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Instruction for use: Zyllt

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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

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

I64 Unspecified Stroke as a bleeding or heart attack: Primary stroke; Stroke; Stroke in the course of; microstroke; stroke; The completed stroke

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

Structure and Composition

active substance: Clopidogrel hydrogen sulfate 97.875 mg

(In terms of clopidogrel - 75 mg)

Auxiliary substances: lactose anhydrous - 108,125 mg; MCC - 30 mg; Pregelatinized starch - 12 mg; Macrogol 6000 - 8 mg; Castor oil, hydrogenated - 4 mg

Membrane film: hypromellose 6cp - 5.6 mg; Titanium dioxide (E171) 1.46 mg; Talc - 0.5 mg; Iron dye oxide red (E172) - 0.04 mg; Propylene glycol 0.4 mg

Description of dosage form

Round, double radius tablets, film-coated, pink color with a brownish tinge.

A view of the cross-section: white or almost white mass with a rough film cover of pink color.

Pharmachologic effect

Mode of action - antiaggregational.

Pharmacodynamics

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 P2Y12 receptor platelets and the subsequent ADP-mediated activation of the glycoprotein GPIIb / IIIa complex, which leads to inhibition of platelet aggregation.

Suppression of platelet aggregation is irreversible and continues throughout the cell life cycle (about 7-10 days), so the rate of recovery of normal platelet function corresponds to the rate of their renewal. Platelet aggregation induced by other agonists other than ADP is also inhibited due to blockade of enhanced platelet activation by ADP.

The active metabolite is formed under the action of CYP450 isoenzymes, some of which may differ in polymorphism or may be inhibited by other drugs, so that adequate inhibition of platelet aggregation is not observed in all patients.

In the treatment of clopidogrel at a dose of 75 mg / day from the first day of therapy, 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, the degree of inhibition of platelet aggregation with clopidogrel at a dose of 75 mg / day was on average 40 to 60%. After stopping the use of clopidogrel, platelet aggregation and bleeding time gradually returned to baseline values, on average, for 5 days.

Clopidogrel prevents the development of atherothrombotic complications in patients with atherosclerotic lesions of vessels of any localization, especially with damage to the cerebral, coronary or peripheral arteries.

Pharmacokinetics

Resorption

After a single and repeated oral administration at a dose of 75 mg / day, clopidogrel is rapidly absorbed. Mean values of Cmax of unchanged clopidogrel in blood plasma are 2.2-2.5 ng / ml after ingestion of a single dose of 75 mg, Tmax - about 45 minutes. According to the study of kidney excretion of clopidogrel metabolites, the degree of absorption is approximately 50%.

Distribution

Clopidogrel and its main circulating in blood plasma inactive metabolite reversibly bind to human plasma proteins in vitro (98 and 94%, respectively). This bond is unsaturated in a wide range of concentrations.

Metabolism

Clopidogrel is actively metabolized in the liver. In vitro and in vivo conditions, clopidogrel is metabolized in two ways: the first is mediated by esterases and leads to hydrolysis with the formation of an inactive metabolite, a carboxylic acid derivative (85% of the circulating metabolites), and the other is catalyzed by various cytochrome P450 isoenzymes. Initially, clopidogrel is converted to the intermediate product - 2-oxo-clopidogrel. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of an active metabolite of clopidogrel-thiol clopidogrel derivative. In vitro, this route is mediated by the isoenzymes CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol clopidogrel metabolite, isolated under in vitro conditions, quickly and irreversibly interacts with the platelet receptors, blocking their aggregation. Cmax of the active metabolite in blood plasma after taking the loading dose (300 mg) of clopidogrel is twice as high as Cmax after 4-day use of clopidogrel in a maintenance dose (75 mg / day). Cmax in the blood plasma is approximately 30-60 minutes after taking the drug.

Excretion

After ingestion of 14C-labeled clopidogrel, approximately 50% of the total radioactivity is excreted by the kidneys and approximately 46% by the intestine within 120 hours after dosing. After a single administration of clopidogrel at a dose of 75 mg of T1 / 2 is approximately 6 hours. T1 / 2 of the main circulating in the blood plasma inactive metabolite after a single and repeated use is 8 hours.

