Instructions for use of Platogril film-coated tablets 75 mg No. 84
Composition
active ingredient: clopidogrel;
1 tablet contains clopidogrel bisulfate equivalent to clopidogrel 75 mg;
excipients: povidone K-30, mannitol (E 421), microcrystalline cellulose, low-substituted hydroxypropylcellulose, hydrogenated castor oil, red iron oxide (E 172); Opadry Y-1-7000 white coating: hypromellose, polyethylene glycol, titanium dioxide (E 171).
Dosage form
Film-coated tablets.
Main physicochemical properties: pink-coated tablets, round, biconvex and smooth on both sides.
Pharmacotherapeutic group
Antithrombotic agents. Platelet aggregation inhibitors excluding heparin. ATC code B01A C04.
Pharmacological properties
Pharmacodynamics
Mechanism of action. Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its 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 modified 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 show a significant inhibition of ADP-induced platelet aggregation. This effect progressively increases and stabilizes between 3 and 7 days. At steady state, the average level of inhibition of aggregation under the influence of a daily dose of 75 mg is from 40% to 60%. Platelet aggregation and bleeding time return to baseline on average 5 days after discontinuation of treatment.
Pharmacokinetics
Absorption: Clopidogrel is rapidly absorbed after single and multiple oral doses of 75 mg/day. Mean peak plasma concentrations of unchanged clopidogrel (approximately 2.2-2.5 ng/mL after a single 75 mg oral dose) were achieved approximately 45 minutes after dosing. Absorption is at least 50% based on urinary excretion of clopidogrel metabolites.
Distribution: Clopidogrel and the major (inactive) circulating metabolite are reversibly bound to human 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 plasma), and the other involves enzymes of the cytochrome P450 system. Clopidogrel is first converted to the intermediate metabolite 2-oxo-clopidogrel. As a result of further metabolism of 2-oxo-clopidogrel, a thiol derivative is formed - the active metabolite. In vitro, this metabolic pathway is mediated by the enzymes CYP3A4, CYP2C19, CYP1A2 and CYP2B6. 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.
Elimination: After 120 hours of oral administration of 14C-labeled clopidogrel in humans, approximately 50% of the label was excreted in the urine and approximately 46% in the feces. After a single oral dose of 75 mg, the elimination half-life of clopidogrel is approximately 6 hours. The elimination half-life of the main (inactive) circulating metabolite is 8 hours after single and multiple administration.
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 the onset), ischemic stroke (treatment should be started within 7 days, but no later than 6 months after the 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 inserted during percutaneous coronary angioplasty, in combination with acetylsalicylic acid (ASA);
Prevention of atherothrombotic and thromboembolic events in atrial fibrillation. Clopidogrel in combination with ASA is indicated in adult patients with atrial fibrillation who have at least one risk factor for vascular events, who have contraindications to treatment with vitamin K antagonists (VKAs) and who are at low risk of bleeding, for the prevention of atherothrombotic and thromboembolic events, including stroke.
Contraindication
Hypersensitivity to the active substance or to any component of the drug. Severe hepatic insufficiency. Acute bleeding (e.g. peptic ulcer or intracranial hemorrhage).
Interaction with other medicinal products and other types of interactions
Oral anticoagulants.
The concomitant use of clopidogrel with oral anticoagulants is not recommended as this combination may increase the intensity of bleeding (see section 4.4). Although clopidogrel 75 mg daily does not alter the pharmacokinetic profile of S-warfarin or the international normalized ratio (INR) in patients receiving long-term warfarin therapy, the concomitant use of clopidogrel and warfarin increases the risk of bleeding due to the existence of independent effects on hemostasis.
Glycoprotein receptor IIb/IIIa inhibitors.
Clopidogrel should be administered with caution to patients receiving glycoprotein IIb/IIIa receptor inhibitors (see section "Special warnings and precautions for use").
Acetylsalicylic acid (ASA).
