Pharmacological properties
Pharmacodynamics. Mechanism of action. Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to the receptor on the platelet surface and the subsequent activation of the GPIIb/IIIa complex by ADP, thereby inhibiting platelet aggregation. Biotransformation of clopidogrel is required to produce active inhibition of platelet aggregation. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the increase in platelet activity by released ADP. Clopidogrel irreversibly modifies platelet ADP receptors. Consequently, platelets that have interacted with clopidogrel are altered until the end of their life cycle. Normal platelet function is restored at a rate that corresponds to the rate of platelet renewal.
Pharmacodynamic effects. From the first day of use, repeated daily doses of 75 mg of the drug significantly slow down ADP-induced platelet aggregation. This effect progressively increases and stabilizes between the 3rd and 7th days. In a stable state, the average level of inhibition of aggregation under the influence of a daily dose of 75 mg is 40-60%. Platelet aggregation and bleeding time return to baseline levels on average 5 days after discontinuation of treatment.
Pharmacokinetics. Absorption. After oral administration of single and multiple doses of 75 mg, clopidogrel is rapidly absorbed. C max of unchanged clopidogrel (about 2.2-2.5 ng / ml after a single dose of 75 mg orally) in plasma was achieved approximately 45 minutes after dosing. Absorption is at least 50% according to the urinary excretion of clopidogrel metabolites.
Distribution: Clopidogrel and the main (inactive) circulating metabolite are reversibly bound to plasma proteins in vitro (98% and 94%, respectively). This binding remains unsaturated in vitro over a wide concentration range.
Metabolism. Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, there are two main pathways of its metabolism: one occurs with the participation of esterases and leads to hydrolysis with the formation of an inactive carboxylic acid derivative (which accounts for 85% of all metabolites circulating in blood plasma), and the other involves enzymes of the cytochrome P450 system. First, clopidogrel is converted to an intermediate metabolite 2-oxoclopidogrel. As a result of further metabolism of 2-oxoclopidogrel, a thiol derivative is formed - the active metabolite. In vitro, this metabolic pathway is mediated by the enzymes CYP 3A4, CYP 2C19, CYP 1A2 and CYP 2B6. The active metabolite of clopidogrel (a thiol derivative), which was isolated in vitro, binds rapidly and irreversibly to receptors on platelets, thereby inhibiting platelet aggregation.
Excretion. After 120 hours after oral administration of 14 C-labeled clopidogrel in humans, about 50% of the label was excreted in the urine and about 46% in the feces. After a single dose of 75 mg, the T½ of clopidogrel is about 6 hours. The T½ of the main (inactive) metabolite circulating in the blood is 8 hours after single and multiple administration of the drug.
Indication
Prevention of atherothrombosis in adults:
in patients who have suffered a myocardial infarction (treatment should be started within a few days, but no later than 35 days after onset), ischemic stroke (treatment should be started within 7 days, but no later than 6 months after onset), or who have been diagnosed with peripheral arterial disease (arterial damage and atherothrombosis of the vessels of the lower extremities);
in patients with acute coronary syndrome:
with acute coronary syndrome without ST segment elevation (unstable angina or non-Q wave myocardial infarction), including in patients who have had a stent placed during percutaneous coronary angioplasty, in combination with acetylsalicylic acid; with acute myocardial infarction with ST segment elevation in combination with acetylsalicylic acid (in patients receiving standard medical treatment for whom thrombolytic therapy is indicated).
Prevention of atherothrombotic and thromboembolic events in atrial fibrillation. Clopidogrel in combination with acetylsalicylic acid is indicated in adult patients with atrial fibrillation who have at least 1 risk factor for vascular events, as well as contraindications to treatment with vitamin K antagonists and a low risk of bleeding, for the prevention of atherothrombotic and thromboembolic events, including stroke.
Application
Adults and elderly patients: Platogril is prescribed at a dose of 75 mg once a day, regardless of meals.