Pharmacogenetics

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, as well as the results of evaluating platelet aggregation under ex vivo conditions, differ depending on the genotype of the isoenzyme CYP2C19.

The allele of the CYP2C19 * 1 isoenzyme gene corresponds to fully functional metabolism, whereas the CYP2C19 * 2 and CYP2C19 * 3 isoenzyme genes are non-functional. Alleles of CYP2C19 * 2 and CYP2C19 * 3 isoenzymes cause a decrease in metabolism in the majority of representatives of Caucasoid (85%) and Mongoloid (99%) races. Other alleles associated with a lack or decrease in metabolism are less common and include, but are not limited to, the alleles of the isoenzyme genes CYP2C19 * 4, * 5, * 6, * 7 and * 8. Patients with a low activity of the CYP2C19 isoenzyme should have the two alleles of the gene with loss of function indicated above. According to published studies, the frequency of genotypes with a low activity of the CYP2C19 isoenzyme, accompanied by a decrease in metabolism, is approximately 2% in representatives of the Caucasoid race, 4% in Negroid and 14% in persons of the Mongoloid race. There are tests to determine the genotype of the isoenzyme CYP2C19. According to the study and meta-analysis, which included people with very high, high, intermediate and low activity of the isoenzyme CYP2C19, a significant difference in the exposure of the active metabolite and the average degree of inhibition of ADP-induced platelet aggregation in volunteers with very high, high and intermediate isoenzyme activity CYP2C19 was absent. In volunteers with a low activity of this isoenzyme, the exposure of the active metabolite decreased compared to that of volunteers with high activity of the isoenzyme CYP2C19.

Using clopidogrel at doses of 600 mg loading dose / 150 mg maintenance dose (600/150 mg) in patients with low metabolism, the exposure of the active metabolite was higher than with the 300/75 mg regimen. In addition, the degree of inhibition of platelet aggregation was similar to that in groups of patients with high CYP2C19 isoenzyme activity who received clopidogrel 300/75 mg. However, the dosage regimen of clopidogrel in the group of patients with a low activity of the isoenzyme CYP2C19 is not defined in studies suggesting the study of clinical outcomes. Clinical studies conducted to date have had insufficient sample size to detect differences in clinical outcome in patients with low CYP2C19 isoenzyme activity.

Special patient groups

The pharmacokinetics of the active metabolite of clopidogrel in specific patient groups (elderly patients, children, patients with impaired renal and hepatic function) has not been studied.

Patients of advanced age. In elderly volunteers (over 75 years), when compared with young volunteers, no differences in platelet aggregation and bleeding time were revealed. Correction of the dose in elderly patients is not required.

Impaired renal function. After the repeated use of clopidogrel at a dose of 75 mg / day in patients with severe renal dysfunction (Cl creatinine 5-15 ml / min), the degree of inhibition of ADP-induced platelet aggregation is lower by 25% than in healthy volunteers. However, the degree of lengthening of bleeding time was similar to that of healthy volunteers who received clopidogrel at a dose of 75 mg / day.

Violation of the function of the liver. After using clopidogrel at a dose of 75 mg / day for 10 days in patients with severe liver dysfunction, the degree of inhibition of ADP-induced platelet aggregation and the mean elongation of bleeding time were comparable to those of healthy volunteers.

Ethnic features. The prevalence of alleles of the CYP2C19 isoenzyme genes associated with intermediate or decreased metabolism is different in representatives of different racial / ethnic groups (see Pharmacogenetics). Limited literature data are available to assess the genotyping value of the CYP2C19 isoenzyme for clinical outcomes in patients of the Mongoloid race.

Indications for Zyllt

Prevention of atherothrombotic complications in adult patients with myocardial infarction (prescription from several days to 35 days), ischemic stroke (from 7 days to 6 months old) or diagnosed by occlusive disease of peripheral arteries;

Prevention of atherothrombotic complications in adult patients with acute coronary syndrome:

- without ST segment elevation (unstable angina or myocardial infarction without Q wave), including patients undergoing stenting with percutaneous coronary intervention, in combination with acetylsalicylic acid;

- with the rise of the ST segment (acute myocardial infarction) with drug treatment and the possibility of performing thrombolytic therapy, in combination with acetylsalicylic acid;

Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation (atrial fibrillation). Adult patients with atrial fibrillation (atrial fibrillation) who have at least one risk factor for vascular complications can not take indirect anticoagulants and have a low risk of bleeding (in combination with acetylsalicylic acid).

