacogenetic testing allows to determine the genotype with the variability of the activity of the isoenzyme CYP2C19.
Genetic variants of other enzymes of the cytochrome P450 system, which affect the ability of formation of active metabolites of clopidogrel, are also possible.
According to a cross-sectional study (40 volunteers) and a meta-analysis of 6 studies (335 volunteers), which included individuals with very high, high, intermediate and low activity of the CYP2C19 isoenzyme, there were no significant differences in the exposure of the active metabolite and the average inhibition of aggregation Platelets (induced by ADP) in volunteers with very high, high and intermediate activity of the CYP2C19 isoenzyme were not detected. In volunteers with a low activity of the isoenzyme CYP2C19, the exposure of the active metabolite was reduced by 63-71% compared to volunteers with high activity of the isoenzyme CYP2C19.
When using the treatment regimen, 300 mg loading dose / 75 mg maintenance dose (300/75 mg) in volunteers with a low activity of the isoenzyme CYP2C19 the antiplatelet effect decreased; Mean platelet aggregation inhibition values were 24% (at 24 hours) and 37% (on the 5th day of treatment), compared with mean platelet aggregation inhibition values of 39% (24 hours) and 58% (on day 5 Treatment) in volunteers with a high activity of the isoenzyme CYP2C19 and 37% (after 24 hours) and 60% (on the 5th 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 treatment regimen. In addition, inhibition of platelet aggregation (32% at 24 hours and 61% at day 5 of treatment) was greater than in individuals with a low activity of the CYP2C19 isoenzyme receiving the 300/75 mg regimen and similar to that in the higher patient groups Activity of the isoenzyme CYP2C19, receiving a treatment regimen of 300/75 mg. However, in studies with clinical outcomes, the dosage regimen of clopidogrel for patients in this group (with low activity of the isoenzyme CYP2C19) 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, compared to volunteers with high CYP2C19 isoenzyme activity in volunteers with an intermediate activity of the CYP2C19 isoenzyme, the exposure of the active metabolite was reduced by 28%, and in volunteers with a low activity of the isoenzyme CYP2C19 - by 72%, while inhibition of platelet aggregation was reduced with differences 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 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, myocardial infarction and stroke) or stent thrombosis compared to 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 isozyme activity CYP2C19).
Individual patient groups
The pharmacokinetics of the active metabolite of clopidogrel in elderly patients, children, patients with kidney and liver diseases has not been studied enough.
Elderly age. In elderly volunteers (> 75 years), compared with young volunteers, there was no difference in platelet aggregation and bleeding time. Do not need dose adjustment for the elderly.
Children. No data available.
Impaired renal function. After repeated use of clopidogrel at a dose of 75 mg / day in patients with severe renal disease (Cl creatinine 5-15 ml / min), inhibition of ADP-induced platelet aggregation was lower by 25% than in healthy volunteers. However, the lengthening of bleeding time was similar in both groups of patients.
Violation of the function of the liver. After daily administration of clopidogrel for 10 days at a daily dose of 75 mg, the value of the inhibition index of ADP-induced platelet aggregation was similar in patients with severe liver damage and healthy volunteers. The mean bleeding time was also comparable in both groups.
Ethnicity. The prevalence of the alleles of the CYP2C19 isoenzyme genes responsible for intermediate and decreased metabolism is different in representatives of different ethnic groups. Due to the limited amount of data, it is not possible to assess the genotyping of the isoenzyme CYP2C19 for use in clinical practice.
Floor. In a large, controlled study of CAPRIE (clopidogrel versus ASA in patients at risk of developing ischemic complications), the frequency of clinical outcomes, other side effects, and abnormalities in clinical and laboratory indicators was the same for both men and women.
Application of substance of the Clopidogrel
Prevention of atherothrombotic complications in patients with myocardial infarction (with a duration of several days to 35 days), ischemic stroke (with a duration of 7 days to 6 months) or with diagnosed occlusive disease of peripheral arteries; In patients with acute coronary syndrome (in combination with ASA) without ST segment elevation (unstable angina or Q-free myocardial infarction), including patients who underwent stenting in percutaneous coronary intervention and with ST segment elevation (acute myocardial infarction) with medical Treatment and the possibility of carrying out thrombolysis.
Prevention of atherothrombotic and thromboembolic complications (including stroke) in atrial fibrillation in adults with atrial fibrillation, which have at least one risk factor for vascular complications, cannot take indirect anticoagulants and have a low risk of bleeding (in combination with ASA).
