Instructions for use: Aterocard film-coated tablets 75 mg, blister pack No. 30
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.
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 slowdown in ADP-induced platelet aggregation. This effect progressively increases and stabilizes between 3 and 7 days. In a stable 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 levels on average 5 days after discontinuation of treatment.
Pharmacokinetics.
Absorption: Clopidogrel is rapidly absorbed after oral administration of single and multiple 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 reached 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 involving esterases, which 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 involving 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. This active metabolite is formed mainly by the enzyme CYP2C19, with the participation of several other CYP enzymes, such as CYP1A2, CYP2B6 and CYP3A4. 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 dose 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.
Pharmacogenetics. CYP2C19 is involved in the formation of both the active metabolite and the intermediate metabolite 2-oxo-clopidogrel. The pharmacokinetics of the active metabolite of clopidogrel and the antiplatelet effects, as measured by ex vivo platelet aggregation, differ depending on the CYP2C19 genotype.
The CYP2C19*1 allele corresponds to a fully functional metabolism, while the CYP2C19*2 and CYP2C19*3 alleles correspond to a non-functional metabolism. The CYP2C19*2 and CYP2C19*3 alleles constitute the majority of alleles in patients of the Caucasoid (85%) and Mongoloid (99%) races with reduced metabolism.
Other alleles associated with absent or impaired metabolism are much less common. These include CYP2C19*4, *5, *6, *7, and *8. A patient with an impaired metabolism has two nonfunctional alleles, as noted above. According to published data, CYP2C19 genotypes corresponding to impaired metabolism are found in 2% of Caucasians, 4% of Negroid patients, and 14% of Chinese patients. Tests are now available to determine the CYP2C19 genotype.
Renal impairment: Following regular administration of 75 mg clopidogrel daily to patients with severe renal impairment (creatinine clearance 5-15 ml/min), inhibition of ADP-induced platelet aggregation was less pronounced (25%) compared with the same effect in healthy volunteers, and bleeding time was prolonged to almost the same extent as in healthy volunteers receiving 75 mg clopidogrel daily. Clinical tolerability was good in all patients.
Hepatic impairment: After regular administration of 75 mg clopidogrel daily for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean prolongation of bleeding time was also similar in both groups.
Race: The prevalence of CYP2C19 alleles that confer intermediate and poor CYP2C19 metabolic activity varies by race/ethnicity. There are limited data in patients of Mongoloid race to assess the clinical relevance of genotyping this CYP.
Indication
Secondary 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);
− with acute myocardial infarction with ST-segment elevation, in combination with ASA (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 for the prevention of atherothrombotic and thromboembolic events, including stroke, 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.
Contraindication
Hypersensitivity to the active substance or to any of the excipients. Severe hepatic impairment. Acute bleeding (e.g. peptic ulcer or intracranial haemorrhage).
Interaction with other medicinal products and other types of interactions
Medicinal products associated with an increased risk of bleeding. Due to the potential additive effect, there is an increased risk of haemorrhagic complications, therefore the concomitant use of such medicinal products with clopidogrel requires caution. Oral anticoagulants. Concomitant use of the drug with oral anticoagulants is not recommended, as such a combination may increase the intensity of bleeding (see section "Special instructions"). Although the use of clopidogrel at a dose of 75 mg per day does not change the pharmacokinetic profile of S-warfarin or the international normalized ratio (INR) in patients receiving long-term treatment with warfarin, the simultaneous use of clopidogrel and warfarin increases the risk of bleeding due to the existence of independent effects on haemostasis.
Glycoprotein IIb/IIIa receptor inhibitors. Aterocard should be administered with caution to patients receiving glycoprotein IIb/IIIa receptor inhibitors (see section "Special warnings and precautions for use").
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 ASA with an increased risk of bleeding is possible, caution should be exercised when using these drugs concomitantly (see section 4.4). However, clopidogrel and ASA have been used together for up to 1 year.
Heparin. According to the study, clopidogrel did not require adjustment of the heparin dose and did not change the effect of heparin on coagulation. Concomitant use of heparin did not change 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 using these drugs concomitantly.
Nonsteroidal anti-inflammatory drugs (NSAIDs). Concomitant use of clopidogrel and naproxen has been shown to increase occult gastrointestinal bleeding. However, due to the lack of interaction studies with other NSAIDs, it is not yet clear whether the risk of gastrointestinal bleeding is increased with all NSAIDs. Therefore, caution should be exercised when NSAIDs, particularly COX-2 inhibitors, are co-administered with clopidogrel.
