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Pharmacological properties

mechanism of action. clopidogrel is a drug, one of the metabolites of which is an inhibitor of platelet aggregation. for the formation of an active metabolite that inhibits platelet aggregation, clopidogrel biotransformation is required under the influence of cyp 450. the active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (adph) to the corresponding platelet p2y12 receptor and subsequent ad-mediated activation of glycoprotein platelet aggregation. due to irreversible binding, platelets that interact with clopidogrel are damaged until the end of their life cycle (about 7–10 days), and normal platelet function is restored at a rate corresponding to the platelet renewal rate. platelet aggregation induced by agonists other than adf is also suppressed by blocking the enhanced activation of platelets by the action of released adf.

Since the active metabolite is formed by the action of CYP 450 enzymes, some of which are marked by polymorphism or are suppressed by other drugs, proper platelet suppression may not be observed in all patients.

Pharmacodynamic effects. When using the drug in repeated daily doses of 75 mg, a significant inhibition of ADP-induced platelet aggregation is observed from the first day; the effect is progressively enhanced, stabilizing on the 3rd – 7th day. In equilibrium, the average level of inhibition when applying a dose of 75 mg / day is 40-60%. Platelet aggregation and bleeding duration return to baseline on average 5 days after discontinuation of treatment.

Pharmacokinetics

Suction. Clopidogrel is rapidly absorbed after a single and repeated oral dose of 75 mg / day. Average cmax unchanged clopidogrel in blood plasma (about 2.2–2.5 ng / ml after taking a single dose of 75 mg) is achieved 45 minutes after administration. Absorption is at least 50%, based on renal excretion of clopidogrel metabolites.

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

Biotransformation. Clopidogrel is rapidly metabolized in the liver. In vitro and in vivo, clopidogrel metabolism occurs in two main metabolic ways: one is mediated by esterases and leads to hydrolysis with the formation of an inactive derivative of a carboxylic acid (which makes up 85% of all metabolites circulating in the blood), and the next along with cytochrome P450. First, clopidogrel is converted into an intermediate metabolite of 2-oxo-clopidogrel. In the course of further metabolism, 2-oxo-clopidogrel turns into an active metabolite - a thiol derivative of clopidogrel. In vitro, this metabolic pathway is mediated by CYP 3A4, CYP 2C19, CYP 1A2 and CYP 2B6. The active thiol metabolite, which was isolated in vitro, quickly and irreversibly binds to platelet receptors, thus inhibiting their aggregation.

Cmax the active metabolite after taking a single loading dose of clopidogrel 300 mg is 2 times higher than after 4 days of applying a maintenance dose of 75 mg. Cmax achieved 30-60 minutes after taking the dose.

After oral administration 14C-labeled clopidogrel in humans is about 50% of the dose excreted in the urine and about 46% with feces within 120 hours. T½ clopidogrel after a single oral dose of 75 mg is about 6 hours. T½ the main circulating (inactive) metabolite after a single and repeated doses was 8 hours

Pharmacogenetics. CYP 2C19 is involved in the formation of both an active metabolite and an intermediate metabolite of 2-oxo-clopidogrel.The pharmacokinetics of the active clopidogrel metabolite and antiplatelet effects, according to ex vivo platelet aggregation measurements, differ depending on the CYP 2C19 genotype.

The CYP 2C19 * 1 allele corresponds to a fully functional metabolism, while the CYP 2C19 * 2 and CYP 2C19 * 3 alleles are non-functional. The alleles CYP 2C19 * 2 and CYP 2C19 * 3 are responsible for the majority of alleles, weaken the function in slow metabolizers of the Caucasian (85%) and Mongoloid (99%) races. Other alleles associated with an absent or impaired metabolism are less frequent; these include CYP 2C19 * 4, * 5, * 6, * 7 and * 8. Slow metabolizers have two non-functional alleles as described above. According to published data, the CYP 2C19 genotype, which causes a decreased metabolism, is observed in approximately 2% of patients of the Caucasian race, 4% of the Negroid race and 14% of Chinese nationality. There are tests to establish the patients CYP 2C19 genotype.

Pharmacokinetics in selected clinical populations. The pharmacokinetics of the active clopidogrel metabolite in individual populations has not been studied.

Impaired renal function. After repeated use of clopidogrel at a dose of 75 mg / day in patients with severe kidney disease (creatinine clearance of 5-15 ml / min), inhibition of ADP-induced platelet aggregation was less pronounced (25%) than in healthy volunteers, however, the duration of bleeding was almost the same as in healthy volunteers who took 75 mg of clopidogrel per day. The clinical tolerance of the drug was also good in all patients.