Acetylsalicylic acid does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of ASA twice daily for one day did not significantly increase the bleeding time prolonged 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 section 4.4).
Heparin. Clopidogrel administration did not require adjustment of the heparin dose and did not alter the effect of heparin on coagulation in healthy volunteers. Concomitant administration of heparin did not alter 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 concomitant use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic agents and heparin was similar to that observed with concomitant use of thrombolytic agents and heparin with ASA (see section "Adverse reactions").
Nonsteroidal anti-inflammatory drugs (NSAIDs).
Concomitant use of clopidogrel and naproxen has been shown to increase occult gastrointestinal bleeding. It is not known whether the risk of gastrointestinal bleeding is increased when clopidogrel is used with all NSAIDs. Therefore, caution should be exercised when NSAIDs, particularly COX-2 inhibitors, are co-administered with clopidogrel (see section 4.4).
Concomitant use of other drugs. Since clopidogrel is converted to its active metabolite partly by CYP2C19, 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 is not known. Therefore, as a precautionary measure, the simultaneous use of strong and moderate inhibitors of CYP2C19 should be avoided (see sections "Special instructions" and "Pharmacokinetics").
Drugs that inhibit CYP2C19 activity include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, and chloramphenicol.
Proton pump inhibitors (PPIs).
Although evidence suggests that the degree of inhibition of CYP2C19 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 absolutely necessary. As a precautionary measure, omeprazole or esomeprazole should not be used concomitantly with clopidogrel.
A less pronounced decrease in the blood concentrations of the active metabolite of clopidogrel was observed when clopidogrel was co-administered with pantoprazole or lansoprazole. The results obtained indicate the possibility of co-administration 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 was virtually unchanged when administered concomitantly with phenobarbital and estrogen.
The pharmacokinetic properties of digoxin or theophylline were not altered when co-administered with clopidogrel.
Antacids did not affect the level of absorption of clopidogrel.
There is evidence that the carboxyl metabolites of clopidogrel may inhibit cytochrome P450 2C9 activity. This may increase plasma levels of drugs such as phenytoin and tolbutamide, and NSAIDs that are metabolized by cytochrome P450 2C9. However, studies suggest that phenytoin and tolbutamide can be safely co-administered with clopidogrel.
There are no data on the signs of clinically significant adverse effects when clopidogrel is used concomitantly with diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, calcium antagonists, cholesterol-lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents and GPIIb/IIIa antagonists.
Application features
Bleeding and hematological 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 section 4.8). 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 ASA, 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 section 4.5).
In the case of elective surgery that temporarily does not require antiplatelet therapy, 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 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 ASA) bleeding may stop later than usual and that they should inform their doctor of any unusual (in terms of location or duration) bleeding.
Thrombotic thrombocytopenic purpura (TTP). Very rare cases of thrombotic thrombocytopenic purpura (TTP) have been reported following the use of clopidogrel, sometimes even after short-term use. TTP is characterized 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 plasma exchange.
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 2 C19 (CYP2C19). Pharmacogenetics: Patients with genetically reduced CYP2C19 function have lower plasma concentrations of the active metabolite of clopidogrel and a less pronounced antiplatelet effect. Tests are now available to identify the CYP2C19 genotype of the patient.
Since clopidogrel is converted to its active metabolite partly by CYP2C19, the use of drugs that reduce the activity of this enzyme is likely to lead to a decrease in the plasma concentration of the active metabolite of clopidogrel. However, the clinical significance of this interaction is not known. Therefore, as a precautionary measure, the simultaneous use of strong and moderate inhibitors of CYP2C19 should be avoided (see section "Interaction with other medicinal products and other forms of interaction"; a list of CYP2C19 inhibitors is given in the section "Pharmacokinetics").
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 section 4.8).
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.
Kidney dysfunction.
Therapeutic experience with clopidogrel in patients with renal insufficiency is limited, therefore the drug should be prescribed with caution to such patients (see section "Method of administration and dosage").