Contraindications

Increased sensitivity to clopidogrel or any excipients included in the preparation;

Severe liver dysfunction;

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

Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption syndrome;

pregnancy;

The period of breastfeeding;

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

With caution: moderate dysfunction of the liver with a predisposition to bleeding (limited experience of use); Impaired renal function (limited experience of use); Pathological conditions that increase the risk of bleeding (including trauma, surgical interventions) (see "Special instructions"); Diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal and intraocular); Simultaneous use with NSAIDs, including COX-2 inhibitors; Simultaneous use of warfarin, heparin or inhibitors of glycoprotein IIb / IIIa; Patients with low activity of the isoenzyme CYP2C19 (when clopidogrel is used in recommended doses, less active metabolite of clopidogrel is formed and its antiplatelet effect is less pronounced, so when using clopidogrel at recommended doses in acute coronary syndrome or percutaneous coronary intervention the incidence of cardiovascular complications may be higher , Than in patients with normal activity of the isoenzyme CYP2C19); Hypersensitivity to other thienopyridines (eg ticlopidine, prasugrel) (see "Special instructions").

Pregnancy and breast-feeding

Since clinical data on the use of clopidogrel during pregnancy are absent, the drug is not recommended for use in pregnancy. Studies in animals have not revealed a direct or indirect adverse effect on pregnancy, embryo / fetal development, childbirth or postnatal development.

In animal studies, it has been proven that clopidogrel and / or its metabolites are excreted into breast milk. Therefore, if necessary, clopidogrel therapy is recommended to stop breastfeeding.

Side effects

The safety of clopidogrel was investigated in patients who received clopidogrel therapy for 1 year or more. The safety of clopidogrel at a dose of 75 mg / day was comparable to that of acetylsalicylic acid at a dose of 325 mg / day, regardless of age, gender and race. The undesirable reactions observed in clinical studies are listed below. In addition, spontaneous reports of unwanted reactions are indicated. In clinical studies and post-marketing surveillance of clopidogrel, the most frequently reported development of bleeding, mainly during the 1st month of therapy.

Classification of the incidence of adverse events (WHO): very often - ≥1 / 10; Often from ≥1 / 100 to <1/10; Infrequently - from ≥1 / 1000 to <1/100; Rarely - from ≥1 / 10000 to <1/1000; Very rarely - <1/10000; Frequency is unknown - cannot be estimated based on available data.

From the blood and lymphatic system: infrequently - thrombocytopenia, leukopenia, eosinophilia; Rarely - neutropenia, including cases of severe neutropenia; Very rarely thrombotic thrombocytopenic purpura (see "Special instructions"), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anemia.

From the side of the immune system: very rarely - serum sickness, anaphylactoid reactions; Frequency unknown - cross-reactive hypersensitivity to thienopyridine (eg ticlopidine, prasugrel).

Disorders of the psyche: very rarely - confusion, hallucinations.

From the side of the nervous system: infrequently - intracranial hemorrhage (several cases with a fatal outcome were reported), headache, dizziness and paresthesia; Very rarely - a violation of taste perception.

From the side of the organ of vision: infrequently - a hemorrhage into the eyeball (in conjunctiva, in tissue and retina of the eye).

From the side of the hearing organ and labyrinthine disturbances: rarely - vertigo.

From the side of the vessels: often - hematoma; Very rarely - serious bleeding from the operating wound, vasculitis, lowering blood pressure.

From the respiratory system, chest and mediastinum: often - nosebleeds; Very rarely - bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonitis.

From the gastrointestinal tract: often - gastrointestinal bleeding, diarrhea, abdominal pain, dyspepsia; Infrequently - stomach ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, bloating; Rarely - retroperitoneal hemorrhage; Very rarely - gastrointestinal and retroperitoneal hemorrhage with a lethal outcome, pancreatitis, colitis (including ulcerative colitis or lymphocytic colitis), stomatitis.