Patients with acute ST-segment elevation myocardial infarction should be given 75 mg 1 time per day, starting with a single loading dose of 300 mg in combination with acetylsalicylic acid, with or without thrombolytic drugs. Treatment of patients over 75 years of age should be started without a loading dose of clopidogrel. Combination therapy should be started as early as possible after the onset of symptoms and continued for at least 4 weeks. The benefit of the combination of clopidogrel with acetylsalicylic acid for more than 4 weeks in this disease has not been studied.
In patients with atrial fibrillation, clopidogrel should be administered as a single daily dose of 75 mg. Acetylsalicylic acid (75-100 mg/day) should be initiated and continued in conjunction with clopidogrel.
If you miss a dose:
If less than 12 hours have passed since the next dose was due, the patient should take the missed dose immediately and take the next dose at the usual time; if more than 12 hours have passed, the patient should take the next dose at the usual time, but should not double the dose to make up for the missed dose.
Renal insufficiency. Therapeutic experience with the drug in patients with renal insufficiency is limited (see Precautions).
Hepatic insufficiency. Therapeutic experience in patients with moderate liver disease and risk of hemorrhagic diathesis is limited (see Precautions).
Contraindication
Hypersensitivity to the active substance or any component of the drug. Severe hepatic insufficiency. Acute bleeding (e.g. peptic ulcer or intracranial hemorrhage).
Side effects
From the blood and lymphatic system: thrombocytopenia, leukopenia, eosinophilia, neutropenia, including severe neutropenia, thrombotic thrombocytopenic purpura, aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anemia, acquired hemophilia a.
On the part of the immune system: serum sickness, anaphylactoid reactions, cross-hypersensitivity between thienopyridines (ticlopidine, prasugrel) (see Features of use).
On the part of the psyche: hallucinations, confusion.
Nervous system: intracranial bleeding (in some cases fatal), headache, paresthesia, dizziness, taste changes.
From the organ of vision: bleeding in the eye area (conjunctival, ocular, retinal).
From the side of the organs of hearing and labyrinth: dizziness.
From the vascular system: hematoma, severe hemorrhage, bleeding from the surgical wound, vasculitis, arterial hypotension.
Respiratory system: epistaxis, respiratory tract bleeding (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.
On the part of the digestive system: gastrointestinal bleeding, diarrhea, abdominal pain, dyspepsia, gastric and duodenal ulcers, gastritis, vomiting, nausea, constipation, flatulence, retroperitoneal hemorrhage, gastrointestinal and retroperitoneal bleeding with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic), stomatitis.
Hepatobiliary system: acute liver failure, hepatitis, abnormal liver function tests.
Skin and subcutaneous tissue disorders: subcutaneous hemorrhages, rash, itching, intradermal hemorrhages (purpura), bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), angioedema, erythematous rash, urticaria, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), eczema, lichen planus.
Musculoskeletal and connective tissue disorders: musculoskeletal hemorrhages (hemarthrosis), arthritis, arthralgia, myalgia.
Renal and urinary system: hematuria, glomerulonephritis, increased blood creatinine levels.
General disorders: fever, bleeding at the injection site.
Laboratory indicators: increased bleeding time, decreased neutrophil and platelet counts.
Reporting of suspected adverse reactions. Reporting of suspected adverse reactions after the approval of a medicinal product by the regulatory authorities is an important procedure. It allows for continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report all suspected adverse reactions via national reporting systems.
Bleeding and haematological disorders. Due to the risk of bleeding and haematological adverse reactions, a complete blood count and/or other appropriate tests should be performed immediately if symptoms suggestive of bleeding occur during treatment (see Adverse Reactions). As with other antiplatelet agents, clopidogrel should be used with caution in patients at increased risk of bleeding from trauma, surgery or other pathological conditions, and in patients receiving acetylsalicylic acid, heparin, glycoprotein IIb/IIIa inhibitors or non-steroidal anti-inflammatory drugs, including COX-2 inhibitors. Patients should be closely monitored for signs of bleeding, including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures and surgical interventions. Concomitant use of clopidogrel with oral anticoagulants is not recommended as it may increase the intensity of bleeding (see Interactions).
