Description
Release form
Tablets
Packing
90 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 P450 isoenzymes, 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 cerebral lesions, 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 achieved 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 to form an inactive derivative of carboxylic acid (85% of the circulating metabolites), and the second through the cytochrome P450 system. Initially, clopidogrel is metabolized to 2-oxo-clopidogrel, being 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). 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 in the mean values of inhibition of platelet aggregation (IAT) (induced by ADP) in volunteers with very high, high and intermediate activity of the CYP2C19 isoenzyme. 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 ² ÑPregnancy and the period of breastfeeding ² Ñ).
– 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 patients with a genetically determined decrease in the function of the Y 2 19 isoenzyme are less exposed to the active metabolite of clopidogrel and have a less pronounced effect of the drug, in addition to this a higher frequency of cardiovascular complications after myocardial infarction may be observed compared with patients with normal function of the CYP2C19 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 cardiac procedures / surgery, 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 warned 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 (in terms of localization or duration) bleeding they should inform the attending physician about this. 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 rare, after the use of the drug Clopidogrel-SZ (sometimes even short-lived), 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 required to drive vehicles or work with mechanisms.
Composition of
1 tablet contains:
Active ingredient: clopidogrel (as clopidogrel hydrosulfate) 75 mg (97.875 mg)
Excipients: lactose monohydrate (200 mesh) 60.0 mg, microcrystalline cellulose (Avicel P, 40 mg) Hyprolose 3.0 mg, microcrystalline cellulose (Avicel RN-112) 26.0 mg, crospovidone 6.0 mg, hydrogenated vegetable oil type I (Sterotex-Dritex) 10.0 mg, sodium lauryl sulfate 7.0 mg.
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, Myocardial infarction without tooth Q)
Treatment with Clopidogrel-SZ should be started with a single dose of a 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 at 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 frequency of development of side effects (WHO):
often – more than 1/100 and less than 1/10,
infrequently – more than 1/1000 and less than 1/100,
rarely – more than 1/10000 and less than 1 / 1000,
is very rare – less than 1/10000).
From the central and peripheral nervous system:
infrequently – headache, dizziness and paresthesia:
rarely – vertigo
very rarely – taste disturbance.
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.
Hemostatic disorders:
infrequently – prolonged bleeding time.
Hematopoietic disorders:
infrequently – thrombocytopenia, leukopenia, neutropenia and eosinophilia,
very rarely – thrombocytopenic thrombohemolytic purpura, severe thrombocytopenia (platelet count? 30 Ã 109, apoptosis, lopenopenia)
Disorders of the skin and subcutaneous tissue:
infrequently – skin rash and pruritus
very rare – angioedema, urticaria, erythematous rash (associated with clopidogrel or acetylsalicylic acid)
very rarely – bullemonous dermatitis, Stevens dermatitis, dermatitis toxic epidermal necrolysis), eczema and lichen planus.
Immune system disorders:
is very rare – anaphylactoid reactions, serum sickness.
Mental disorders:
is very rare – confusion, hallucinations.
Disorders of the vascular system:
is very rare – vasculitis, marked decrease in blood pressure (BP), intracranial hemorrhage, ocular hemorrhage (conjunctival, in the tissue and retina), hematoma, nosebleed, airway bleeding, gastrointestinal bleeding fatal retroperitoneal hemorrhage, hemorrhages in muscles and joints, hematuria, etc.
Respiratory disorders:
very rarely – bronchospasm, interstitial pneumonitis.
Disorders from the hepatobiliary system:
is very rare – acute liver failure, hepatitis.
Disorders of the musculoskeletal system:
is very rare – arthralgia, arthritis, myalgia.
Disorders of the kidneys and urinary tract:
is very rare – glomerulonephritis.
General Disorders:
is very rare – fever.
Changes in laboratory parameters:
is very rare – a change in liver samples, an increase in the concentration of serum creatinine.
Drug Interactions
Warfarin
Concomitant use with clopidogrel can increase the intensity of bleeding, so this combination is not recommended.
Blockers of IIb / IIIa receptors
The use of blockers of IIb / IIIa receptors in conjunction with clopidogrel requires caution in patients who have an increased risk of bleeding (with injuries and surgical interventions or other pathological conditions).
Acetylsalicylic acid
Acetylsalicylic acid does not alter the effect of clopidogrel, which inhibits ADP-induced platelet aggregation, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. Nonetheless, simultaneous administration of acetylsalicylic acid with clopidogrel as an antipyretic agent 500 mg 2 times / day for 1 day did not cause a significant increase in bleeding time caused by clopidogrel administration. Between clopidogrel and acetylsalicylic acid, a pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, with their simultaneous use, caution should be exercised, although in clinical studies, patients received combination therapy with clopidogrel and acetylsalicylic acid for up to one year.
Heparin
According to a clinical study conducted with the participation of healthy volunteers, when taking clopidogrel, there was no need to change the dose of heparin and its anticoagulant effect did not change. The simultaneous use of heparin did not change the antiplatelet effect of clopidogrel. Between clopidogrel and heparin, a 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 simultaneous use of clopidogrel, fibrin-specific or fibrin-specific thrombolytic drugs and heparin has been studied in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the case of the simultaneous use of thrombolytic agents and heparin with acetylsalicylic acid.
NSAIDs
In a clinical study conducted with healthy volunteers, the simultaneous use of clopidogrel and naproxen increased latent blood loss through the gastrointestinal tract. However, due to the lack of studies on the interaction of clopidogrel with other NSAIDs, it is currently unknown whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel with other NSAIDs. Therefore, the appointment of NSAIDs, including selective COX-2 inhibitors in combination with clopidogrel should be carried out with caution.
Another combination therapy
clopidogrel is metabolized to the formation of its active metabolite in part by the isoenzyme CYP2C19, the use of drugs that inhibit this system can lead to a decrease in the concentration of the active metabolite of clopidogrel and a decrease in its clinical effectiveness. Concomitant use of drugs that inhibit the CYP2C19 isoenzyme (e.g. omeprazole) is not recommended.
A series of clinical studies have been performed with clopidogrel and other concomitantly prescribed drugs in order to study possible pharmacodynamic and pharmacokinetic interactions, which showed that:
– when using clopidogrel together with atenolol, nifedipine or with both drugs at the same time a clinically significant pharmacodynamic interaction – not observed the simultaneous use of phenobarbital, cimetidine and estrogens did not significantly affect the pharmacodynamics of clopidogrel
– the pharmacokinetic parameters of digoxin and theophylline did not change when they were used simultaneously with clopidogrel
– antacids did not reduce the absorption of clopidogrel
– phenytoin and tolbutamide can be safely used simultaneously with clopidogrel, despite the fact that the data obtained in studies with human liver microsomes indicate that the carboxyl metabolite of clopidogrel can inhibit the activity of the isoenzyme CYP2C9, which can lead to increased plasma concentrations of certain drugs (phenytoin, tolbutamide and some NSAIDs), which metabolized by the isoenzyme CYP2C9
– ACE inhibitors, diuretics, beta-blockers, slow calcium channel blockers, hypoglycemic agents (including insulin), hypol ipidemic agents, antiepileptic drugs, HRT and GP IIb / IIIa receptor blockers – no clinically significant adverse interactions were detected in clinical studies.
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
The product should be stored out of the reach of children, in a dry, dark place at a temperature not exceeding 25 ° C.
Expiration date
3 years. Do not use after the expiration date indicated on the package.
Deystvuyushtee substance
Clopidogrel
Terms and conditions
prescription
Appointment
Appointment
Adults doctor’s prescription