Selective serotonin reuptake inhibitors (SSRIs): Caution should be exercised when SSRIs are used concomitantly with clopidogrel, as SSRIs affect platelet activation and increase the risk of bleeding.
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.
Drugs that inhibit CYP2C19 activity include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, and efavirenz.
Proton pump inhibitors (PPIs). Omeprazole 80 mg once daily, when co-administered with clopidogrel or within 12 hours of the two drugs, reduced the concentration of the active metabolite in the blood by 45% (loading dose) and 40% (maintenance dose). This reduction was accompanied by a 39% (loading dose) and 21% (maintenance dose) reduction in inhibition of platelet aggregation. Esomeprazole is expected to interact similarly with clopidogrel.
Observational and clinical studies have provided conflicting data on the clinical consequences of these pharmacokinetic and pharmacodynamic interactions in terms of major cardiovascular events. As a precautionary measure, omeprazole or esomeprazole should not be used concomitantly with clopidogrel.
A less pronounced decrease in the concentration of the metabolite in the blood was observed with the use of pantoprazole or lansoprazole.
When pantoprazole 80 mg once daily was co-administered, plasma concentrations of the active metabolite decreased by 20% (loading dose) and 14% (maintenance dose). This decrease was accompanied by a decrease in the mean platelet aggregation inhibition index by 15% and 11%, respectively. The results obtained indicate the possibility of concomitant use of clopidogrel and pantoprazole.
There is no evidence that other drugs that reduce stomach acid production, such as H2 blockers or antacids, affect the antiplatelet activity of clopidogrel.
Combinations with other drugs. There is evidence that a number of clinical studies have been conducted with clopidogrel and other drugs to study potential pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was administered concomitantly with atenolol, nifedipine, or both drugs. In addition, the pharmacodynamic activity of clopidogrel remained almost 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.
It is known that data obtained in human liver microsome studies indicate that the carboxyl metabolites of clopidogrel can inhibit the activity of cytochrome P4502C9. This could potentially increase the plasma levels of drugs such as phenytoin and tolbutamide and NSAIDs that are metabolized by cytochrome P4502C9. Despite this, the results of the study indicate that phenytoin and tolbutamide can be safely used concomitantly with clopidogrel.
Medicinal products that are substrates of the CYP2C8 enzyme. Clopidogrel has been shown to increase the exposure of repaglinide in healthy volunteers. In vitro studies have shown that the increase in repaglinide exposure is due to inhibition of the CYP2C8 enzyme by the glucuronide metabolite of clopidogrel. Given the risk of increased plasma concentrations, concomitant use of clopidogrel and medicinal products that are predominantly eliminated by metabolism mediated by the CYP2C8 enzyme (such as repaglinide, paclitaxel) requires caution.
Antiretroviral therapy (ART). Reduced exposure to the active metabolite of clopidogrel and reduced platelet inhibition in HIV-infected patients receiving ritonavir- or cobicistat-boosted antiretroviral therapy (ART). Although the clinical relevance of these findings is uncertain, there have been spontaneous reports of HIV-infected patients receiving boosted ART experiencing recurrent occlusive events after deobstruction or thrombotic events while receiving clopidogrel. The effects of clopidogrel and moderate platelet inhibition may be reduced by concomitant use of ritonavir.
Application features
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 promptly 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 who may be at increased risk of bleeding from trauma, surgery or other pathological conditions, and in patients receiving ASA, heparin, glycoprotein IIb/IIIa inhibitors or NSAIDs, including COX-2 inhibitors or SSRIs, or other medicinal products such as pentoxifylline, which are associated with an increased risk of haemorrhagic events (see section 4.5). 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 surgery. 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, when the antiplatelet effect is temporarily undesirable, 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 other medicinal product is prescribed to them. 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 patients should report any unusual bleeding (in terms of location or duration) to their doctor.
Thrombotic thrombocytopenic purpura (TTP). Very rare cases of 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 that requires immediate treatment, including plasma exchange.
Acquired hemophilia. Cases of acquired hemophilia have been reported following the use of clopidogrel. In the case of confirmed isolated increases in activated partial thromboplastin time (aPTT), 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 appropriately; clopidogrel should be discontinued in such patients.
Recent ischemic stroke: Due to insufficient data, clopidogrel is not recommended for use within 7 days after acute ischemic stroke.
Cytochrome P4502C19 (CYP2C19). Pharmacogenetics: Patients with genetically reduced CYP2C19 function have lower plasma concentrations of the active metabolite of clopidogrel and a less pronounced antiplatelet effect when using recommended doses of clopidogrel.
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 CYP2C19 should be avoided (see section "Interaction with other medicinal products and other forms of interaction").
Cross-sensitivity to thienopyridines. Patients should be checked for a history of hypersensitivity to other thienopyridines (such as clopidogrel, ticlopidine, prasugrel) as cross-sensitivity to thienopyridines has been reported. Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological reactions such as thrombocytopenia and neutropenia. Patients with a history of allergic 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 signs of hypersensitivity is recommended in patients with a known allergy to thienopyridines.
Renal impairment: Therapeutic experience with clopidogrel in patients with renal insufficiency is limited, therefore the drug should be prescribed with caution in such patients (see section "Method of administration and dosage").
Hepatic impairment: Experience in patients with moderate liver disease and a potential for bleeding diathesis is limited, therefore clopidogrel should be administered with caution to such patients (see section 4.2).
Excipients: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Special precautions for the disposal of waste materials Any unused product or waste material should be disposed of in accordance with local requirements.
Use during pregnancy or breastfeeding
Pregnancy: Due to the lack of clinical data on the use of clopidogrel during pregnancy, it is not advisable 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.
Breastfeeding: It is not known whether clopidogrel is excreted in human milk. Animal studies have shown that it is excreted in breast milk, therefore, breastfeeding 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
Clopidogrel has no or negligible influence on the reaction rate when driving or operating other mechanisms.
Method of administration and doses
Adults, including elderly patients: Aterocard should be taken 75 mg once daily, regardless of meals.
In 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, and then continued with a dose of 75 mg once daily (with 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 not recommended to exceed the dose of ASA 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 receive 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 using the combination of clopidogrel with ASA for more than 4 weeks in this condition has not been studied.
In patients with atrial fibrillation, clopidogrel should be administered at a dose of 75 mg once daily. 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.
Renal insufficiency: 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 the possibility 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 effectiveness of the drug in this age group of patients.
Overdose
Treatment. 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, TTP (see section "Special warnings and precautions for use"), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired hemophilia A, granulocytopenia, anemia.
Cardiac: Kounis syndrome (vasospastic allergic angina/allergic myocardial infarction) as a consequence of a hypersensitivity reaction to clopidogrel.
Immune system disorders: serum sickness, anaphylactoid reactions; cross-hypersensitivity between thienopyridines such as ticlopidine, prasugrel (see section "Special warnings and precautions for use").
Mental disorders: hallucinations, confusion.
Nervous system: intracranial hemorrhages (in some cases fatal), headache, paresthesia, dizziness; change in taste perception.
From the organs of vision: hemorrhage in the eye area (conjunctival, ocular, retinal).
From the side of the organs of hearing and labyrinth: vertigo.
Vascular disorders: hematoma; severe hemorrhage, bleeding from the surgical wound, vasculitis, arterial hypotension.
From the respiratory system, thoracic organs and mediastinum: epistaxis; respiratory tract bleeding (hemoptysis, pulmonary hemorrhage), 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 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), acute generalized exanthematous pustulosis, angioedema, erythematous rash, urticaria, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), erythematous or exfoliative rashes, eczema, lichen planus.
Reproductive system and breast disorders: gynecomastia.
Musculoskeletal and connective tissue disorders: musculoskeletal hemorrhages (hemarthrosis), arthritis, arthralgia, myalgia.
Renal and urinary disorders: hematuria; glomerulonephritis, increased blood creatinine levels.
General disorders and administration site conditions: injection site bleeding, fever.
Changes in laboratory test results: 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 in the original packaging at a temperature not exceeding 25 ºС.
Keep out of reach of children.
Packaging
10 tablets in a blister; 1 blister in a pack.
10 tablets in a blister; 3 blisters in a pack.
10 tablets in a blister; 4 blisters in a pack.
10 tablets in a blister; 7 blisters in a pack.
Vacation category
According to the recipe.
Producer
JSC "KYIV VITAMIN FACTORY".
Location of the manufacturer and address of its place of business
04073, Ukraine, Kyiv, Kopylivska St., 38.
Website: www.vitamin.com.ua
