Atorocard

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATEROCARD (ATEROCARD)

Composition:

Active substance: clopidogrel;

1 tablet contains 75 mg of clopidogrel;

Excipients: microcrystalline cellulose; lactose monohydrate; pregelatinized starch; povidone; polyethylene glycol 6000; magnesium stearate;

Coating: film-coating mixture Opadry II Pink (aluminum lakes of brilliant red (E 129) and indigo carmine (E 132); hypromellose (hydroxypropylmethylcellulose); lactose monohydrate; triacetin; polyethylene glycol; titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex tablets with a pink film coating.

Pharmacotherapeutic group. Antithrombotic agents. Antiaggregants.

ATC code B01AC04.

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 ADP-mediated activation of the GPIIb/IIIa complex, thereby suppressing platelet aggregation. A biotransformation of clopidogrel is required to generate active inhibition of platelet aggregation. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the amplification of platelet activation caused by released ADP. Clopidogrel irreversibly modifies platelet ADP receptors. Therefore, platelets exposed to clopidogrel are affected for the duration of their life cycle. Normal platelet function gradually returns at a rate consistent with platelet turnover.

Pharmacodynamic effects. With repeated daily doses of 75 mg, a significant reduction in ADP-induced platelet aggregation is observed from the first day of treatment. This effect progressively increases and stabilizes between days 3 and 7. At steady state, the average level of inhibition of aggregation with a daily dose of 75 mg ranges from 40 to 60%. Platelet aggregation and bleeding time return to baseline values on average within 5 days after discontinuation of therapy.

Pharmacokinetics.

Absorption. After oral administration of single and multiple daily doses of 75 mg, clopidogrel is rapidly absorbed. The mean peak plasma concentration of unchanged clopidogrel (approximately 2.2–2.5 ng/mL after a single 75 mg oral dose) is reached about 45 minutes after administration. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Distribution. Clopidogrel and the main circulating (inactive) metabolite are reversibly bound to human plasma proteins in vitro (98% and 94%, respectively). This binding remains non-saturable in vitro over a wide concentration range.

Metabolism. Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, two major metabolic pathways exist: one involving esterases leading to hydrolysis and formation of an inactive carboxylic acid derivative (which accounts for 85% of all circulating metabolites in plasma), and another involving the cytochrome P450 enzyme system. Initially, clopidogrel is converted into an intermediate metabolite, 2-oxo-clopidogrel. Further metabolism of 2-oxo-clopidogrel leads to the formation of a thiol derivative – the active metabolite. This active metabolite is formed predominantly by the CYP2C19 enzyme, with contributions from several other CYP enzymes such as CYP1A2, CYP2B6, and CYP3A4. The active metabolite of clopidogrel (thiol derivative), isolated in vitro, rapidly and irreversibly binds to platelet receptors, thereby preventing platelet aggregation.

Elimination. Within 120 hours after administration of radiolabeled 14C-clopidogrel in humans, approximately 50% of the dose was excreted in urine and about 46% in 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 both single and repeated dosing.

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 antiplatelet effects, as measured by ex vivo platelet aggregation, vary depending on the CYP2C19 genotype.

The CYP2C19*1 allele corresponds to fully functional metabolism, whereas the CYP2C19*2 and CYP2C19*3 alleles correspond to non-functional metabolism. CYP2C19*2 and CYP2C19*3 alleles constitute the majority of alleles in Caucasian (85%) and Mongoloid (99%) patients with reduced metabolism.

Other alleles associated with absent or reduced metabolism occur less frequently, including CYP2C19*4, *5, *6, *7, and *8. A patient with reduced metabolism has two non-functional alleles as specified above. According to published data, CYP2C19 genotypes associated with reduced metabolism occur in 2% of Caucasian populations, 4% of Black patients, and 14% of Chinese patients. Tests are currently available to determine CYP2C19 genotype.

Special patient populations. The pharmacokinetics of the active metabolite of clopidogrel have not been studied in the special patient populations listed below.

