Description
Release form
Film-coated tablets.
Packing
28 pcs.
Pharmacological action
Pharmacotherapeutic group: antiplatelet agent.
ATX code: [B01AC04]
PHARMACOLOGICAL PROPERTIES
Pharmacodynamics
Clopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. The active clopidogrel metabolite selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y12 platelet receptor and subsequent ADP-mediated activation of the GPIIb / IIIa complex, leading to suppression of platelet aggregation. Due to irreversible binding, platelets remain immune to ADP stimulation for the rest of their life (approximately 7-10 days), and the restoration of normal platelet function occurs at a speed corresponding to the platelet renewal rate. Platelet aggregation caused by agonists other than ADP is also inhibited by the blockade of increased platelet activation by the released ADP. Since the formation of the active metabolite occurs using isoenzymes of the P450 system, some of which may differ in polymorphism or may be inhibited by other drugs, not all patients may have adequate platelet suppression. Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular with lesions of the cerebral, coronary or peripheral arteries.
With daily intake of clopidogrel at a dose of 75 mg from the first day of administration, there is a significant suppression of ADP-induced platelet aggregation, which gradually increases over 3-7 days and then reaches a constant level (upon reaching equilibrium). In equilibrium, platelet aggregation is suppressed by an average of 40-60%. After discontinuation of clopidogrel, platelet aggregation and bleeding time gradually return to baseline for an average of 5 days.
Pharmacokinetics
Absorption
When administered orally at a dose of 75 mg per day, clopidogrel is rapidly absorbed. Average maximum plasma concentrations of unchanged clopidogrel (approximately 2.2-2.5 ng / ml after oral administration of a single dose of 75 mg) are reached approximately 45 minutes after administration. According to the excretion of clopidogrel metabolites by the kidneys, its absorption is approximately 50%.
In vitro distribution of
clopidogrel and its main inactive metabolite circulating in the blood 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 – through enzymes and subsequent hydrolysis with the formation of an inactive derivative of carboxylic acid (85% of the circulating metabolites), and the second way – through the cytochrome P450 system. Initially, clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of an active metabolite of clopidogrel – a thiol derivative of clopidogrel. In vitro, this metabolic pathway occurs with the help of the isoenzymes CYP2CI9, CYP1A2 and CYP2B6. The active thiol metabolite of clopidogrel, which was isolated in in vitro studies, quickly and irreversibly binds to platelet receptors, thus blocking platelet aggregation.
Excretion of
Within 120 hours after human ingestion of 14C-labeled clopidogrel, about 50% of the radioactivity is excreted by the kidneys and approximately 46% of the radioactivity is excreted through the intestines. After a single oral dose of 75 mg, the elimination half-life of clopidogrel is approximately 6 hours. After a single dose and repeated doses, the half-life of the main inactive metabolite circulating in the blood is 8 hours.
Pharmacogenetics
Using the CYP2C19 isoenzyme, both the active metabolite and the intermediate metabolite, 2-oxo-clopidogrel, are formed. The pharmacokinetics and antiplatelet effect of the active clopidogrel metabolite, when examining platelet aggregation ex vivo, vary depending on the genotype of CYP2C19 isoenzyme. The allele of the ¡YP2C19 * 1 gene corresponds to a fully functional metabolism, while the alleles of the CYP2C19 * 2 and CYP2C19 * 3 genes are non-functional. Alleles of the CYP2C19 * 2 and CYP2C19 * 3 genes cause a decrease in metabolism in most representatives of the Caucasoid (85%) and Mongoloid race (99%). Other alleles associated with a lack or decrease in metabolism are less common and include, but are not limited to, alleles of the CYP2C19 * 4, * 5, * 6, * 7 and * 8 genes. Patients with low activity of the CYP2C19 isoenzyme should have the two aforementioned gene alleles with loss of function. Published phenotypic frequencies of individuals with low CYP2C19 isoenzyme activity are 2% in Caucasians, 4% in Negroid people and 14% in Chinese. There are relevant tests to determine the patient s genotype for the CYP2C19 isoenzyme. According to a cross-sectional study (40 volunteers) and a meta-analysis of six studies (335 volunteers). These included individuals with a very high, high, intermediate