Clopidogrel-Pharmex film-coated tablets 75 mg blister No. 30

Translation of the instructions can be

Instruction

For medical use of the medicinal product

Clopidogrel-Pharmex

(Clopidogrel-pharmex)

Composition:

Active ingredient: clopidogrel;

1 tablet contains clopidogrel bisulfate equivalent to clopidogrel 75 mg;

excipients: mannitol (E 421), microcrystalline cellulose, hydroxypropylcellulose, macrogol 6000, hydrogenated castor oil, crospovidone, colloidal anhydrous silicon dioxide;

shell: Opadry II pink (hypromellose, lactose monohydrate, titanium dioxide (E 171), triacetin, iron oxide red (E 172)).

Dosage form.

The pills are coated.

Main physicochemical properties: round tablets with a biconvex surface, covered with a pink shell.

Pharmacotherapeutic group.

Platelet aggregation inhibitors, except heparin.

PBX 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. 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. Thus, platelets that interact 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 use of the drug in repeated daily doses of 75 mg, a significant slowdown in ADP-induced platelet aggregation is detected. This effect progressively increases and stabilizes between the 3rd and 7th days. In a stable state, the average level of inhibition of aggregation under the influence of a daily dose of 75 mg is 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 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 after 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) metabolite circulating in the blood is 8 hours after single and multiple administration of the drug.

Pharmacogenetics.

Clopidogrel is known to be activated by several polymorphic CYP450 enzymes. 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 metabolizer, while the CYP2C19*2 and CYP2C19*3 alleles correspond to a non-functional metabolizer. 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 impaired metabolism are much less common. These include CYP2C19 *4, *5, *6, *7, and *8, but they are much less common in the population.

Renal impairment. After regular administration of 75 mg of clopidogrel per day in 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: Following regular dosing 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 increase in 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 (see Pharmacogenetics). There are limited data in patients of Mongoloid race to assess the clinical relevance of genotyping this CYP.

Clinical characteristics.

Indication.

Prevention of atherothrombosis in adults:

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 drugs 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 simultaneous use of such medicinal products with clopidogrel requires caution (see section "Special warnings and precautions for use").

Oral anticoagulants. The simultaneous use of Clopidogrel-Pharmex 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 warfarin treatment, the simultaneous use of clopidogrel and warfarin increases the risk of bleeding due to the existence of independent effects on hemostasis.

Glycoprotein IIb/IIIa receptor 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 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). However, clopidogrel and ASA can be used together for up to 1 year (see section 5.1).

Heparin: There is evidence that clopidogrel did not require adjustment of the heparin dose and did not alter the effect of heparin on coagulation. Concomitant use of heparin altered the inhibitory effect of clopidogrel on platelet aggregation. Since a pharmacodynamic interaction between clopidogrel and heparin is possible, with an increased risk of bleeding, caution should be exercised when these drugs are used concomitantly.

Nonsteroidal anti-inflammatory drugs (NSAIDs). Concomitant use of clopidogrel and naproxen increases the incidence of 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 (see section 4.4).

Selective serotonin reuptake inhibitors (SSRIs): Caution should be exercised when SSRIs are used concomitantly with clopidogrel because 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 plasma, as well as to a decrease in clinical efficacy. Concomitant use of drugs that inhibit the activity of CYP2C19 should be avoided.

Drugs that preferentially induce CYP2C19 activity include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, and efavirenz.

Proton pump inhibitors (PPIs). Omeprazole 80 mg once daily, when administered concomitantly with clopidogrel or within 12 hours of each other, reduced the concentration of the active metabolite in the blood by 45% (loading dose) and 40% (maintenance dose). This reduction was accompanied by a reduction in inhibition of platelet aggregation by 39% (loading dose) and 21% (maintenance dose). It is expected that the interaction of esomeprazole with clopidogrel is similar.

Observational and clinical studies have provided conflicting evidence on 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.

A less pronounced decrease in the concentration of the metabolite in the blood was observed when using 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 (except cimetidine, which is a CYP2C19 inhibitor) or antacids, affect the antiplatelet activity of clopidogrel.

Combination with other drugs. No clinically significant pharmacodynamic interaction was observed when clopidogrel was administered concomitantly with atenolol, nifedipine, or both drugs. In addition, the pharmacodynamic activity of clopidogrel remained virtually unchanged when phenobarbital, cimetidine, or estrogens were administered concomitantly.