Renal impairment. With repeated daily dosing of 75 mg clopidogrel in patients with severe renal impairment (creatinine clearance 5–15 mL/min), inhibition of ADP-induced platelet aggregation was less pronounced (25%) compared to healthy volunteers, while the prolongation of bleeding time was nearly the same as in healthy volunteers receiving 75 mg clopidogrel daily. Clinical tolerability was good in all patients.

Hepatic impairment. With repeated daily dosing of 75 mg clopidogrel for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy volunteers. The mean prolongation of bleeding time was also similar in both groups.

Racial considerations. The prevalence of CYP2C19 alleles associated with intermediate and poor metabolic activity varies by race/ethnicity. Limited data are available in Mongoloid patients to assess the clinical significance of genotyping for this CYP.

Clinical characteristics.

Indications.

Secondary prevention of atherothrombotic events in adults:

• in patients who have had myocardial infarction (treatment initiation – within a few days, but no later than 35 days after onset), ischemic stroke (treatment initiation – after 7 days, but no later than 6 months after onset), or diagnosed peripheral arterial disease (arterial disease and atherothrombosis of lower limb vessels);
• in patients with acute coronary syndrome:

− with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), including patients who have undergone percutaneous coronary intervention with stent placement, in combination with acetylsalicylic acid (ASA);

− with acute myocardial infarction with ST-segment elevation, in combination with ASA (in patients receiving standard medical therapy 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, in whom vitamin K antagonist (VKA) therapy is contraindicated and who have a low risk of bleeding, for the prevention of atherothrombotic and thromboembolic events, including stroke.

Contraindications.

Hypersensitivity to the active substance or to any component of the medicinal product. Severe hepatic impairment. Active bleeding (e.g., peptic ulcer or intracranial hemorrhage).

Interaction with other medicinal products and other forms of interaction.

Medicinal products associated with increased risk of bleeding. Due to potential additive effects, the risk of hemorrhagic complications is increased; therefore, concomitant use of such medicinal products with clopidogrel requires caution. Oral anticoagulants. Concomitant use of clopidogrel with oral anticoagulants is not recommended, as this combination may increase the severity of bleeding (see section "Special precautions for use"). Although administration of clopidogrel at a dose of 75 mg once daily does not alter the pharmacokinetic profile of S-warfarin or the international normalized ratio (INR) in patients on long-term warfarin therapy, concomitant use of clopidogrel and warfarin increases the risk of bleeding due to their independent effects on hemostasis.

Glycoprotein IIb/IIIa inhibitors. Aterocard should be used with caution in patients receiving glycoprotein IIb/IIIa inhibitors (see section "Special precautions for use").

ASA. Acetylsalicylic acid does not affect the inhibitory action of clopidogrel on ADP-induced platelet aggregation, whereas clopidogrel enhances 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 bleeding time prolonged by clopidogrel. Since a pharmacodynamic interaction between clopidogrel and ASA with an increased risk of bleeding is possible, concomitant use of these agents requires caution (see section "Special precautions for use"). Nevertheless, clopidogrel and ASA have been used concomitantly for up to 1 year.

Heparin. Clinical study data indicate that clopidogrel does not require heparin dose adjustment and does not alter heparin's effect on coagulation. Concomitant administration of heparin did not change the inhibitory effect of clopidogrel on platelet aggregation. Since a pharmacodynamic interaction between clopidogrel and heparin, increasing the risk of bleeding, is possible, concomitant use of these agents requires caution.

Thrombolytic agents. The safety of concomitant use of clopidogrel with fibrin-specific or non-fibrin-specific thrombolytic agents and heparins was evaluated 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.

Non-steroidal anti-inflammatory drugs (NSAIDs). Concomitant use of clopidogrel and naproxen increased the number of occult gastrointestinal bleeding episodes. However, due to the lack of interaction studies with other NSAIDs, it is not yet established whether the risk of gastrointestinal bleeding increases with all NSAIDs. Therefore, caution is required when using NSAIDs, particularly COX-2 inhibitors, concomitantly with clopidogrel.