Contraindications for Clopidogrel
Hypersensitivity to clopidogrel; Severe hepatic impairment; Acute bleeding, incl. From a peptic ulcer or intracranial hemorrhage; Pregnancy and the period of breastfeeding (see "Application in pregnancy and lactation"); Children under 18 years of age (safety and efficacy not established); For medicinal forms containing lactose (in addition) - rare hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption.
Moderate hepatic insufficiency (7-9 points on the Child-Pugh scale), in which a predisposition to bleeding is possible (limited clinical experience of use); Chronic renal failure of mild to moderate severity (Cl creatinine 60-30 ml / min) (limited clinical experience); Diseases in which there is a predisposition to the development of bleeding (in particular, gastrointestinal or intraocular), especially with the simultaneous use of drugs that can cause damage to the mucous membrane of the digestive tract (ASA, NSAID); Patients with increased risk of bleeding (trauma, surgery or other pathological conditions, as well as patients receiving ASA, heparin, warfarin, glycoprotein IIb / IIIa inhibitors, NSAIDs, including selective inhibitors of COX-2, other drugs, The use of which is associated with the risk of bleeding, SSRIs, drugs that are substrates of the isoenzyme CYP2C8 (repaglinil, paclitaxel) (see "Interaction", "Precautions"), patients with low isozyme activity CYP2C19 (see "Pharmacology", "Precautions ), History of allergic and hematological reactions to other thienopyridines (ticlopidine, prasugrel) (the possibility of cross-allergic and hematological reactions, see "Precautions"), recent transient impairment of cerebral circulation or ischemic stroke (in combination with ASA, ref. "Precautionary measures").
Pregnancy and breast-feeding
As a precautionary measure, the use of clopidogrel is contraindicated during pregnancy due to the lack of clinical data on its intake by pregnant women, although animal studies have revealed neither direct nor indirect adverse effects on pregnancy, embryonic development, childbirth and postnatal development.
Breastfeeding in case of treatment with clopidogrel should be discontinued. In studies in rats, it has been shown that clopidogrel and / or its metabolites are excreted into breast milk. Whether clopidogrel penetrates into human milk is unknown.
Fertility. In animal studies, there was no adverse effect of clopidogrel on fertility.
Side effect of Clopidogrel
Results of 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. Below are listed the clinically significant adverse effects observed in 5 large clinical trials - CAPR1E, 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 bleeding in patients taking clopidogrel, and in patients taking ASA was 2 and 2.7%, respectively, including. The incidence of gastrointestinal bleeding that required 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 versus 6.5%, respectively). However, the incidence of severe bleeding with clopidogrel and ASA was comparable (0.6 and 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 and 0.5%, respectively).
Comparison of the combined therapy of clopidogrel + ASA and placebo + ASA. In the CURE clinical trial, in patients treated with clopidogrel + ASA, compared with patients receiving placebo + ASA, there was an increase in the incidence of major (3.7 versus 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 hemorrhages in patients treated with clopidogrel + ASA was significantly unchanged from patients receiving placebo + ASA (2.2 and 1.8%, respectively), the incidence of fatal bleeding was the same (0.2% Both types of therapy).
The incidence of major bleeding that did not threaten life was significantly higher in patients receiving clopidogrel + ASA than in patients receiving placebo + ASA (1.6 and 1%, respectively), but the incidence of intracranial hemorrhage was similar (0.1 % For 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). In patients who had continued antiplatelet therapy for the last five days before aortocoronary bypass surgery, the incidence of these events after intervention was 9.6% in the clopidogrel + ASA group and 6.3% in the placebo + ASA group.
In the CLARITY clinical trial, the incidence of major bleeding (defined as intracranial bleeding or bleeding with a decrease in Hb> 5 g / dl) in both groups (clopidogrel + ASA and placebo + ASA) was comparable (1.3 vs. 1.1% in the clopidogrel group + ASA and placebo + ASA group, respectively). It was the same in groups of patients, divided by their initial characteristics and by the types of fibrinolytic therapy or heparin therapy.
The incidence of fatal bleeding (0.8 vs. 0.6%) and intracranial hemorrhages (0.5 vs. 0.7%) in combination with 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 (0.6 in the clopidogrel + ASA group and 0.5 in the 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 versus 4.3%, respectively). Large bleeding was mostly extracranial in both groups (5.3 versus 3.5%), mainly from the gastrointestinal tract (3.5 versus 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%).