and low activity of the CYP2C19 isoenzyme, any significant differences in the exposure of the active metabolite and in the average values of inhibition of platelet aggregation (IAT) (induced ADP) in volunteers with very high, high and intermediate activity no CYP2C19 isoenzyme was detected. In volunteers with low activity of the CYP2C19 isoenzyme, the exposure of the active metabolite was reduced compared with volunteers with high activity of the CYP2C19 isoenzyme. When volunteers with low CYP2C19 isoenzyme activity received a 600 mg loading dose / 150 mg maintenance dose (600 mg / 150 mg) treatment regimen, the exposure of the active metabolite was higher than with a 300 mg / 75 mg treatment regimen. In addition, IAT was similar to that in groups of patients with a higher metabolic rate using the CYP2C19 isoenzyme receiving a treatment regimen of 300 mg / 75 mg. However, in studies taking into account clinical outcomes, the dosage regimen of clopidogrel for patients of this group (patients with low activity of the CYP2C19 isoenzyme) has not yet been established. Clinical trials conducted to date have not had a sufficient sample size to detect differences in clinical outcome in patients with low CYP2C19 isoenzyme activity.
Selected patient groups
The pharmacokinetics of the active metabolite of clopidogrel in elderly patients, children, patients with kidney and liver diseases has not been studied.
Indications
– Prevention of atherothrombotic events in patients after myocardial infarction (with a duration from several days to 35 days), ischemic stroke (with a duration of 7 days to 6 months) or those with a diagnosed peripheral arterial occlusive disease.
– Prevention of atherothrombotic events (in combination with acetylsalicylic acid) in patients with acute coronary syndrome:
– without ST segment elevation (unstable angina or myocardial infarction without Q wave), including patients who underwent stenting with percutaneous coronary artery disease ST segment elevation (acute myocardial infarction) with drug treatment and the possibility of thrombolysis.
Contraindications
– Hypersensitivity to clopidogrel or any of the excipients of the drug.
– Severe liver failure.
– Acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage.
– Rare hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption.
– Pregnancy and lactation (see “Pregnancy and the period of breastfeeding”).
– Children under 18 years of age (safety and efficacy have not been established).
Precautions
– Moderate liver failure, in which a predisposition to bleeding is possible (limited clinical experience).
– Renal failure (limited clinical experience).
– Injury, surgery (see “Special instructions”).
– Diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal or intraocular).
– Concomitant use of non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors (COX-2).
– Concomitant administration of warfarin, heparin, glycoprotein IIb / IIIa inhibitors.
– In patients with a genetically determined decrease in the function of the Y 2 19 isoenzyme in the recommended doses (there are literature data indicating that that patients with a genetically determined decrease in the function of the Y 2 19 isoenzyme undergo a less systemic exposure by the active metabolite of clopidogrel and have a less pronounced effect of the drug, in addition, they may have a higher frequency of cardiovascular complications after myocardial infarction compared with patients with normal function of the Y 2 19 isoenzyme).
Use during pregnancy and lactation
As a precaution, clopidogrel is not recommended during pregnancy due to the lack of clinical data on its use by pregnant women, although animal studies have not revealed any direct or indirect adverse effects on pregnancy. embryonic development, childbirth and postnatal development. Breastfeeding should be discontinued if treated with clopidogrel, as studies in rats have shown that clopidogrel and / or its metabolites are excreted in breast milk. Whether clopidogrel passes into human breast milk is not known.
Special instructions
When treating with clopidogrel-SZ, especially during the first weeks of therapy and / or after invasive cardiological procedures / surgical procedures, careful monitoring of patients should be carried out to exclude signs of bleeding, including and hidden.
Due to the risk of bleeding and hematological undesirable effects, in the event of clinical symptoms that are suspicious of bleeding during treatment, an urgent clinical blood test should be performed, APTT, platelet count, platelet functional activity indices and other necessary studies should be performed.