Selective serotonin reuptake inhibitors (SSRIs). Concomitant use of SSRIs with clopidogrel should be done with caution, as SSRIs affect platelet activation and increase the risk of bleeding.

Concomitant use with other drugs. Since clopidogrel is partially converted into its active metabolite by CYP2C19, concomitant use of drugs that reduce the activity of this enzyme will most likely result in decreased plasma concentrations of the active metabolite of clopidogrel. The clinical significance of this interaction is not established. Therefore, as a precaution, concomitant use of strong and moderate CYP2C19 inhibitors 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 administered concomitantly with clopidogrel or within 12 hours of dosing of either drug, reduced plasma concentrations of the active metabolite by 45% (loading dose) and by 40% (maintenance dose). This reduction was associated with a 39% decrease in platelet aggregation inhibition (loading dose) and a 21% decrease (maintenance dose). A similar interaction with clopidogrel is expected with esomeprazole.

Observational and clinical trial data on the clinical consequences of these pharmacokinetic and pharmacodynamic interactions in terms of major cardiovascular events have been conflicting. As a precaution, omeprazole or esomeprazole should not be used concomitantly with clopidogrel.

A less pronounced reduction in metabolite concentration was observed with pantoprazole or lansoprazole.

When pantoprazole 80 mg once daily was administered concomitantly, plasma concentrations of the active metabolite decreased by 20% (loading dose) and 14% (maintenance dose). This reduction was associated with a mean decrease in platelet aggregation inhibition of 15% and 11%, respectively. These results suggest that concomitant use of clopidogrel and pantoprazole is possible.

There is no evidence that other medicinal products that reduce gastric acid secretion, such as H2-receptor antagonists or antacids, affect the antiplatelet activity of clopidogrel.

Combinations with other medicinal products. Clinical studies have been conducted with clopidogrel and other drugs to evaluate potential pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interaction was observed when clopidogrel was administered concomitantly with atenolol, nifedipine, or both. Furthermore, the pharmacodynamic activity of clopidogrel remained nearly unchanged when administered concomitantly with phenobarbital and estrogen.

The pharmacokinetic properties of digoxin or theophylline were not altered when administered concomitantly with clopidogrel.

Antacid agents did not affect the absorption of clopidogrel.

It is known that data from human liver microsome studies indicate that carboxylic acid metabolites of clopidogrel may inhibit CYP2C9 enzyme activity. This could potentially increase plasma levels of medicinal products such as phenytoin, tolbutamide, and NSAIDs, which are metabolized by CYP2C9. Despite this, study results indicate that phenytoin and tolbutamide can be safely used concomitantly with clopidogrel.

Drugs that are substrates of the CYP2C8 enzyme. Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies demonstrated that increased 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 with medicinal products primarily eliminated via CYP2C8-mediated metabolism (such as repaglinide, paclitaxel) requires caution.

Except for the information on interactions with specific medicinal products mentioned above, interaction studies between clopidogrel and drugs commonly prescribed to patients with atherothrombosis have not been conducted. However, patients participating in clinical trials with clopidogrel were concomitantly using other medications, 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, without signs of clinically significant adverse reactions.

Antiretroviral therapy (ART). Reduced effect of the active metabolite of clopidogrel and reduced platelet inhibition have been observed in HIV-infected patients receiving ritonavir- or cobicistat-boosted antiretroviral therapy (ART). Although the clinical significance of these findings is uncertain, spontaneous reports have been received of HIV-infected patients receiving boosted ART who experienced recurrent occlusive events after revascularization or thrombotic events during clopidogrel treatment. The effect of clopidogrel and mean platelet inhibition may be reduced when coadministered with ritonavir.

Special precautions for use.