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 who took 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, a check should be made 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% in patients taking clopidogrel and 0.1% in patients taking ASA; Reported very rare cases of a decrease in the number of thrombocytes <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
Unwanted reactions that were observed during the above clinical trials are divided into system-organ classes according to the MedDRA classification. The frequency of adverse reactions was determined according to WHO classification as very often (> 1/10); Often (> 1/100, <1/10); Infrequently (> 1/1000, <1/100); Rarely (> 1/10000, <1/1000); Very rarely (<1/10000, including individual messages); The frequency is unknown (it is not possible to determine the incidence of side effects from 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 the peripheral blood, eosinophilia.
Postmarketing experience with clopidogrel
On the part of the blood and lymphatic system: the frequency is unknown - cases of serious bleeding, mainly subcutaneous, musculoskeletal, ocular hemorrhage (conjunctival, tissue and retina), bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage), nosebleeds, hematuria and bleeding From postoperative wounds and cases of bleeding with a lethal outcome (especially intracranial hemorrhages, gastrointestinal bleeding and retroperitoneal hemorrhage); Agranulocytosis, granulocytopenia, aplastic anemia / pancytopenia, thrombotic thrombocytopenic purpura, acquired hemophilia A.
On the part of the immune system: the frequency is unknown - anaphylactoid reactions, serum sickness, cross allergic and hematologic reactions with other thienopyridines (such as ticlopidine, prasugrel) (see "Precautions").
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.
On the part of the respiratory system, chest and mediastinum: the frequency is unknown - 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 erythematous or exfoliative rash, hives, itching, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), acute generalized exanthematous pustulosis, 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.
From the genitals and the breast: the frequency is unknown - gynecomastia.
General disorders and disorders at the injection site: frequency unknown - fever.
Indicators of laboratory and instrumental studies: the frequency is unknown - the deviation from the norm of laboratory indicators of the functional state of the liver, an increase in the concentration of creatinine in the blood plasma.
Medicines, the use of which is associated with a risk of bleeding. Increased risk of bleeding due to their potential additive effect with clopidogrel. Concurrent with clopidogrel, the use of drugs associated with the risk of bleeding should be done with caution.
Warfarin. Despite the fact that taking clopidogrel 75 mg / day did not change the pharmacokinetics of warfarin (substrate of the isoenzyme CYP2C9) or INR in patients receiving long-term treatment with warfarin, the simultaneous use of clopidogrel increases the risk of bleeding due to its independent additional effect on blood clotting. Therefore, care should be taken when using warfarin and clopidogrel simultaneously.
Blockers of IIb / IIIa receptors. 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 "Precautions").
ASA. ASA does not alter the effect of clopidogrel, which inhibits ADP-induced platelet aggregation, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. However, simultaneous with clopidogrel administration of ASA 500 mg twice daily for 1 day did not cause a significant increase in bleeding time associated with the use of clopidogrel. Between clopidogrel and ASA, pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, when they are used simultaneously, care should be taken, although in clinical trials patients received combination therapy with clopidogrel and ASA (75-325 mg once a day) for up to 1 year.
Heparin. According to a clinical trial conducted with the participation of healthy volunteers, when taking clopidogrel did not require a change in the dose of heparin and did not change its anticoagulant effect. The simultaneous use of heparin did not alter 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 these drugs requires caution.
Thrombolytics. The safety of the combined use of clopidogrel, fibrin-specific or fibrin-specific thrombolytic drugs and heparin was investigated in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed with the combined use of thrombolytic drugs and heparin with ASA.
SSRIs. Since SSRIs disrupt the activation of platelets and increase the risk of bleeding, simultaneous use of SSRI with clopidogrel should be carried out with caution.
NSAIDs. In a clinical study conducted with the participation of healthy volunteers, the combined use of clopidogrel and naproxen increased latent 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 using clopidogrel together with other NSAIDs. Therefore, the appointment of NSAIDs, incl. Inhibitors of COX-2, in combination with clopidogrel should be carried out with caution (see "Precautions").
Inhibitors of CYP2C19. 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 active metabolite of clopidogrel and a decrease in its clinical efficacy. The clinical significance of this interaction remains unknown, however, as a precautionary measure, simultaneous use of clopidogrel with drugs that inhibit CYP2C19 (omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol) should be avoided.