From the liver and bile ducts: very rarely - hepatitis, acute liver failure, deviation from the norm of liver function indicators.

From the skin and subcutaneous tissues: often - subcutaneous bruising; Infrequently - skin rash, skin itch, purpura (subcutaneous hemorrhage); Very rarely - bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), angioedema, erythematous rash, urticaria, eczema and flat lichen; Frequency unknown - drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS-syndrome).

From the musculoskeletal and connective tissue: very rarely - hemorrhages in the muscles and joints (hemarthrosis), arthralgia, arthritis, myalgia.

From the side of the kidneys and urinary tract: infrequently - hematuria; Very rarely - glomerulonephritis, an increase in the concentration of creatinine in the blood serum.

General disorders and disorders at the injection site: often - bleeding from the point of vascular puncture; Very rarely - a fever.

Laboratory and instrumental data: often - lengthening the time of bleeding, reducing the number of neutrophils, reducing the number of platelets.

Interaction

Anticoagulants for oral administration: the simultaneous use of clopidogrel and anticoagulants for oral administration may increase the intensity of bleeding, and therefore the use of this combination is not recommended.

The use of clopidogrel at a dose of 75 mg / day does not change the pharmacokinetics of warfarin (the substrate of the isoenzyme CYP2C9) or INR in patients receiving long-acting warfarin. However, simultaneous use with warfarin increases the risk of bleeding due to its independent additional effect on blood coagulability. Therefore, care should be taken when using warfarin and clopidogrel simultaneously.

Inhibitors of glycoprotein IIb / IIIa: simultaneous use of clopidogrel and glycoprotein IIb / IIIa inhibitors requires caution in patients with an increased risk of bleeding (with trauma, surgical interventions or other pathological conditions) (see "Special instructions").

Acetylsalicylic acid: acetylsalicylic acid does not affect the clopidogrel-induced platelet aggregation inhibition induced by ADP, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, the simultaneous administration of 500 mg of acetylsalicylic acid 2 times a day for one day does not significantly prolong the bleeding time caused by the use of clopidogrel. Pharmacodynamic interaction between clopidogrel and acetylsalicylic acid, possibly, leads to an increased risk of bleeding. Given this, caution should be exercised while taking these medications simultaneously, although in clinical trials, patients took combination therapy with clopidogrel and acetylsalicylic acid for one year.

Heparin: according to the clinical study, in healthy individuals with the use of clopidogrel did not require a change in the dose of heparin, and also did not change the anticoagulant effect of heparin. Simultaneous use of heparin did not affect the suppression of platelet aggregation with clopidogrel. Possible pharmacodynamic interaction between clopidogrel and heparin, leading to an increased risk of bleeding. Therefore, the simultaneous use of these drugs requires caution.

Thrombolytics: the safety of simultaneous use of clopidogrel, fibrin-specific or fibrin-specific thrombolytics and heparin was evaluated in patients with acute myocardial infarction. The frequency of clinically significant bleeding was comparable with their frequency with the simultaneous use of thrombolytics, heparin with acetylsalicylic acid.

NSAID: According to a clinical study involving healthy volunteers, the simultaneous use of clopidogrel and naproxen increased latent gastrointestinal bleeding. However, due to the lack of research on interactions with other NSAID at present, it is not known whether the risk of developing gastrointestinal bleeding increases when used together with other NSAID. Therefore, concurrent therapy with NSAIDs, including COX-2 inhibitors, and clopidogrel should be performed with caution (see "Special instructions").

Inhibitors of the isoenzyme CYP2C19: clopidogrel is metabolized to the formation of its active metabolite partially under the action of the CYP2C19 isoenzyme. Therefore, drugs that inhibit this isoenzyme can cause a decrease in the concentration of the active metabolite clopidogrel. The clinical significance of this interaction is unknown.

Simultaneous application with potent or moderate inhibitors of the CYP2C19 isoenzyme should be avoided. CYP2C19 inhibitors include: omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, and chloramphenicol.