Impaired liver function. After repeated use of clopidogrel at a dose of 75 mg for 10 days in patients with severely impaired liver function, the suppression of ADP-induced platelet aggregation was similar to that in healthy volunteers. The average increase in bleeding time was also similar in the two groups.

Racial affiliation. The prevalence of CYP 2C19 alleles, which are the cause of intermediate and weak metabolic activity of CYP 2C19, differs depending on race / ethnic origin (see Pharmacogenetics). In the literature, there are limited data on patients of Asian origin that allow us to evaluate the clinical significance of genotyping of this CYP in terms of clinical results.

Indications

Prevention of atherothrombosis in adults:

  • after a myocardial infarction (the beginning of treatment - a few days, but no later than 35 days after the occurrence), ischemic stroke (the beginning of treatment - 7 days, but no later than 6 months after the occurrence), or patients who are diagnosed with the disease peripheral arteries;
  • with acute coronary syndrome:
  • with acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without Q wave), including in patients who had a stent installed during percutaneous coronary angioplasty, in combination with acetylsalicylic acid (ASA);
  • with acute myocardial infarction with an increase in the ST segment in combination with ASA (in patients receiving drug treatment and who are shown thrombolytic therapy).

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation. Clopidogrel in combination with ASA is indicated for adult patients with atrial fibrillation, who have at least one risk factor for the occurrence of vascular events, who have contraindications for treatment with vitamin K antagonists (AVK) and a low risk of bleeding, for the prevention of atherothrombotic and thromboembolic events, including number of stroke.

Application

Adults and elderly patients. clopidogrel is prescribed in a dose of 75 mg 1 time per day, regardless of food intake.

In patients with acute coronary syndrome:

  • acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without Q wave): treatment with clopidogrel begins with a single loading dose of 300 mg, and then 75 mg of clopidogrel are used once a day (with ASA at a dose of 75–325 mg / day). Since the use of higher doses of ASA was associated with a high risk of bleeding, it is recommended not to exceed the dose of ASA 100 mg. The optimal duration of treatment has not been officially established. The results of the studies testify in favor of using up to 12 months, and the maximum effect was observed after 3 months of treatment;
  • acute myocardial infarction with ST segment elevation: clopidogrel is prescribed 75 mg once a day, starting with a single daily loading dose of 300 mg in combination with ASA, thrombolytics or without them. Treatment of patients over the age of 75 years begins without a loading dose of clopidogrel. Combination therapy should be started as soon as possible after symptoms have been identified and should be continued for at least 4 weeks. The benefits of a combination of clopidogrel with ASA for more than 4 weeks have not been studied with this disease.

In patients with atrial fibrillation, clopidogrel is used in a single dose of 75 mg. Together with clopidogrel, the use of ASA should be started and continued (at a dose of 75-100 mg / day).

In case of a missed dose:

  • if less than 12 hours have passed since the moment when it was necessary to take the next dose, you should immediately take the missed dose and take the next at the usual time;
  • if more than 12 hours have passed, the next dose should be taken at the usual time; a double dose should not be taken.

Impaired renal function. The therapeutic experience of using the drug in patients with impaired renal function is limited.

Impaired liver function. The therapeutic experience of using the drug in patients with moderate liver diseases and the possibility of hemorrhagic diathesis is limited.

Children. Clopidogrel should not be used in children, since there is no data on the effectiveness of the drug.

Contraindications

Hypersensitivity to the active substance or any component of the drug. severe dysfunction of the liver. acute bleeding (e.g., an ulcer or intracranial hemorrhage).

Side effects

The frequency of occurrence of the reaction is distributed as follows: often (≥1 / 100 and 1/10); infrequently (≥1 / 1000 and 1/100); rarely (≥1 / 10,000 and 1/1000); very rarely (1/10 000), the frequency is unknown (it is impossible to determine from the available data). for each class of organ system, adverse reactions are listed in decreasing order of severity.