Bleeding and hematological disorders. Due to the risk of bleeding and hematological adverse reactions, a complete blood count and/or other appropriate tests should be performed immediately if symptoms suggesting possible bleeding occur during treatment with the drug (see section "Adverse reactions"). As with other antiplatelet agents, clopidogrel should be used with caution in patients with an increased risk of bleeding due to trauma, surgical procedures, or other pathological conditions, and also when patients are receiving acetylsalicylic acid (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 hemorrhagic events (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be closely monitored for signs of bleeding, including occult bleeding, particularly during the first weeks of treatment and/or after invasive cardiac procedures or surgery. Concomitant use of clopidogrel with oral anticoagulants is not recommended, as this may increase the intensity of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

In case of planned surgical intervention, when the antiplatelet effect is temporarily undesirable, clopidogrel treatment should be discontinued 7 days prior to surgery. Patients should inform their physician (including dentist) that they are taking clopidogrel before any surgical procedure or before starting another medicinal product. Clopidogrel prolongs bleeding time; therefore, it should be used with caution in patients with an increased risk of bleeding (particularly gastrointestinal and intraocular bleeding).

Patients should be informed that during treatment with clopidogrel (alone or in combination with ASA), bleeding may stop later than usual, and that they should report any episodes of unusual bleeding (in location or duration) to their physician.

Thrombotic thrombocytopenic purpura (TTP). Cases of TTP have been reported very rarely following clopidogrel use, sometimes even after short-term treatment. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological symptoms, renal dysfunction, or fever. TTP is a potentially life-threatening condition that may lead to death and therefore requires immediate treatment, including plasma exchange.

Acquired hemophilia. Cases of acquired hemophilia have been reported following clopidogrel use. In the presence of a confirmed isolated prolongation of activated partial thromboplastin time (aPTT), with or without bleeding, the diagnosis of acquired hemophilia should be considered. Patients with confirmed diagnosis of acquired hemophilia should be under medical supervision and receive appropriate treatment; clopidogrel should be discontinued in such patients.

Recent ischemic stroke. Due to insufficient data, clopidogrel is not recommended within the first 7 days after 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 when receiving the recommended doses of clopidogrel.

Since clopidogrel is partially converted to its active metabolite by CYP2C19, concomitant use of drugs that reduce the activity of this enzyme will most likely lead to reduced plasma concentrations of the active metabolite of clopidogrel. However, the clinical significance of this interaction has not been established. Therefore, as a precautionary measure, concomitant use of strong and moderate inhibitors of CYP2C19 should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Substrates of the CYP2C8 enzyme. Caution is required in patients receiving clopidogrel concomitantly with medicinal products that are substrates of the CYP2C8 enzyme.

Cross-sensitivity to thienopyridines. Patients should be screened for history of hypersensitivity to other thienopyridines (such as clopidogrel, ticlopidine, prasugrel), as cases of cross-hypersensitivity to thienopyridines have been reported. Use of thienopyridines may lead to allergic reactions ranging from mild to severe, such as rash, Quincke's edema, or hematological reactions such as thrombocytopenia and neutropenia. Patients with a history of allergic and/or hematological reactions to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for signs of hypersensitivity is recommended in patients with known allergy to thienopyridines.

Renal function impairment. Experience with clopidogrel use in patients with renal impairment is limited; therefore, the drug should be administered with caution in such patients (see section "Dosage and administration").

Hepatic function impairment. Experience with use of the drug in patients with moderate liver disease and potential for hemorrhagic diathesis is limited; therefore, clopidogrel should be used with caution in these patients (see section "Dosage and administration").

Excipients. The medicinal product contains lactose. This product should not be administered to patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Special precautions for disposal of unused medicine and waste. Unused medicine or waste should be disposed of in accordance with local requirements.

Use during pregnancy or breastfeeding.

Pregnancy. Due to the lack of clinical data on clopidogrel use during pregnancy, the drug should not be administered to pregnant women (precautionary measure).

Animal studies did not reveal any direct or indirect adverse effects on pregnancy, embryonic/fetal development, parturition, or postnatal development.

Breastfeeding period. It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion in milk; therefore, breastfeeding should be discontinued during treatment with this drug.