Proton pump inhibitors: the use of omeprazole at a dose of 80 mg once daily with clopidogrel or with a 12-hour break between taking two drugs decreased the systemic exposure (AUC) of the active metabolite of clopidogrel by 45% (after taking a loading dose of clopidogrel) and by 40 % (After taking a maintenance dose of clopidogrel). Reduction of AUC of active metabolite of clopidogrel is associated with a decrease in the degree of inhibition of platelet aggregation (39% after taking a loading dose of clopidogrel and 21% after taking a maintenance dose of clopidogrel). An analogous interaction of clopidogrel with esomeprazole is suggested.

In observational and clinical studies, conflicting data on the clinical manifestations of CAS regarding the pharmacokinetic / pharmacodynamic interaction were recorded. Avoid concomitant use with omeprazole or esomeprazole.

To inhibitors of the proton pump with minimal inhibitory effect on the isoenzyme CYP2C19 are: pantoprazole and lansoprazole.

With the simultaneous use of pantoprazole at a dose of 80 mg once a day, the concentration of the active metabolite of clopidogrel in the blood plasma was reduced by 20% (after taking a loading dose of clopidogrel) and by 14% (after taking a maintenance dose of clopidogrel).

This was accompanied by a decrease in the degree of inhibition of platelet aggregation by an average of 15 and 11%, respectively. Therefore, the simultaneous use of clopidogrel with pantoprazole is possible.

Other medications

When studying the pharmacodynamic and pharmacokinetic interaction of clopidogrel and other drugs, the following is revealed:

- with simultaneous application of clopidogrel with atenolol and / or nifedipine, clinically significant pharmacodynamic interaction was not detected;

- pharmacodynamic activity of clopidogrel did not change significantly when used concurrently with phenobarbital, cimetidine or estrogens;

- the pharmacokinetics of digoxin or theophylline did not change;

- antacids do not affect the degree of absorption of clopidogrel;

- Phenytoin and tolbutamide can safely be used simultaneously with clopidogrel. 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;

- Diuretics, beta-blockers, ACE inhibitors, BCC, lipid-lowering agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, drugs used in hormone replacement therapy: clinical studies have not revealed clinically significant undesirable interactions.

Dosing and Administration

Inside, regardless of food intake, once a day.

Adults and elderly patients with normal activity of the isoenzyme CYP2C19

Myocardial infarction, ischemic stroke or diagnosed occlusive disease of peripheral arteries. The drug Zilt® is taken in a dose of 75 mg (1 table) once a day.

Acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without Q wave). Treatment with Silt® should be started with a single dose of loading dose (300 mg), and then continued with a 75 mg dose once a day (in combination with acetylsalicylic acid at doses of 75-325 mg / day). Since the use of higher doses of acetylsalicylic acid is associated with a greater risk of bleeding, the recommended dose of acetylsalicylic acid should not exceed 100 mg. The maximum favorable effect is observed by the 3rd month of treatment. The optimal duration of treatment with this indication is not officially defined. The results of clinical studies confirm the advisability of taking clopidogrel up to 12 months after the development of acute coronary syndrome without ST segment elevation.

Acute coronary syndrome with ST segment elevation (acute myocardial infarction) with drug treatment and the possibility of performing thrombolytic therapy, in combination with acetylsalicylic acid. The drug Zilt® should be taken at a dose of 75 mg (1 table) once a day, starting with a loading dose, in combination with acetylsalicylic acid in combination or without thrombolytics. For patients older than 75 years, treatment with Zilt® should be performed without the use of a loading dose. Combination therapy is started as soon as possible after the onset of symptoms and lasts for at least 4 weeks. The effectiveness of combined therapy with clopidogrel and acetylsalicylic acid lasting more than 4 weeks in such patients has not been studied.

Atrial fibrillation (atrial fibrillation). The preparation Zilt® is prescribed in a dose of 75 mg once a day. In combination with clopidogrel, you should begin therapy and then continue taking acetylsalicylic acid at a dose of 75-100 mg / day.

Skipping the next dose

If less than 12 hours have elapsed after missing the next dose, you should immediately take the missed dose of Zilt® and then take the next dose at the usual time.

If more than 12 hours have passed after missing the next dose, the next dose should be taken at the usual time; Thus it is not necessary to double the dose.