Organ System Class Often Infrequently Highly

rarely

Frequency unknown
On the part of the blood and lymphatic system   Thrombocytopenia, leukopenia, eosinophilia Neutropenia, including severe Thrombotic thrombocytopenic purpura (TTP), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired hemophilia A, granulocytopenia, anemia
From the immune system       Serum sickness, anaphylactoid reactions, cross-reactions of hypersensitivity to drugs of the thienopyridine group (such as ticlopidine, prasugrel) *
From the psyche       Hallucinations, confusion
From the nervous system   Intracranial bleeding (in some cases fatal), headache, paresthesia, dizziness   Change in taste
On the part of the organ of vision   Bleeding in the eye area (conjunctival, ocular, retinal)    
On the part of the organ of hearing and balance     Dizziness  
From the cardiovascular system Hematoma     Severe hemorrhage, bleeding from an operating wound, vasculitis, hypotension
From the respiratory system Nose bleed     Bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonitis, eosinophilic pneumonia
From the digestive system Gastrointestinal bleeding, diarrhea, abdominal pain, dyspepsia Gastric and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence Retroperitoneal bleeding Gastrointestinal and retroperitoneal hemorrhages with fatal consequences, pancreatitis, colitis (including ulcerative or lymphocytic), stomatitis
From the hepatobiliary system       Acute renal failure, hepatitis, abnormal results of liver function indicators
On the part of the skin and subcutaneous tissue Subcutaneous hemorrhage Rash, itching, intradermal hemorrhage (purpura)   Bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), angioedema, drug hypersensitivity syndrome, drug-induced skin rash with eosinophilia and systemic manifestations (DRESS-syndrome), erythematous or exfoliative syphilis, lichen planus,
From the musculoskeletal system       Musculoskeletal hemorrhages (hemarthrosis), arthritis, arthralgia, myalgia
From the urinary system   Hematuria   Glomerulonephritis, increased creatinine in the blood
General state Injection bleeding     Fever
Study   An increase in bleeding time, a decrease in the number of neutrophils and platelets    

* Information on phenomena of unknown frequency associated with the use of clopidogrel.

special instructions

Bleeding and hematological disorders. due to the risk of bleeding and hematological adverse reactions, an extensive blood test and / or other appropriate tests should be immediately carried out if clinical symptoms that indicate the possibility of bleeding are observed during the use of the drug. like other antiplatelet agents, clopidogrel should be used carefully in patients with an increased risk of bleeding due to trauma, surgery or other pathological conditions, as well as in the case of patients using ASK, heparin, iib / iiia glycoprotein inhibitors or NSAIDs, including cog- 2 or selective serotonin reuptake inhibitors (syoses). it is necessary to carefully monitor the manifestations in patients of any symptoms of bleeding, including hidden bleeding, especially in the first weeks of treatment and / or after invasive procedures on the heart or surgical interventions. the simultaneous use of clopidogrel with oral anticoagulants is not recommended, since it can increase the intensity of bleeding.

In the case of a planned surgical intervention, which temporarily does not require the use of antiplatelet agents, treatment with clopidogrel should be discontinued 7 days before surgery. Patients must inform their doctors, including dentists, that they are taking clopidogrel before any surgery or any new medicine is prescribed. Clopidogrel increases the duration of bleeding, so it should be used carefully in patients with an increased risk of bleeding (especially gastrointestinal and intraocular).

Patients should be warned that during treatment with clopidogrel (alone or in combination with ASA), bleeding may stop later than usual, and that they should inform the doctor about each case of unusual (in place or duration) bleeding.

Thrombotic thrombocytopenic purpura (TTP). Very rarely, cases of TTP have been observed after the use of clopidogrel, sometimes even after its short-term use. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia with neurological manifestations, renal dysfunction, or fever. TTP is a potentially lethal condition that requires immediate treatment, including plasmapheresis.

Acquired hemophilia.Cases of acquired hemophilia after the use of clopidogrel have been reported. With confirmed individual cases of elongation of activated partial thromboplastin time (APTT) with or without bleeding, the possibility of acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should undergo treatment under the supervision of specialists, and the use of clopidogrel should be discontinued.

Recent ischemic stroke. Due to insufficient data, it is not recommended to prescribe clopidogrel in the first 7 days after an acute ischemic stroke.

Cytochrome P450 2C19 (CYP 2C19). Pharmacogenetics: in patients with a slow metabolism of CYP 2C19, when used in recommended doses of clopidogrel, a lower concentration of the active metabolite and a less pronounced antiplatelet effect are observed. There are tests to establish the patients CYP 2C19 genotype.

Since clopidogrel is converted into its active metabolite partially by the action of CYP 2C19, the use of drugs that reduce the activity of this enzyme is likely to lead to a decrease in the concentration of the active metabolite of clopidogrel. The clinical significance of this interaction has not been established. As a precaution, simultaneous use should be avoided.

Tags: Clopidogrel