Clopidogrel-SZ, as well as other antiplatelet drugs, should be used with caution in patients with an increased risk of bleeding associated with injuries, surgical interventions or other pathological conditions, as well as in patients receiving acetylsalicylic acid, NSAIDs, including . COX-2 inhibitors, heparin or glycoprotein IIb / IIIa inhibitors.
The combined use of clopidogrel with warfarin can increase the intensity of bleeding, therefore, with the exception of special rare clinical situations (such as the presence of a floating thrombus in the left ventricle, stenting in patients with atrial fibrillation), the combined use of clopidogrel and warfarin is not recommended.
If the patient has planned surgery, and there is no need for an antiplatelet effect, then 7 days before surgery, the drug Clopidogrel-SZ 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).
Patients should be cautioned that that when using the drug Clopidogrel-SZ (alone or in combination with acetylsalicylic acid), it may take longer to stop the bleeding, and that if they have unusual (by localization or duration) bleeding, they should inform the attending physician . Before any upcoming operation and before starting to take any new drug, patients must inform the doctor (including the dentist) about taking Clopidogrel-SZ.
Very rarely, after the use of the drug Clopidogrel-SZ (sometimes even brief), there have been cases of thrombocytopenic thrombohemolytic purpura (TGP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever. TGP is a potentially life-threatening condition that requires immediate treatment, including plasmapheresis.
During the treatment period, it is necessary to monitor the functional activity of the liver. In severe violations of liver function, remember the risk of developing hemorrhagic diathesis.
Taking Clopidogrel-SZ is not recommended for acute stroke with a duration of less than 7 days (because there is no data on its use in this condition).
Clopidogrel-SZ should not be taken in patients with rare hereditary galactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome.
Influence on the ability to drive vehicles and control mechanisms
Clopidogrel-SZ does not significantly affect the ability, necessary for driving or working with machinery.
Composition
1 tablet contains clopidogrel hydrosulfate 97.875 mg, in terms of clopidogrel – 75 mg
excipients: pregelatinized starch. anhydrous lactose (anhydrous milk sugar), macrogol (polyethylene glycol 6000). magnesium stearate. microcrystalline cellulose (PH 112), castor oil hydrogenated film coating composition: Selecout AQ-01673 (hypromellose (hydroxypropyl methylcellulose), macrogol (polyethylene glycol 400), macrogol (polyethylene glycol 6000), titanium dioxide, aluminum varnish based on Ponso 4 R dye)
Dosage and administration of
Adults and elderly patients with normal activity of the isoenzyme CYP2C19
Clopidogrel-SZ should be taken orally, regardless of food intake.
Myocardial infarction, ischemic stroke and diagnosed peripheral arterial occlusion disease
The drug is taken 75 mg 1 time / day.
In patients with myocardial infarction (MI), treatment can be started from the first days to the 35th day of MI, and in patients with ischemic stroke (MI) – from 7 days to 6 months after MI.
Acute coronary syndrome without ST segment elevation (unstable angina pectoris, myocardial infarction without Q wave)
Treatment with clopidogrel-SZ should be started with a single loading dose of 300 mg and then continued at a dose of 75 mg 1 time / day (in combination with acetylsalicylic acid as an antiplatelet agent in doses of 75-325 mg / day). Since the use of acetylsalicylic acid in higher doses is associated with an increased risk of bleeding, the recommended dose of acetylsalicylic acid for this indication should not exceed 100 mg. The maximum therapeutic effect is observed by the third month of treatment. The course of treatment is up to 1 year.
Acute coronary syndrome with ST-segment elevation (acute myocardial infarction with ST-segment elevation)
Clopidogrel is prescribed at a dose of 75 mg 1 time / day with an initial single dose of a loading dose in combination with acetylsalicylic acid as an antiplatelet agent and thrombolytics (or without thrombolytics) . Combination therapy is started as soon as possible after the onset of symptoms and continues for at least 4 weeks. In patients over the age of 75, treatment with Clopidogrel-SZ should be started without taking a loading dose.
Patients with a genetically determined decrease in the function of the CYP2C19 isoenzyme
Weakening of metabolism with the CYP2C19 isoenzyme may lead to a decrease in the antiplatelet effect of clopidogrel. The optimal dosage regimen for patients with weakened metabolism using the CYP2C19 isoenzyme has not yet been established.