Adults and elderly patients with genetically determined reduced activity of the isoenzyme CYP2C19

The low activity of the isoenzyme CYP2C19 is associated with a decrease in the antiplatelet effect of clopidogrel. The use of Zilt® at higher doses (loading dose 600 mg, then 150 mg 1 time per day) in patients with low activity of the isoenzyme CYP2C19 leads to an increase in the antiplatelet effect of clopidogrel (see "Pharmacokinetics"). However, clinical studies on clinical outcomes have not established an optimal dosing regimen for clopidogrel in patients with reduced metabolism due to the genetically determined low activity of the CYP2C19 isoenzyme.

Special patient groups

Patients of advanced age. In elderly volunteers (over 75 years), when compared with young volunteers, no differences in platelet aggregation and bleeding time were revealed. Correction of the dose in elderly patients is not required.

Impaired renal function. After the repeated use of clopidogrel at a dose of 75 mg / day in patients with severe renal dysfunction (Cl creatinine 5-15 ml / min), the degree of inhibition of ADP-induced platelet aggregation is lower by 25% than in healthy volunteers. However, the degree of lengthening of bleeding time was similar to that of healthy volunteers who received clopidogrel at a dose of 75 mg / day. The tolerability of the drug in all patients was good.

Violation of the function of the liver. After using clopidogrel at a dose of 75 mg / day for 10 days in patients with severe liver dysfunction, the degree of inhibition of ADP-induced platelet aggregation and the mean elongation of bleeding time were comparable to those of healthy volunteers.

Ethnic features. The prevalence of alleles of the CYP2C19 isoenzyme genes associated with intermediate or decreased metabolism is different in representatives of different racial / ethnic groups (see Pharmacogenetics). There are limited literature data that allow one to assess the impact of genotyping of the CYP2C19 isoenzyme on the clinical outcomes for patients of the Mongoloid race.

Gender Effects. When comparing the pharmacodynamic properties of clopidogrel in men and women, a less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in lengthening the bleeding time. When comparing clopidogrel with acetylsalicylic acid in patients at risk of developing ischemic complications, the frequency of clinical outcomes, other side effects and deviations from the norm of clinical and laboratory indicators was the same for both men and women.

Overdose

Symptoms: an overdose of clopidogrel may lead to prolonged bleeding time and the development of hemorrhagic complications. In the presence of bleeding, adequate therapy is necessary.

Treatment: when bleeding occurs, appropriate treatment is required. If rapid correction of prolonged bleeding time is necessary, transfusion of platelet mass is recommended. The antidote of clopidogrel is not established.

Precautionary measures

During treatment with clopidogrel, especially in the first weeks and / or after invasive cardiac procedures / surgical interventions, careful monitoring of patients should be performed to exclude signs of bleeding (including latent). Given the risk of bleeding and hematological adverse events (see "Side effects"), when clinical symptoms of possible bleeding occur during treatment, it is necessary to immediately perform a clinical blood test with the definition of APTT, platelet function indicators, platelet count and other necessary studies.

Clopidogrel prolongs bleeding time, so it should be used with caution in patients with an increased risk of bleeding due to trauma, surgery and other pathological conditions or diseases in which there is a predisposition to developing bleeding (especially gastrointestinal or intraocular), and patients , Receiving acetylsalicylic acid, NSAIDs, including COX-2 inhibitors, heparin and glycoprotein IIb / IIIa inhibitors.

The simultaneous use of clopidogrel with warfarin may increase the risk of bleeding (see "Interaction"). Therefore, care should be taken when using warfarin and clopidogrel simultaneously.

If the patient undergoes a planned surgical procedure and the antiplatelet effect is undesirable, then clopidogrel should be discontinued 5-7 days before the operation.

The patient should be informed that taking clopidogrel (as monotherapy or in combination with acetylsalicylic acid) may take longer to stop bleeding. Patients should inform the attending physician about each case of unusual (for localization or duration) bleeding. It is also necessary to inform the doctor about taking clopidogrel if the patient is to have surgery (including dental surgery) or before starting a new medication.

Very rarely, with the use of clopidogrel (sometimes even a short one), there have been cases of thrombotic thrombocytopenic purpura. The condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia, associated with neurologic 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 function of the liver. In severe violations of liver function should be remembered about the risk of hemorrhagic diathesis.

