Instructions for use: Aterocard film-coated tablets 75 mg, blister pack No. 70
Composition
active ingredient: clopidogrel;
1 tablet contains 75 mg of clopidogrel;
Excipients: microcrystalline cellulose; lactose monohydrate; pregelatinized starch; povidone; polyethylene glycol 6000; magnesium stearate;
shell: Opadry II Pink film coating mixture (aluminum lakes magic red (E 129) and indigo carmine (E 132); hypromellose (hydroxypropyl methylcellulose); lactose monohydrate; triacetin; polyethylene glycol; titanium dioxide (E 171)).
Dosage form
Film-coated tablets.
Main physicochemical properties: round tablets with a biconvex surface, coated with a pink film coating.
Pharmacotherapeutic group
Antithrombotic agents. Antiplatelet agents. ATC code B01A C04.
Pharmacological properties
Pharmacodynamics
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. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the increase in platelet activity by the released ADP, irreversibly modifying the ADP receptors of platelets. 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.
From the first day of administration, 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
After oral administration, a dose of 75 mg is rapidly absorbed from the gastrointestinal tract.
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 administration. Absorption is at least 50%, as demonstrated by urinary excretion of clopidogrel metabolites. Clopidogrel and the major (inactive) circulating metabolite are reversibly bound to human plasma proteins in vitro (98% and 94%, respectively). This binding remains saturable in vitro over a wide concentration range.
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-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, which was isolated in vitro, binds rapidly and irreversibly to receptors on platelets, thereby preventing platelet aggregation.
After 120 hours after oral administration, approximately 50% of the administered dose is excreted in the urine and 46% in the feces. After a single oral dose, the elimination half-life of clopidogrel is approximately 6 hours. The elimination half-life of the main (inactive) metabolite circulating in the blood is 8 hours after single and multiple doses of the drug.
Pharmacogenetics. Several polymorphic CYP450 enzymes convert clopidogrel to its active metabolite, activating it. CYP2C19 is involved in the formation of both the active metabolite and the intermediate metabolite 2-oxo-clopidogrel. The pharmacokinetics of the active metabolite and the antiplatelet effects, as measured by platelet aggregation, differ depending on the CYP2C19 genotype. The CYP2C19*1 allele corresponds to a fully functional metabolism, whereas the CYP2C19*2 and CYP2C19*3 alleles correspond to a reduced metabolism. These alleles are responsible for 85% of the alleles that impair function in whites and 99% in Asians. Other alleles associated with reduced metabolism include CYP2C19*4, *5, *6, *7, and *8, but they are much less common in the general population.
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 myocardial infarction with ST-segment elevation in combination with acetylsalicylic acid (in patients receiving standard medical treatment and for whom thrombolytic therapy is indicated).
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. See also section "Pharmacological properties".
Contraindication
Hypersensitivity to clopidogrel or to any of the components of the drug, severe liver dysfunction, acute bleeding (peptic ulcer, intracranial hemorrhage).
Interaction with other medicinal products and other types of interactions
Oral anticoagulants: Concomitant use with clopidogrel is not recommended as there is a risk of increased bleeding.
Glycoprotein IIb/IIIa inhibitors: Aterocard should be administered with caution to patients at increased risk of bleeding due to trauma, surgery or other pathological conditions in whom glycoprotein IIb/IIIa inhibitors are concomitantly used.
Acetylsalicylic acid (ASA). ASA 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 1 day did not significantly increase the prolongation of bleeding time caused by clopidogrel. Since there is a potential interaction between clopidogrel and acetylsalicylic acid with an increased risk of bleeding, caution should be exercised when these drugs are used concomitantly. However, clopidogrel and ASA have been used together for up to 1 year.
Heparin. In a study, clopidogrel did not require adjustment of the heparin dose and did not alter the effect of heparin on coagulation. Concomitant use of heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation. Since there is a potential interaction between clopidogrel and heparin with an increased risk of bleeding, concomitant use should be undertaken with caution.
Thrombolytic agents: The safety of concomitant use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic agents, and heparin has been studied in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed with concomitant use of thrombolytic agents and heparin with ASA.
Nonsteroidal anti-inflammatory drugs (NSAIDs). Concomitant use of clopidogrel and naproxen may increase the incidence of occult gastrointestinal bleeding. However, there are no data on drug interactions with other NSAIDs and it is not yet clear whether the risk of bleeding increases with use with all NSAIDs. Therefore, caution is required when NSAIDs, particularly COX-2 inhibitors, are used concomitantly with clopidogrel.
Combination with other drugs.
Since clopidogrel is converted to its active metabolite partly by CYP2C19, the use of drugs that reduce the activity of this enzyme may lead to a decrease in the concentration of the active metabolite of clopidogrel in the blood plasma, as well as a decrease in clinical efficacy. The simultaneous use of drugs that inhibit the activity of CYP2C19 should be avoided.
Drugs that inhibit CYP2C19 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 CYP2C19 activity by different drugs belonging to the proton pump inhibitor class is not the same, there is evidence that interactions are possible with almost all drugs of this class. Therefore, concomitant use of proton pump inhibitors should be avoided unless clearly necessary. There is no evidence that other drugs that reduce gastric acid production, such as H2 blockers (except cimetidine, which is a CYP2C9 inhibitor) or antacids, affect the antiplatelet activity of clopidogrel.
Studies have shown no clinically significant interactions when clopidogrel is used concomitantly with atenolol, nifedipine, or both. In addition, the pharmacodynamic activity of clopidogrel remains virtually unchanged when used concomitantly with phenobarbital and estrogen.
The pharmacokinetics of digoxin or theophylline were not altered by co-administration with clopidogrel. Antacids do not affect the extent of clopidogrel absorption.