Liver dysfunction.
Experience with the drug in patients with moderate liver disease and risk of hemorrhagic diathesis is limited, therefore clopidogrel should be prescribed with caution to such patients (see section "Method of administration and dosage").
Platogril contains hydrogenated castor oil, which may cause stomach upset and diarrhea.
Special precautions for disposal of residues and waste.
Any unused tablets or waste material should be disposed of in accordance with local requirements.
Use during pregnancy or 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 measure).
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 is excreted in human milk. Animal studies have shown that clopidogrel is excreted in human milk, therefore, breast-feeding should be discontinued during treatment with Platogril.
Fertility: Studies in laboratory animals have not shown any adverse effects of clopidogrel on fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
Clopidogrel has no or negligible influence on the reaction rate when driving or using other mechanisms.
Method of administration and doses
Adults and elderly patients.
Platogril should be prescribed at a dose of 75 mg once a day, regardless of meals.
For patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q wave myocardial infarction on the ECG), treatment with clopidogrel should be initiated with a single loading dose of 300 mg, followed by 75 mg once daily (with acetylsalicylic acid (ASA) 75-325 mg daily). Since higher doses of ASA increase the risk of bleeding, it is recommended that the dose of acetylsalicylic acid not exceed 100 mg. The optimal duration of treatment has not been formally established. There is published data on the benefit of using the drug for up to 12 months (the maximum effect was observed after 3 months of treatment).
Patients with acute myocardial infarction with ST-segment elevation should be given clopidogrel 75 mg once daily, starting with a single loading dose of 300 mg in combination with ASA, with or without thrombolytic agents. Treatment of patients aged 75 years and older should be initiated without a loading dose of clopidogrel. Combination therapy should be initiated as early as possible after the onset of symptoms and continued for at least 4 weeks. The benefit of the combination of clopidogrel with ASA for more than four weeks in this condition has not been studied.
In patients with atrial fibrillation, clopidogrel should be administered in a single daily dose of 75 mg. ASA (75-100 mg daily) should be initiated and continued in conjunction with clopidogrel.
In case of missed 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 scheduled dose at the usual time and not double the dose to make up for the missed dose.
Kidney failure.
Therapeutic experience in patients with renal insufficiency is limited (see section "Special warnings and precautions for use").
Hepatic insufficiency. Therapeutic experience in patients with moderate liver disease and risk of hemorrhagic diathesis is limited (see section "Special warnings and precautions for use").
Children.
Clopidogrel should not be used in children as there is no data on the drug's effectiveness.
Overdose
Symptoms: prolonged bleeding time may occur 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.
Adverse reactions
From the blood and lymphatic system: thrombocytopenia, leukocytopenia, eosinophilia, neutropenia, including severe neutropenia, thrombotic thrombocytopenic purpura, aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anemia, acquired hemophilia A.
Immune system disorders: serum sickness, anaphylactoid reactions, cross-hypersensitivity between thienopyridines (such as ticlopidine, prasugrel) (see section "Special warnings and precautions for use").
On the part of the psyche: hallucinations, confusion.
Nervous system: intracranial bleeding (in some cases fatal), headache, paresthesia, dizziness, change in taste perception.
On the part of the organs 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: nosebleeds, respiratory tract bleeding (hemoptysis, pulmonary bleeding), bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.
Gastrointestinal: 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 disorders: acute liver failure, hepatitis, abnormal liver function tests.
Skin and subcutaneous tissue disorders: subcutaneous hemorrhage, rash, pruritus, 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: prolonged 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 use of this medicinal product. Healthcare professionals are asked to report all suspected adverse reactions via national reporting systems.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 ºС in the original packaging.
Keep out of reach of children.
Packaging
14 tablets in a blister; 2 or 4 or 6 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
"KUSUM FARM" LLC.
Location of the manufacturer and its business address
40020, Ukraine, Sumy region, Sumy city, Skryabina st., 54