The pharmacokinetics of digoxin and theophylline are not altered by co-administration of clopidogrel. Antacids do not affect the extent of clopidogrel absorption.

Carboxylic metabolites of clopidogrel may inhibit cytochrome P4502C9 activity. This could potentially lead to increased plasma levels of drugs such as phenytoin and tolbutamide, and NSAIDs that are metabolized by P4502C9. Phenytoin and tolbutamide can be safely administered 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 this increase in repaglinide exposure is due to inhibition of the CYP2C8 enzyme by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant use of clopidogrel and medicinal products that are predominantly metabolised by the CYP2C8 enzyme (such as repaglinide, paclitaxel) requires caution (see section 4.4).

Except for the specific drug interaction information provided above, no studies have been conducted on the interaction of clopidogrel with drugs commonly prescribed for patients with atherothrombosis. However, no clinically significant adverse reactions have been observed in patients receiving concomitant medications, including diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, cholesterol-lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, hormone replacement therapy, and GPIIb/IIIa antagonists.

Bleeding and haematological disorders. Due to the risk of bleeding and haematological adverse reactions, a complete blood count and/or other appropriate tests should be performed immediately if symptoms suggestive of possible 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 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 in 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 "Interaction with other medicinal products and other types of interactions").

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 doctor (including dentists) that they are taking clopidogrel before any surgery is prescribed to them or before using a new drug. Clopidogrel prolongs bleeding time, so it should be used with caution in patients with an 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 haemolytic anaemia with neurological manifestations, renal dysfunction or fever. TTP is a potentially fatal condition and therefore requires immediate treatment, including plasmapheresis.

Acquired hemophilia. Cases of acquired hemophilia have been reported following the use of clopidogrel. In cases of confirmed isolated increases in aPTT (activated partial thromboplastin time), with or without bleeding, the diagnosis of acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated, and clopidogrel should be discontinued.

Recent ischemic stroke: Due to insufficient data, clopidogrel is not recommended for use within 7 days of acute ischemic stroke.

Cytochrome P450 2C19 (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 detect the CYP2C19 genotype of a 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 types of interactions"; a list of CYP2C19 inhibitors is given in the section "Pharmacokinetics").

Cross-reactivity between thienopyridines. Patients should be checked for a history of hypersensitivity to other thienopyridines (such as ticlopidine, prasugrel), as there is evidence of cross-allergy between thienopyridines (see section "Adverse reactions"). The use of thienopyridines can lead to the occurrence of mild to severe allergic reactions, such as rash, angioedema, or haematological reactions, such as thrombocytopenia and neutropenia. Patients who have had 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.

Renal impairment: 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").

Hepatic impairment: Experience in patients with moderate liver disease and risk of bleeding diathesis is limited, therefore clopidogrel should be administered with caution to such patients (see section "Method of administration and dosage").

Clopidogrel-Pharmex contains hydrogenated castor oil, which may cause stomach upset and diarrhea.

Special precautions for the disposal of unused medicinal product or waste materials: Any unused medicinal product or waste materials should be disposed of in accordance with local requirements.

Use during pregnancy or breastfeeding.

Since there are no clinical data on the use of clopidogrel during pregnancy, it is undesirable to prescribe clopidogrel to pregnant women.

Animal studies have not revealed direct or indirect negative effects on the course of pregnancy, embryonal/fetal development, parturition and postnatal development.

It is not known whether clopidogrel is excreted in human milk. Animal studies have shown that the drug passes into breast milk. Therefore, breastfeeding should be discontinued during treatment with Clopidogrel-Pharmex.

The ability to influence the 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: clopidogrel should be taken at a dose of 75 mg once daily, regardless of meals.

For patients with acute coronary syndrome without ST segment elevation (unstable angina or non-Q wave myocardial infarction on the ECG), treatment with clopidogrel should be started with a single loading dose of 300 mg, and then continued with a dose of 75 mg 1 time per day (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. There is evidence 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 over 75 years of age should be started without a loading dose of clopidogrel. Combination therapy should be started as early as possible after the onset of symptoms and continued for at least 4 weeks. The benefit of using the combination of clopidogrel with ASA for more than four weeks in this disease has not been studied.