In the case of elective surgery, where antiplatelet therapy is temporarily not required, clopidogrel treatment should be discontinued 7 days before surgery. Patients should inform their physician (including dentist) that they are taking clopidogrel before undergoing any surgery or before starting a new medication. Clopidogrel prolongs bleeding time and should be used with caution in patients at increased risk of bleeding (especially gastrointestinal and intraocular).
Patients should be warned that during treatment with clopidogrel (alone or in combination with acetylsalicylic acid) bleeding may stop later than usual and that they should inform their doctor about any unusual (in terms of location or duration) bleeding.
Thrombotic thrombocytopenic purpura (TTP). Very rare cases of TTP have been observed after the use of clopidogrel, sometimes even after short-term use. TTP is manifested by thrombocytopenia and microangiopathic hemolytic anemia with neurological manifestations, renal dysfunction or fever. TTP is a potentially fatal condition and therefore requires immediate treatment, including plasmapheresis.
Acquired hemophilia. Cases of acquired hemophilia have been reported following the use of clopidogrel. In cases of confirmed isolated increases in APTT (activated partial thromboplastin time), with or without bleeding, the diagnosis of acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated, and clopidogrel should be discontinued.
Recent ischemic stroke: Due to insufficient data, clopidogrel is not recommended for use within 7 days of acute ischemic stroke.
Cytochrome P450 2C19 (CYP 2C19). Pharmacogenetics: Patients with genetically reduced CYP 2C19 function have lower plasma concentrations of the active metabolite of clopidogrel and a less pronounced antiplatelet effect. Tests are now available to detect the CYP 2C19 genotype in a patient.
Since clopidogrel is converted to its active metabolite partly by 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 in the blood plasma. However, the clinical significance of this interaction is not known. Therefore, as a precautionary measure, the simultaneous use of strong and moderate inhibitors of CYP 2C19 should be avoided (see Interactions with other drugs, a list of CYP 2C19 inhibitors is given in the Pharmacokinetics section).
Allergic cross-reactions. The patient should be checked for a history of hypersensitivity to other thienopyridines (such as ticlopidine, prasugrel), as cross-allergy between thienopyridines has been reported (see Adverse Reactions).
Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or hematologic reactions such as thrombocytopenia and neutropenia. Patients with a history of allergic and/or hematologic reactions to one thienopyridine may be at increased risk of developing the same or a different reaction to another thienopyridine. Monitoring for cross-reactivity is recommended.
Renal impairment: Therapeutic experience with clopidogrel in patients with renal insufficiency is limited, therefore the drug should be administered with caution to such patients (see Method of administration).
Hepatic impairment: Experience in patients with moderate liver disease and risk of bleeding diathesis is limited, therefore clopidogrel should be administered with caution to such patients (see Dosage & Administration).
Platogril contains hydrogenated castor oil, which can cause stomach upset and diarrhea.
Use during pregnancy and breastfeeding. Due to the lack of clinical data on the use of clopidogrel during pregnancy, it is undesirable to prescribe the drug to pregnant women (precautionary measures).
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition, or postnatal development.
It is not known whether clopidogrel passes into breast milk. Animal studies have shown that it passes into breast milk, therefore, breastfeeding should be discontinued during treatment with Platogril.
Fertility: Studies in laboratory animals have not shown any adverse effects of clopidogrel on fertility.
Children: Clopidogrel should not be used in children as there is no data on its effectiveness.
Ability to influence the reaction rate when driving vehicles or operating other mechanisms. Clopidogrel has no or negligible influence on the reaction rate when driving vehicles or operating other mechanisms.
Interactions
Oral anticoagulants. Concomitant use of clopidogrel with oral anticoagulants is not recommended as this combination may increase the intensity of bleeding (see special instructions). Although the use of clopidogrel at a dose of 75 mg/day does not alter the pharmacokinetic profile of S-warfarin or the international normalized ratio (INR) in patients receiving long-term warfarin treatment, the simultaneous use of clopidogrel with warfarin increases the risk of bleeding due to the existence of an independent effect on hemostasis.
