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Active ingredients
Clopidogrel
Release form
Pills
Composition
Active ingredient: Clopidogrel (Clopidogrel) Active ingredient concentration (mg): 75
Pharmacological effect
Antiaggregatory.
Pharmacokinetics
Absorption After a single dose and repeated oral administration at a dose of 75 mg / day, clopidogrel is rapidly absorbed. The mean Cmax values of unchanged clopidogrel in the blood plasma are 2.2–2.5 ng / ml after oral administration of a single dose of 75 mg, Tmax approximately 45 minutes. According to a study of the excretion of clopidogrel metabolites by the kidneys, the degree of absorption is approximately 50%. Distribution of clopidogrel and its main inactive metabolite circulating in the blood plasma are reversibly associated with human plasma proteins in vitro (98 and 94%, respectively). This bond is unsaturated in a wide range of concentrations. MetabolismClopidogrel is actively metabolized in the liver. In vitro and in vivo, clopidogrel is metabolized in two ways: the first is mediated by esterases and leads to hydrolysis to form an inactive metabolite, a carboxylic acid derivative (85% of circulating metabolites), and the other is catalyzed by various cytochrome P450 isoenzymes. Initially, clopidogrel is converted to an intermediate product, 2-oxo-clopidogrel. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of an active metabolite of clopidogrel, a thiol derivative of clopidogrel. In vitro, this pathway is mediated by isoenzymes CYP3A4, CYP2C19, CYP1A2, and CYP2B6. The active thiol metabolite of clopidogrel, isolated in vitro, rapidly and irreversibly interacts with platelet receptors, blocking their aggregation. Cmax of the active metabolite in the blood plasma after administration of a loading dose (300 mg) of clopidogrel is twice as high as Cmax after a 4-day application of clopidogrel in a maintenance dose (75 mg / day). Cmax in the blood plasma is reached about 30–60 minutes after taking the drug. Withdrawal After ingestion of 14C-labeled clopidogrel, approximately 50% of the total radioactivity is excreted by the kidneys and approximately 46% by the intestines within 120 hours after dosing. After a single intake of clopidogrel in a dose of 75 mg T1 / 2 is about 6 hours. T1 / 2 of the main inactive metabolite circulating in the blood plasma after a single and repeated use is 8 hours. Pharmacogenetics CYP2C19 enzyme participates in the formation of both the active metabolite and the intermediate metabolite - 2-oxo-clopidogrel.The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel, as well as the results of the evaluation of platelet aggregation in ex vivo conditions, differ depending on the genotype of the CYP2C19 isoenzyme. non-functional. Alleles of the CYP2C19 * 2 and CYP2C19 * 3 isoenzymes cause a decrease in metabolism in the majority of Caucasoid (85%) and Mongoloid (99%) races. Other alleles associated with the absence or decrease in metabolism are less common and include, but are not limited to, the alleles of the CYP2C19 * 4, * 5, * 6, * 7, and * 8 isoenzyme genes. Patients with low CYP2C19 isoenzyme activity should have the two gene alleles indicated above with loss of function. According to published studies, the frequency of genotypes with low activity of the isoenzyme CYP2C19, accompanied by a decrease in metabolism, is about 2% in Caucasians, 4% in people of the Negroid race, and 14% in people 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 a very high, high, intermediate and low activity of the CYP2C19 isoenzyme, 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 low activity of this isoenzyme, the exposure of the active metabolite decreased compared to that of volunteers with high activity of the isoenzyme CYP2C19. When using clopidogrel in doses of 600 mg, the loading dose / 150 mg of the maintenance dose (600/150 mg) in patients with low metabolism is active the metabolite was higher than with the 300/75 mg treatment regimen. In addition, the degree of inhibition of platelet aggregation was similar to that in the groups of patients with high activity of the CYP2C19 isoenzyme who received clopidogrel according to the 300/75 mg scheme. However, the clopidogrel dosing regimen in the group of patients