In patients with atrial fibrillation, clopidogrel should be administered in a single daily dose of 75 mg. Along with clopidogrel, ASA (75-100 mg per day) should be initiated and continued.

If you miss a dose:

Children and adolescents: The safety and efficacy of the drug in children and adolescents have not been established.

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.

The safety and effectiveness of the drug in children have not been established, so it should not be used in patients under 18 years of age.

Overdose.

In case of overdose with clopidogrel, prolonged bleeding time may be observed with subsequent complications. In case of bleeding, symptomatic treatment is recommended.

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.

Adverse reactions are classified according to the system organ class, their frequency of occurrence is determined as follows: common (from 1/100 to 1/1000 to 1/10000 to

Bleeding is the most common adverse reaction, most often occurring in the first month of treatment.

From the blood and lymphatic system.

Uncommon: Thrombocytopenia, leukopenia, eosinophilia.

Rare: Neutropenia, including severe neutropenia.

Very rare, frequency unknown *. Thrombotic thrombocytopenic purpura (TTP) (see section "Special warnings and precautions for use"), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired hemophilia A, granulocytopenia, anemia.

From the heart.

Very rare, frequency unknown *. Kounis syndrome (vasospastic allergic angina / allergic myocardial infarction) as a consequence of a hypersensitivity reaction to clopidogrel *.

From the immune system.

Very rare, frequency unknown *. Serum sickness, anaphylactoid reactions, cross-hypersensitivity between thienopyridines (such as ticlopidine, prasugrel) (see section "Special warnings and precautions for use") *.

Mental disorders.

Very rare, frequency unknown *. Hallucinations, confusion.

From the nervous system.

Uncommon: Intracranial bleeding (in some cases fatal), headache, paresthesia, dizziness.

Very rare, frequency unknown *. Change in taste perception.

Uncommon: Hemorrhage into the eye area (conjunctival, ocular, retinal).

From the side of the organs of hearing and labyrinth.

Rare: Vertigo.

From the side of the vessels.

Often. Hematoma.

Very rare, frequency unknown *. Severe hemorrhage, bleeding from the surgical wound, vasculitis, arterial hypotension.

On the part of the respiratory system, chest organs and mediastinum.

Often. Nosebleed.

Very rare, frequency unknown *. Respiratory tract bleeding (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.

From the gastrointestinal tract.

Common: Gastrointestinal bleeding, diarrhea, abdominal pain, dyspepsia.

Uncommon: Gastric and duodenal ulcers, gastritis, vomiting, nausea, constipation, flatulence.

Rare: Retroperitoneal hemorrhage.

Very rare, frequency unknown *. Gastrointestinal and retroperitoneal bleeding with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic), stomatitis.

On the part of the hepatobiliary system.

Very rare, frequency unknown *. Acute hepatic failure, hepatitis, abnormal liver function tests.

On the skin and subcutaneous tissue.

Common: Subcutaneous hemorrhages.

Uncommon: Rash, itching, intradermal hemorrhages (purpura).

Very rare, frequency unknown *. 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.

Disorders of the reproductive system and mammary glands.

Rare: gynecomastia

Musculoskeletal and connective tissue disorders.

Very rare, frequency unknown *. Musculoskeletal hemorrhages (haemarthrosis), arthritis, arthralgia, myalgia.

On the part of the kidneys and urinary tract.

Uncommon: Hematuria.

Very rare, frequency unknown *. Glomerulonephritis, increased blood creatinine.

General violations.

Common: Bleeding at the injection site.

Very rare, frequency unknown *. Fever.

Changes in laboratory test results.

Uncommon: 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. This allows for continuous monitoring of the benefit/risk ratio of the use of this medicinal product. Healthcare professionals are asked to report all suspected adverse reactions.

* - information with a frequency of "frequency unknown".

Expiration date.

2 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 ° C. Keep out of the reach of children.

Packaging.

10 tablets in a blister; 1 or 3 blisters in a cardboard pack.

Vacation category.

According to the recipe.

Producer.

LLC "Pharmex group".

Location of production and its address of place of business.

Ukraine, 08301, Kyiv region, Boryspil city, Shevchenko street, building 100.