No clinically significant drug interactions have been observed with diuretics, beta-blockers, ACE inhibitors, calcium channel blockers, coronary vasodilators, antacids, antidiabetic agents (including insulin), hypocholesterolemic agents, antiepileptic agents, GPIIb/IIIa antagonists, or hormone replacement therapy.
Application features
Bleeding and hematological disorders.
Due to the risk of bleeding and haematological adverse reactions, complete blood count and/or other appropriate tests should be performed immediately if symptoms suggestive of bleeding occur during treatment with clopidogrel (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 inhibitors
IIb/IIIa or nonsteroidal 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. The 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 the use of antiplatelet agents, treatment with clopidogrel should be discontinued 7 days before surgery. Patients should inform their physician (including dentist) that they are taking clopidogrel before 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 ASA) 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 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 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 elevations 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; 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 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 CYP2C 19 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").
Cross-reactivity among thienopyridines. The patient should be checked for a history of hypersensitivity to other thienopyridines (such as ticlopidine, prasugrel), as cross-allergy among thienopyridines has been reported.
(see section "Adverse reactions"). The use of thienopyridines may result in allergic reactions ranging from mild to severe, such as rash, angioedema, or haematological reactions, such as thrombocytopenia and neutropenia. Patients with a history of allergic reactions and/or haematological 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").
Experience with the use of the drug in patients with moderate liver disease and the likelihood of hemorrhagic diathesis is limited, therefore clopidogrel should be prescribed with caution to such patients (see section "Method of administration and dosage").
Excipients: Aterocard contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use during pregnancy or breastfeeding
Due to the lack of clinical data on the use of clopidogrel during pregnancy, the drug is not recommended for use in pregnant women (as a precautionary measure). Animal studies have not shown any adverse effects of clopidogrel on pregnancy, embryonal/fetal development, parturition or postnatal development.
It is not known whether clopidogrel is excreted in human milk. Animal studies have shown that it is excreted in human milk, therefore, breast-feeding should be discontinued during treatment with the drug.
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
The drug has no or negligible effect on the speed of reaction when driving or operating other mechanisms. In cases where dizziness is observed during treatment with the drug, you should refrain from driving or operating other mechanisms.
Method of administration and doses
Adults and elderly patients: Aterocard is prescribed at a dose of 75 mg once a day, regardless of meals.
For patients with acute coronary syndrome (ACS) without ST segment elevation (unstable angina or non-Q wave myocardial infarction on ECG), treatment with clopidogrel should be initiated with a single loading dose of 300 mg, and then continued with a dose of 75 mg once daily (with acetylsalicylic acid (ASA) at a dose of 75-325 mg per day). Since the use of higher doses of ASA increases the risk of bleeding, it is recommended not to exceed a dose of acetylsalicylic acid of 100 mg. The optimal duration of treatment has not been formally established. The results of clinical studies indicate in favor of using the drug for up to 12 months, and 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 treatment with a combination of clopidogrel and ASA for more than 4 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/day) should be initiated and continued in conjunction with clopidogrel (see section 5.1).
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 dose at the usual time and not double the dose to make up for the missed dose.
Children and adolescents: Clopidogrel should not be used in children as there is no data on efficacy (see section 5.1).
Kidney dysfunction.
Therapeutic experience with the drug in patients with impaired renal function is limited (see section "Special warnings and precautions for use").
Liver dysfunction.
Therapeutic experience of the drug in patients with moderate liver disease and the likelihood of hemorrhagic diathesis is limited (see section "Special warnings and precautions for use").
Children: The safety and efficacy of the drug in children have not been established.
Overdose
Symptoms: prolonged bleeding time with subsequent complications.
Treatment: symptomatic. If rapid correction of prolonged bleeding time is required, the effect of the drug can be reversed by platelet transfusion. The antidote to the pharmacological activity of clopidogrel is unknown.
Adverse reactions
From the blood and lymphatic system:
thrombocytopenia, leukocytopenia, eosinophilia; neutropenia, including severe neutropenia; thrombotic thrombocytopenic purpura (TTP) (see section "Special warnings and precautions for use"); aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired hemophilia A, granulocytopenia, anemia.
On the part of the immune system:
Serum sickness, anaphylactoid reactions, cross-hypersensitivity between thienopyridines (such as ticlopidine, prasugrel) (see section "Special warnings and precautions for use").
Nervous system: intracranial hemorrhages (in some cases fatal), headache, paresthesia, dizziness; change in taste perception.
From the organs of hearing and balance: dizziness.
From the vascular system: hematoma; severe hemorrhage, bleeding from the surgical wound, vasculitis, arterial hypotension.
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 system: 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, connective and bone tissue: musculoskeletal hemorrhages (hemarthrosis), arthritis, arthralgia, myalgia.
Renal and urinary disorders: hematuria; glomerulonephritis, increased blood creatinine levels.
Psychiatric disorders: hallucinations, confusion.
Respiratory, thoracic and mediastinal disorders: epistaxis; respiratory tract bleeding (hemoptysis, pulmonary bleeding), bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.
General disorders: fever.
Laboratory tests: prolonged bleeding time, decreased neutrophil and platelet counts.
Expiration date
. 3 years.
Storage conditions
In the original packaging at a temperature not exceeding 25 ºС.
Keep out of reach of children.
Packaging
10 tablets in a blister; 1 or 4 blisters in a pack.
Vacation category
According to the recipe.
Producer
PJSC "Kyiv Vitamin Plant".
Location of the manufacturer and address of its place of business
04073, Ukraine, Kyiv, Kopylivska St., 38.
Website: www.vitamin.com.ua