with low activity of the CYP2C19 isoenzyme was not determined in studies suggesting a study of clinical outcomes. Clinical studies conducted to date have had an insufficient sample size to detect differences in clinical outcome in patients with low CYP2C19 isoenzyme. Specific groupspatients The pharmacokinetics of the active metabolite of clopidogrel in special groups of patients (elderly patients, children, patients with impaired renal function and liver) has not been studied. Elderly patients. Elderly volunteers (over 75 years of age), when compared with young volunteers, showed no differences in platelet aggregation and bleeding time. Dose adjustment in elderly patients is not required. Disruption of renal function. After repeated use of clopidogrel in 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 25% lower than in healthy volunteers. However, the degree of prolongation of bleeding time was similar to that in healthy volunteers who received clopidogrel in a dose of 75 mg / day. Violation of the liver. After applying clopidogrel in a dose of 75 mg / day for 10 days in patients with severely impaired liver function, the degree of inhibition of ADP-induced platelet aggregation and the average rate of bleeding time were comparable to those in healthy volunteers. Ethnic features. The prevalence of alleles of CYP2C19 isoenzyme genes associated with intermediate or reduced metabolism differs in members of different racial / ethnic groups (see Pharmacogenetics). There are limited literature data to evaluate the significance of the genotyping of the CYP2C19 isoenzyme for clinical outcomes in patients of a Mongoloid race.
Indications
Symptomatic therapy of painful inflammatory processes of various origins (including postoperative and post-traumatic pain, ischialgia, myalgia, sciatica, bruises and muscle strain, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, acute attack of gout, tenosinovitis, bursitis).
Contraindications
- liver failure; - hemorrhagic syndrome; - acute bleeding (including intracranial hemorrhage); - diseases predisposing to the development of bleeding (gastric ulcer and duodenal ulcer in the acute stage, ulcerative colitis, tuberculosis, lung tumors, hyperfibrinolysis); - pregnancy; - lactation period (breastfeeding); - age up to 18 years; - Hypersensitivity to clopidogrel and / or any of the components of the drug.
Use during pregnancy and lactation
Since there are no clinical data on the use of clopidogrel during pregnancy, the drug is not recommended for use during pregnancy. Animal studies did not reveal a direct or indirect adverse effect on pregnancy, embryo / fetus development, childbirth or postnatal development. In animal studies, it was proved that clopidogrel and / or its metabolites are excreted into breast milk. Therefore, if clopidogrel therapy is necessary, it is recommended to stop breastfeeding.
Dosage and administration
The recommended dose for adults (including elderly patients) is 75 mg / day, regardless of the meal.
Side effects
General: chest pain, trauma, flu-like symptoms, pain, fatigue, asthenia, hernia. Central and peripheral nervous system: headache, dizziness, paresthesia, leg cramps, hyperesthesia, neuralgia. Vegetative nervous system: syncope, palpitations. Cardiovascular system: peripheral edema, arterial hypertension, heart failure, generalized edema. Gastrointestinal tract: abdominal pain, dyspepsia, diarrhea, nausea, constipation, vomiting, taste disturbances, perforation of gastric ulcers, hemorrhagic gastritis, bleeding from ulcers of the upper GI tract. Liver and biliary tract: increased activity of liver enzymes, hyperbilirubinemia, hepatitis, liver steatosis. Blood and blood-forming organs: thrombocytopenia, anemia (aplastic or hypochromic), agranulocytosis, leukopenia, neutropenia. Coagulation disorders and hemorrhages: purpura, extravasation, epistaxis, gastrointestinal hemorrhages, headaches, onions of hemorrhage, hemorrhages from the urinary tract, hemorrhages, intracranial hemorrhages, retroperitoneal hemorrhages, hemorrhages, intracranial hemorrhages, eye hemorrhages, retroperitoneal hemorrhages, hemorrhages, intracranial hemorrhages thrombocytopenic purpura. Musculoskeletal system: arthralgia, back pain, arthritis, arthrosis.