Proton pump inhibitors. The simultaneous use of clopidogrel and proton pump inhibitors (omeprazole and esomeprazole) is not recommended. If proton pump inhibitors should be used in conjunction with clopidogrel, LS should be chosen with the least effect on the isoenzyme CYP2C19, for example, pantoprazole and lansoprazole.
Another combination therapy. A number of clinical studies with clopidogrel and other concurrently prescribed drugs were conducted to study possible pharmacodynamic and pharmacokinetic interactions that showed that:
- with simultaneous application of clopidogrel together with atenolol, nifedipine or both drugs, clinically significant pharmacodynamic interaction was not observed;
- simultaneous use of phenobarbital and estrogens did not significantly affect 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 with the cytochrome P450 cyanochrome P450 isoenzyme CYP2C9;
ACE inhibitors, diuretics, beta adrenoblockers, CCB, lipid-lowering drugs, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptics and hormone replacement therapy. Clinical studies have not shown clinically significant adverse interactions.
Medicines 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 drugs, mainly excreted from the body by metabolism with the help of the CYP2C8 isoenzyme (eg repaglinide, paclitaxel) due to the risk of increasing their plasma concentrations.
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 rapid correction of prolonged bleeding time is necessary, then transfusion of platelet mass is recommended.
Routes of administration
Precautions for the substanceof Clopidogrel
In the treatment of clopidogrel, especially during the first weeks and / or after invasive cardiac procedures / surgical intervention, it is necessary to carefully monitor patients for the exclusion of signs of bleeding, including latent.
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 do a clinical blood test, determine APTT, the number of platelets, the indicators of functional Activity of thrombocytes and conduct other necessary studies.
Acquired hemophilia. 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, it is necessary to suspect the possibility of developing acquired hemophilia. Patients with a confirmed diagnosis of acquired hemophilia should be observed and treated by specialists in this disease. You should stop taking clopidogrel.
Clopidogrel, as well as other antiplatelet drugs, 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 receiving ASA, NSAIDs, incl. Inhibitors of COX-2, heparin or inhibitors of glycoprotein IIb / IIIa receptors, SSRIs or thrombolytic drugs.
Joint use of clopidogrel with warfarin may increase the intensity of bleeding (see "Interaction"), so the combined use of clopidogrel and warfarin should be done with caution.
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 choose a therapeutic strategy. Consideration should be given to the use of higher doses of clopidogrel in patients with low CYP2C19 activity (see Pharmacology, Restrictions on Use).
If the patient has 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). Drugs 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 when taking clopidogrel (in the form of monotherapy or in combination with ASA), it may take longer to stop bleeding, and that if they have an unusual bleeding (localization or duration) they should Inform your doctor about it. Before any future 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 thrombotic thrombocytopenic purpura, which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever. Thrombotic thrombocytopenic purpura is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.
During the treatment it is necessary to monitor the functional activity 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 (there is no data on its use in this condition).
Cross-allergic and / or hematologic reactions between thienopyridines. It should be clarified the history of allergic and / or hematological reactions to other thienopyridine derivatives (such as ticlopidine and prasugrel) in patients; Cases of such reactions between thienopyridines are described. Tienopyridines can cause mild and severe allergic (rash, angioedema) or hematologic (thrombocytopenia, neutropenia) reactions. Patients who had previously experienced allergic and / or hematologic reactions to one of the thienopyridine derivatives, may have an increased risk of developing such reactions when taking another drug from the thienopyridine group. Such patients require careful follow-up during the entire period of therapy to identify signs of hypersensitivity to clopidogrel.
In patients who have recently undergone ischemic stroke or transient ischemic attack with a high risk of recurrent atherothrombotic events, combination therapy with clopidogrel and ASA has not demonstrated greater efficacy in comparison with clopidogrel monotherapy, but may increase the risk of major bleeding. Therefore, such combination therapy should be conducted with caution and only in the case of proven clinical benefit from its use.
Since lactose is present in one of the dosage forms (tablets) of clopidogrel, patients with a rare hereditary intolerance to galactose, a deficiency of lactase and a glucose-galactose malabsorption syndrome, use of this dosage form is contraindicated.
Influence on the ability to drive vehicles and work with machinery. Clopidogrel does not have a significant effect on the abilities needed to drive vehicles and work with machinery.