GPIIb/IIIa glycoprotein receptor inhibitors: Clopidogrel should be administered with caution to patients receiving GPIIb/IIIa glycoprotein receptor inhibitors (see Precautions).
Acetylsalicylic acid. Acetylsalicylic acid does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of acetylsalicylic acid twice daily for one day did not significantly increase the prolongation of bleeding time caused by clopidogrel. Since a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid with an increased risk of bleeding is possible, caution should be exercised when these drugs are used concomitantly (see Precautions).
Heparin. Clopidogrel administration did not require adjustment of the heparin dose, but did not alter the effect of heparin on coagulation in healthy volunteers. Concomitant administration of heparin altered the inhibitory effect of clopidogrel on platelet aggregation. Since a pharmacodynamic interaction between clopidogrel and heparin is possible, with an increased risk of bleeding, caution should be exercised when these drugs are used concomitantly.
Thrombolytic agents. The incidence of clinically significant bleeding in patients with myocardial infarction with the simultaneous use of clopidogrel, fibrin-specific or fibrin-nonspecific thrombolytic agents and heparin was similar to that observed with the simultaneous use of thrombolytic agents and heparin with acetylsalicylic acid (see Adverse Reactions).
NSAIDs. Concomitant use of clopidogrel and naproxen has been shown to increase the incidence of occult gastrointestinal bleeding. It is not known whether there is a risk of gastrointestinal bleeding with clopidogrel and all NSAIDs. Therefore, caution should be exercised when NSAIDs, particularly COX-2 inhibitors, are co-administered with clopidogrel (see Precautions).
Concomitant use of other drugs. Since clopidogrel is converted to its active metabolite partly by 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 in the blood plasma. The clinical significance of this interaction has not been established. Therefore, as a precautionary measure, the simultaneous use of strong and moderate inhibitors of CYP 2C19 should be avoided (see Precautions and excipients).
Drugs that inhibit CYP 2C19 activity include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, and chloramphenicol.
Proton pump inhibitors. Although evidence suggests that the degree of inhibition of CYP 2C19 activity by different drugs belonging to the proton pump inhibitor class is not the same, clinical studies indicate that interactions exist with almost all members of this class. Therefore, concomitant use of proton pump inhibitors should be avoided unless clearly necessary. As a precautionary measure, omeprazole or esomeprazole should not be used concomitantly with clopidogrel.
A less pronounced decrease in the concentration of the active metabolite of clopidogrel in the blood was observed when clopidogrel was used simultaneously with pantoprazole or lansoprazole. The results obtained indicate the possibility of simultaneous use of clopidogrel and pantoprazole.
Combination with other medicinal products. No clinically significant pharmacodynamic interaction was observed when clopidogrel was administered concomitantly with atenolol, nifedipine, or both. In addition, the pharmacodynamic activity of clopidogrel remained virtually unchanged when administered concomitantly with phenobarbital and estrogen.
The pharmacokinetic properties of digoxin or theophylline were not altered by concomitant administration with clopidogrel.
Antacids did not affect the level of absorption of clopidogrel.
There is evidence that the carboxyl metabolites of clopidogrel may inhibit CYP 2C9 activity. This may increase plasma levels of drugs such as phenytoin, tolbutamide, and NSAIDs that are metabolized by CYP 2C9. However, studies suggest that phenytoin and tolbutamide can be safely co-administered with clopidogrel.
There is no data on the risk of concomitant use of clopidogrel with diuretics, β-adrenergic blockers, ACE inhibitors, calcium antagonists, cholesterol-lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents and GPIIb/IIIa antagonists.
Overdose
Symptoms: possible prolongation of bleeding time with subsequent complications.
Treatment: symptomatic.
There is no known antidote to the pharmacological activity of clopidogrel. If immediate correction of prolonged bleeding time is required, the effect of clopidogrel can be reversed by platelet transfusion.
Storage conditions
At a temperature not exceeding 25 °C.