The use of clopidogrel is not recommended for patients with acute ischemic stroke less than 7 days old (no data on use in this condition).

Cross-reactive hypersensitivity. Patients should be examined for hypersensitivity to other thienopyridine (eg, ticlopidine, prasugrel), because they are not susceptible to hypersensitivity. It is known about cross-reactive hypersensitivity between thienopyridines (see "Side effect"). Patients with a hypersensitivity to other thienopyridine in a history should be carefully monitored to detect signs of hypersensitivity to clopidogrel during therapy.

Special information on excipients: Zyllt® should not be taken in patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome, because Contains lactose. The drug Zyllt® contains castor oil hydrogenated, which can cause patients indigestion and diarrhea.

Influence on the ability to drive vehicles and work with machinery. Zyllt® does not significantly affect the ability to drive or engage in other potentially hazardous activities.

Release Form

Tablets, film-coated, 75 mg. In the planar cell package (blister) 7 pcs. For 2, 4 or 12 contour packs (blisters) in a pack of cardboard.

Manufacturer

1. JSC "Krka, dd, Novo mesto". Shmaryoshka cesta 6, 8501 Novo mesto, Slovenia.

2. OOO KRKA-RUS. 143500, Russia, Moscow Region, Istra, ul. Moscow, 50; In cooperation with JSC "Krka, dd, Novo mesto".

The owner of the registration certificate: OOO KRKA-RUS.

Representation of JSC "Krka, dd, Novo mesto" in the RF / organization that accepts customer claims: 125212, Moscow, Golovinskoye shosse, 5.

A comment

In a number of studies the following data were obtained:

The drug Zyllt ® proved its clinical equivalence to the original clopidogrel in a comparative study. The study included 160 patients with acute coronary syndrome (ACS) without ST segment elevation. Observation period - 5 months. According to the results of the study, there was no statistically significant difference between the Zyllt ® preparation and the original clopidogrel, both in terms of therapeutic efficacy (effects on hard endpoints-relapses of angina, death, Q-myocardial infarction, revascularization by PCI or CABG) Function of thrombocytes.

In the open randomized comparative study "ZEVS", the efficacy and safety of Zyllt ® was compared with ASA in patients with coronary artery atherosclerosis after CABG. The study included 94 patients with stable coronary artery disease and initially increased platelet aggregation. It was found that in the 12-14th day and after 3 months of therapy with Zyllt ®, a significant decrease in the intensity of ADP-induced platelet aggregation was achieved in 100% of patients with IHD after CABG. Also, there were no undesirable vascular events (acute myocardial infarction (AMI), unstable angina, cardiovascular death).

Complications in the form of large or small bleeding, gastrointestinal lesions, allergic reactions to therapy with Zyllt ® have not been revealed. Thus, therapy with Zyllt ® in patients with IHD after CABG has a favorable prognosis for cardiovascular events.

A study of the effectiveness of Zyllt ® in 34 patients with ST-segment elevation myocardial infarction, depending on the genetic variants of cytochrome P 4503A and platelet receptors for ADP, fibrinogen, and collagen. The study showed that, during 30 days of observation, Zyllt ® effectively reduced platelet aggregation in patients with ST-segment STEMI, while only Leu33Pro GPIIIa medication reduced its effectiveness.

A study of the efficacy and safety of Zyllt ® in a single dose of 600 mg in 100 men with ischemic heart disease (IHD) in percutaneous transluminal coronary angioplasty (PTCA). The effect of therapy on platelet hemostasis and the assessment of coronary complications and adverse events were evaluated within 12 months after the intervention. The study showed that Zyllt ® significantly reduces the level of induced platelet aggregation. Cases of occurrence of undesirable phenomena, incl. Small and pronounced are not recorded. There are no signs of laboratory resistance to Zyllt ®. It has been shown that combined antiplatelet therapy, including the Zyllt ® preparation (with a 600 mg dose saturation for 2 hours before PTCA and subsequent 75 mg / day therapy) and ASA (75-100 mg / day), is effective for the prevention of acute / subacute thromboses Stents.

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Zyllt

At a temperature of no higher than 25 ° C, in the original packaging

Keep out of the reach of children.

The shelf life of the drug Zyllt

3 years.

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

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