Overdose
Symptoms: Overdose of clopidogrel can lead to prolonged bleeding time and the development of hemorrhagic complications. In the presence of bleeding, adequate therapy is needed. Treatment: When bleeding occurs, appropriate therapeutic measures are required.If rapid correction of prolonged bleeding time is required, platelet transfusion is recommended. Clodidogrel antidote is not installed.
Interaction with other drugs
Anticoagulants for oral administration: the simultaneous use of clopidogrel and anticoagulants for oral administration can increase the intensity of bleeding, and therefore the use of this combination is not recommended. The use of clopidogrel in a dose of 75 mg / day does not alter the pharmacokinetics of warfarin (the substrate CYP2C9 isoenzyme) or in patients with INR, long-term receiving warfarin. However, simultaneous use with warfarin increases the risk of bleeding due to its independent additional effect on blood clotting. Therefore, caution should be exercised with the simultaneous use of warfarin and clopidogrel. Inhibitors of glycoprotein IIb / IIIa: simultaneous use of clopidogrel and glycoprotein IIb / IIIa inhibitors requires caution in patients with an increased risk of bleeding (for injuries, surgical interventions or other pathological conditions) (see "Special indications "). Acetylsalicylic acid: acetylsalicylic acid does not affect clopidogrel-induced inhibition of platelet aggregation induced by ADP, but clopidogrel sweat ntsiruet effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, the simultaneous intake of 500 mg of acetylsalicylic acid 2 times a day for one day does not significantly lengthen the bleeding time caused by the use of clopidogrel. The pharmacodynamic interaction between clopidogrel and acetylsalicylic acid may increase the risk of bleeding. With this in mind, caution should be exercised while taking these drugs, although in clinical studies, patients took combination therapy with clopidogrel and acetylsalicylic acid for one year. Heparin: according to a clinical study, in healthy people, taking clopidogrel did not require a change in the dose of heparin, and the anticoagulant effects of heparin did not change. The simultaneous use of heparin did not affect the suppression of platelet aggregation by clopidogrel.Perhaps the 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 the simultaneous use of clopidogrel, fibrin-specific or fibrin-specific thrombolytic agents and heparin was evaluated in patients with acute myocardial infarction. The incidence of clinically significant bleeding was comparable to their frequency with simultaneous use of thrombolytics, heparin with acetylsalicylic acid. NPVS: according to a clinical study with healthy volunteers, the simultaneous use of clopidogrel and naproxen increased latent gastrointestinal bleeding. However, due to the lack of research on the interaction with other NSAIDs at the present time, it is not known whether the risk of developing gastrointestinal bleeding increases when used together with other NSAIDs. Therefore, simultaneous therapy with NSAIDs, including COX-2 inhibitors, and clopidogrel should be carried out with caution (see "Special Instructions"). CYP2C19 isoenzyme inhibitors: Clopidogrel is metabolized to form its active metabolite partially under the action of CYP2C19 isoenzyme. Therefore, drugs that inhibit this isoenzyme, can cause a decrease in the concentration of the active metabolite of clopidogrel. The clinical significance of this interaction is unknown. Concurrent use with potent or mild inhibitors of the CYP2C19 isoenzyme should be avoided. The inhibitors of CYP2C19 include: omeprazole and ozomer with a 12-hour break between taking two drugs, the value of systemic exposure (AUC) of the active metabolite of clopidogrel decreased by 45% (after taking a loading dose of clopidogrel) and by 40% (after taking a maintenance dose clopidogrel). The decrease in AUC of the active metabolite of clopidogrel is associated with a decrease in the degree of inhibition of platelet aggregation (39% after receiving a loading dose of clopidogrel and 21% after receiving a maintenance dose of clopidogrel).A similar interaction of clopidogrel with esomeprazole is assumed. In observational and clinical studies, conflicting data on the clinical manifestations of CVS regarding this pharmacokinetic / pharmacodynamic interaction have been recorded. Simultaneous use with omeprazole or esomeprazole should be avoided. Proton pump inhibitors with minimal inhibitory effects on the CYP2C19 isoenzyme include: pantoprazole and