Fertility. No adverse effects of clopidogrel on fertility were observed in studies conducted in laboratory animals.

Ability to affect reaction speed when driving or operating machinery.

Clopidogrel has no effect or has a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

Adults, including elderly patients: Aterocard should be taken once daily at a dose of 75 mg, regardless of food intake.

In patients with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), clopidogrel therapy should be initiated with a single loading dose of 300 mg, followed by a maintenance dose of 75 mg once daily (in combination with aspirin at a dose of 75–325 mg per day). Since higher aspirin doses increase the risk of bleeding, aspirin doses exceeding 100 mg are not recommended. The optimal duration of treatment has not been formally established. Clinical trial data support treatment for up to 12 months, with maximum benefit observed after 3 months of therapy.

In patients with acute ST-segment elevation myocardial infarction, clopidogrel should be administered at a dose of 75 mg once daily, starting with a single 300 mg loading dose in combination with aspirin, with or without thrombolytic agents. In patients aged 75 years and older, treatment should be initiated without a clopidogrel loading dose. Combination therapy should be started as early as possible after symptom onset and continued for at least 4 weeks. The benefit of using clopidogrel in combination with aspirin beyond 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. Aspirin (at a dose of 75–100 mg per day) should be initiated and continued concomitantly with clopidogrel.

In case of a missed dose:

• If less than 12 hours have passed since the missed 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 should not double the dose to compensate for the missed dose.

Renal impairment: Therapeutic experience with the use of the drug in patients with renal impairment is limited (see section "Special Instructions").

Hepatic impairment: Therapeutic experience with the use of the drug in patients with moderate liver disease and potential risk of hemorrhagic diathesis is limited (see section "Special Instructions").

Children:
Clopidogrel should not be used in children, as there is no data on efficacy of the drug in this age group.

Overdose

Overdose of clopidogrel may result in prolonged bleeding time with subsequent complications. In case of bleeding, symptomatic treatment is recommended.

Treatment: There is no known antidote for the pharmacological activity of clopidogrel. If immediate correction of prolonged bleeding time is required, the effect of clopidogrel may be reversed by platelet transfusion.

Adverse Reactions

Blood and lymphatic system disorders: thrombocytopenia, leukopenia, 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 disorders: Kounis syndrome (vasospastic allergic angina/allergic myocardial infarction) as a result of hypersensitivity reaction to clopidogrel.

Immune system disorders: serum sickness, anaphylactoid reactions; cross hypersensitivity among thienopyridines such as ticlopidine, prasugrel (see section "Special Warnings and Precautions for Use").

Psychiatric disorders: hallucinations, confusion.

Nervous system disorders: intracranial bleeding (in some cases with fatal outcome), headache, paresthesia, dizziness; taste disturbance.

Eye disorders: ocular hemorrhage (conjunctival, ocular, retinal).

Ear and labyrinth disorders: vertigo.

Vascular disorders: hematoma; severe hemorrhage, bleeding from surgical wound, vasculitis, arterial hypotension.

Respiratory, thoracic and mediastinal disorders: epistaxis; respiratory tract hemorrhage (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonia, eosinophilic pneumonia.

Gastrointestinal disorders: gastrointestinal bleeding, diarrhea, abdominal pain, dyspepsia; gastric and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence; retroperitoneal hemorrhage; gastrointestinal and retroperitoneal hemorrhages with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis.

Hepatobiliary disorders: acute liver failure, hepatitis, abnormal liver function test results.

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, angioneurotic edema, erythematous rash, urticaria, drug hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), erythematous or exfoliative rash, 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: bleeding at injection site, fever.

Laboratory test abnormalities: prolonged bleeding time, decreased neutrophil and platelet counts.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting systems.

**Shelf life. **3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 1 blister in a carton.

10 tablets in a blister; 3 blisters in a carton.

10 tablets in a blister; 4 blisters in a carton.

10 tablets in a blister; 7 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and place of business.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua