Instructions Trombonet film-coated tablets 0.075 g blister No. 60
Composition
active ingredient clopidogrel;
1 tablet contains clopidogrel bisulfate (clopidogrel hydrosulfate) 97.875 mg, equivalent to clopidogrel 75 mg;
excipients: lactose monohydrate, microcrystalline cellulose (101), corn starch, hydrogenated castor oil, macrogol 6000, magnesium stearate;
shell composition: hydroxypropylmethylcellulose (5), titanium dioxide (E 171), macrogol 6000, candurin (silver glitter), red iron oxide (E 172).
Dosage form
Film-coated tablets.
Main physicochemical properties: round tablets with a biconvex surface, coated with a dark pink film coating with a pearlescent tint.
Pharmacotherapeutic group
Antithrombotic agents. ATX 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 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 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.
Pharmacogenetics. CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. 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 are responsible for the majority of alleles that impair function in patients of the Caucasian (85%) and Mongoloid (99%) races with reduced metabolism. Other alleles associated with absent or reduced metabolism are much less common. These include CYP2C19*4, *5, *6, *7 and *8. A poor metabolizer has two nonfunctional alleles, as described above. According to published data, CYP2C19 genotypes corresponding to poor metabolizers are found in 2% of Caucasians, 4% of Negroids, and 14% of Chinese. Tests are available to determine the CYP2C19 genotype.
Renal impairment: After regular administration of 75 mg of clopidogrel per day 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 almost as much as in healthy volunteers receiving 75 mg of clopidogrel per day. 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 CYP genotyping in terms of clinical outcomes.
Clinical characteristics.
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;
– 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.
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. Concomitant use of TrombonetÒ
with oral anticoagulants is not recommended, as this combination may increase the intensity of bleeding (see section "Special instructions for use"). 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 warfarin treatment, the simultaneous 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 4.4).
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 ASA 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 section 4.4). However, clopidogrel and ASA have been used together for up to 1 year.
Heparin: Concomitant use with clopidogrel did not require adjustment of the heparin dose and did not alter the effect of heparin on coagulation, 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.
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.
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 known 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 (see section 4.4).
Serotonin reuptake inhibitors (SSRIs): SSRIs have an effect on platelet activation and increase the risk of bleeding, so concomitant use of SSRIs with clopidogrel should be done with caution.
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 plasma concentration of the active metabolite of clopidogrel. 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 4.4 and 5.2). Drugs that inhibit CYP2C19 activity include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.
Proton pump inhibitors (PPIs). Omeprazole 80 mg once daily, when co-administered with clopidogrel or within 12 hours between doses of these two drugs, reduced the concentration of the active metabolite in the blood by 45% (loading dose) and 40% (maintenance dose). This decrease was accompanied by a decrease in the inhibition of platelet aggregation by 39% (loading dose) and 21% (maintenance dose). It is expected that esomeprazole will also interact in a similar way with clopidogrel.
There is conflicting evidence regarding the clinical consequences of these pharmacokinetic (PK) and pharmacodynamic (PD) interactions in terms of major cardiovascular events. As a precautionary measure, omeprazole or esomeprazole should not be used concomitantly with clopidogrel (see section 4.4).
A less pronounced decrease in metabolite concentrations in the blood was observed with pantoprazole or lansoprazole.
When co-administered with pantoprazole 80 mg once daily, 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 (except cimetidine, which is a CYP2C9 inhibitor) or antacids, affect the antiplatelet activity of clopidogrel.
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.
Carboxylic metabolites of clopidogrel may inhibit cytochrome P450 2C9 activity. This could potentially increase plasma levels of drugs such as phenytoin and tolbutamide and NSAIDs that are metabolized by cytochrome P450 2C9. However, the results of the CAPRIE study suggest that phenytoin and tolbutamide can be safely co-administered with clopidogrel.
No clinically significant adverse effects were observed when clopidogrel was used concomitantly with other drugs, including 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.
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 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 available to determine 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 CYP2C19 should be avoided (see section "Interaction with other medicinal products and other forms of interaction").
Cross-reactivity among thienopyridines. Patients should be evaluated for a history of hypersensitivity to other thienopyridines (such as ticlopidine, prasugrel) as cross-reactivity among thienopyridines has been reported. Thienopyridines may be associated with 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 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 use of the drug in patients with moderate liver disease and the possibility of hemorrhagic diathesis is limited, therefore clopidogrel should be prescribed with caution to such patients (see section "Method of administration and dosage").
Excipients: Since TrombonetÒ contains lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
TrombonetÒ contains hydrogenated castor oil, which may cause stomach upset and diarrhea.
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 it is excreted in human milk, therefore, breast-feeding should be discontinued during treatment with Trombonet.
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 and elderly patients. Trombonet® is prescribed at a dose of 75 mg once a day, regardless of meals.
In patients with acute coronary syndrome 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 trials of clopidogrel indicate that the drug should be used for up to 12 months, and the maximum effect was observed after 3 months of treatment.
In patients with acute myocardial infarction with ST-segment elevation, clopidogrel should be administered at a dose of 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 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.
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 and adolescents: Clopidogrel should not be used in children as there is no data on the effectiveness of the drug in this age group.
Children
Clopidogrel should not be used in children, as there is no data on the effectiveness of the drug in this age group.
Overdose
In case of overdose with clopidogrel, prolonged bleeding time may occur with subsequent complications. In case of bleeding, symptomatic treatment is recommended.
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
Nervous system: dizziness, headache, paresthesia, intracranial bleeding (in some cases fatal), change in taste perception.
Psychiatric disorders: hallucinations, confusion.
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: vertigo.
From the vascular system: hematoma, severe hemorrhage, bleeding from the surgical wound, vasculitis, arterial hypotension.
Respiratory, thoracic and mediastinal disorders: epistaxis, 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 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, maculopapular, erythematous or exfoliative 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.
Blood and lymphatic system disorders: 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, granulocytopenia, anemia, acquired hemophilia A.
Renal and urinary system: hematuria, glomerulonephritis, increased blood creatinine levels.
General disorders and local reactions: bleeding at the injection site, fever.
Laboratory indicators: prolonged bleeding time, decreased neutrophil and platelet counts.
Expiration date
2 years.
Do not use the drug after the expiration date indicated on the package.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
10 tablets in a blister. 1 or 3, or 6, or 8 blisters in a pack.
Vacation category
According to the recipe.
Producer
PJSC "Farmak".
Location of the manufacturer and its business address
Ukraine, 04080, Kyiv, Frunze St., 74.