lansoprazole. When using pantoprazole at a dose of 80 mg, a decrease in the concentration of active metabolite of clopidogrel in plasma was observed per 20% (after receiving a loading dose of clopidogrel) and by 14% (after receiving a maintenance dose of clopidogrel). This was accompanied by a decrease in the degree of inhibition of platelet aggregation in the medi m is 15 and 11%, respectively. Therefore, the simultaneous use of clopidogrel with pantoprazole is possible. Other drugsWhen studying the pharmacodynamic and pharmacokinetic interaction of clopidogrel and other drugs, the following was revealed: while using clopidogrel with atenolol and / or nifedipine, we did not identify the pharmacodynamic interaction; simultaneous use with phenobarbital, cimetidine or estrogen and - The pharmacokinetics of digoxin or theophylline was not changed; - Antacids do not affect the extent of absorption of clopidogrel - phenytoin and tolbutamide can be safely used in conjunction with clopidogrel. It is unlikely that clopidogrel can affect the metabolism of other drugs, such as phenytoin and tolbutamide, as well as NSAIDs that are metabolized by the isoenzyme CYP2C9; (including insulin), antiepileptic drugs, drugs used in hormone replacement therapy: in clinical studies there were no clinically significant unwanted interactions.
special instructions
During treatment with clopidogrel, especially during the first weeks and / or after invasive cardiac procedures / surgical interventions, it is necessary to carefully monitor patients in order to rule out signs of bleeding (including latent). Considering the risk of bleeding and hematological adverse events (see “Side Effects”), if clinical symptoms of possible bleeding appear during treatment, a blood test should be performed immediately to determine APTT, platelet function indicators, platelet counts and other necessary studies. Clopidogrel prolongs bleeding time, so it must be used with caution in patients with an increased risk of bleeding associated with injury, surgery and other pathological conditions or diseases that are prone to bleeding (especially gastrointestinal or intraocular), and patients receiving acetylsalicylic acid, NSAIDs, including COX-2 inhibitors, heparin and glycoprotein IIb / III inhibitors. Simultaneous use clopidogrel with warfarin may increase the risk of bleeding (see "Interaction"). Therefore, caution should be exercised with the simultaneous use of warfarin and clopidogrel. If a patient undergoes a planned surgical intervention, and the antiplatelet effect is undesirable, then clopidogrel should be canceled 5–7 days before the operation. in combination with acetylsalicylic acid) it may take longer to stop the bleeding. Patients should inform the attending physician about each case of unusual (by localization or duration) bleeding. It is also necessary to inform the doctor about taking clopidogrel if the patient has to undergo surgery (including dental treatment) or before starting a new drug. Very rarely during the use of clopidogrel (sometimes even short) there were cases of thrombotic thrombocytopenic purpura. The condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia associated with neurological disorders, impaired renal function and fever.Thrombotic thrombocytopenic purpura is a potentially life-threatening condition that requires immediate treatment, including plasmapheresis. During the treatment period, liver function must be monitored. In severe liver function impairment, the risk of hemorrhagic diathesis should be remembered. Clopidogrel is not recommended for patients with acute ischemic stroke less than 7 days old (there are no data on the use in this state). Cross-reactive hypersensitivity. Patients should be examined to identify hypersensitivity to other thienopyridines (for example, ticlopidine, prasugrel), because aware of cross-reactive hypersensitivity between thienopyridines (see “Side Effects”). Patients with hypersensitivity to other thienopyridines history should be carefully monitored in order to detect signs of hypersensitivity to clopidogrel during terapii.Spetsialnaya information of auxiliary substances: Zilt drug should not be taken in patients with lactase deficiency, lactose intolerance syndrome glucose-galactose malabsorption, t .to. contains lactose. The drug Zilt contains hydrogenated castor oil, which can cause stomach upset and diarrhea in patients. Effects on the ability to drive and work with mechanisms. The drug Zilt does not have a significant impact on the ability to drive vehicles or engage in other potentially hazardous activities.