After repeated doses of Clopidogrel-SZ at a dose of 75 mg / day in patients with severe kidney damage (CC from 5 to 15 ml / min), the inhibition of ADP-induced platelet aggregation (25%) was lower compared to that in healthy volunteers, however, the prolongation of bleeding time was similar to that in healthy volunteers who received clopidogrel-SZ at a dose of 75 mg / day. In addition, all patients had good tolerance to the drug.
After daily administration of Clopidogrel-SZ 75 mg daily for 10 days in patients with severe liver damage, inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. Mean bleeding time was also comparable in both groups.
The prevalence of the alleles of the CYP2C19 isoenzyme genes responsible for the intermediate and decreased metabolism of clopidogrel prior to its active metabolite varies among representatives of different ethnic groups. There is only limited data for members of the Mongoloid race to assess the effect of the CYP2C19 isoenzyme genotype on clinical outcome events.
Side effects
Classification of the incidence of side effects (WHO): often (> 1/100 and <1/10), infrequently (> 1/1000 and <1/100), rarely (> 1/10 000 and <1 / 1000), very rarely (<1/10 000). From the central and peripheral nervous system: infrequently – headache, dizziness and paresthesia are rare – vertigo is very rare – a violation of taste. Mental disorders: very rarely – confusion, hallucinations. From the cardiovascular system: very rarely – vasculitis, marked decrease in blood pressure, intracranial hemorrhage, ocular hemorrhage (conjunctival, in the tissue and retina), hematoma, nosebleeds, bleeding from the respiratory tract, gastrointestinal bleeding, retroperitoneal hemorrhage with fatal, hemorrhages in muscles and joints, hematuria. From the respiratory system: very rarely – bronchospasm, interstitial pneumonitis. From the digestive system: often – diarrhea, abdominal pain, dyspepsia infrequently – stomach and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence is very rare – pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis, acute liver failure, hepatitis. From the urinary system: very rarely – glomerulonephritis. From the blood coagulation system: infrequently – prolongation of bleeding time. From the hemopoietic system: infrequently – thrombocytopenia, leukopenia, neutropenia and eosinophilia very rarely – thrombocytopenic thrombohemolytic purpura, severe thrombocytopenia (platelet count? 30? 109 / l), agranulocytenia, granulocytopenia, ananulocytopenia. From the skin and subcutaneous tissues: infrequently – skin rash and itching are very rare – angioedema, urticaria, erythematous rash (associated with clopidogrel or acetylsalicylic acid) is very rare – bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), eczema and lichen planus. From the musculoskeletal system: very rarely – arthralgia, arthritis, myalgia. On the part of the immune system: very rarely – anaphylactoid reactions, serum sickness. On the part of laboratory parameters: very rarely – a change in liver samples, an increase in the concentration of serum creatinine. Other: very rare – fever. Drug interaction The combined use of clopidogrel with warfarin is not recommended, since such a combination can increase the intensity of bleeding. Prescribing glycoprotein IIb / IIIa inhibitors together with clopidogrel increases the risk of bleeding. The use of non-steroidal anti-inflammatory drugs in conjunction with clopidogrel increases the risk of bleeding. Concomitant use of clopidogrel with CYP2C19 inhibitors (e.g. omeprazole) is not recommended. No clinically significant pharmacodynamic interaction was observed with clopidogrel combined with atenolol, nifedipine, phenobarbital, cimetidine, estrogen, digoxin, theophylline, tolbutamide, antacids. Overdose Symptoms: prolonged bleeding time and subsequent complications. Treatment: If bleeding occurs, appropriate therapy should be performed. If rapid correction of prolonged bleeding time is required, platelet transfusion is recommended. There is no specific antidote. Storage Conditions Keep this medicine out of the reach of children, dry, protected from light at a temperature not exceeding 25 ° C. Shelf life 3 years. Do not use after the expiration date indicated on the package. Deystvuyushtee substance Clopidogrel Terms and conditions otpuska IZ drugstore prescription Appointment Appointment Adults
