Clopidogrel

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

Composition:

Active substance: clopidogrel;

One tablet contains clopidogrel bisulfate (clopidogrel hydrogen sulfate), equivalent to 75 mg of clopidogrel;

Excipients: lactose monohydrate; corn starch; microcrystalline cellulose (E 460); macrogol (polyethylene glycol 1500) (E 1521); sodium croscarmellose; calcium stearate; Opadry II Pink, containing hypromellose, lactose monohydrate, titanium dioxide (E 171), triacetin, iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex film-coated tablets of pink color.

Pharmacotherapeutic group. Antithrombotic agents. Inhibitors of platelet aggregation except heparin. 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 produce 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 remainder of their lifespan. Normal platelet function gradually recovers 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 repeated 75 mg daily doses, 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 dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Distribution. Clopidogrel and its main circulating (inactive) 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, two major metabolic pathways exist: one involves esterases leading to hydrolysis and formation of an inactive carboxylic acid derivative (which accounts for 85% of all circulating metabolites in plasma), and the other involves 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. In vitro, this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2, and CYP2B6 enzymes. 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 oral administration of radiolabeled 14C-clopidogrel in humans, approximately 50% of the dose was excreted in urine and about 46% in feces. After oral administration of a single 75 mg dose, 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 multiple doses.

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. The 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 are less common and include 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 individuals, 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. Data are available showing that after regular administration of 75 mg clopidogrel daily 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. Data are available showing that 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 observed in healthy volunteers. The mean prolongation of bleeding time was also similar in both groups.

Racial factors. The prevalence of CYP2C19 alleles associated with intermediate and poor metabolic activity varies according to racial/ethnic background (see section "Pharmacogenetics"). Limited data are available in Mongoloid patients to assess the clinical significance of genotyping this CYP from the standpoint of clinical outcomes.

When therapeutic doses of clopidogrel are administered to humans, no effect on liver metabolism enzymes has been observed. The drug does not exhibit carcinogenic, genotoxic, or teratogenic effects, nor does it affect reproductive function.

Clinical characteristics.

Indications.

Secondary prevention of atherothrombotic events in adults:

• patients who have had myocardial infarction (treatment initiation – within a few days, but no later than 35 days after onset), ischaemic stroke (treatment initiation – within 7 days, but no later than 6 months after onset), or diagnosed peripheral arterial disease (peripheral arterial disease and atherothrombosis of lower limb vessels);
• patients with acute coronary syndrome:
  • acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), including patients who underwent percutaneous coronary intervention with stent placement, in combination with acetylsalicylic acid (ASA);
  • acute myocardial infarction with ST-segment elevation, in combination with acetylsalicylic acid (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 antagonists (VKA) are contraindicated and who have a low risk of bleeding, for the prevention of atherothrombotic and thromboembolic events, including stroke.

For additional information, see section "Pharmacological properties".

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 haemorrhage).

Interaction with other medicinal products and other forms of interaction.

MEDICINAL PRODUCTS ASSOCIATED WITH INCREASED RISK OF BLEEDING. Due to the potential additive effect, there is an increased risk of haemorrhagic complications; therefore, concomitant use of such medicinal products with clopidogrel requires caution (see section "Special warnings and precautions for use").

ORAL ANTICOAGULANTS. Concomitant use of clopidogrel with oral anticoagulants is not recommended, as this combination may increase the risk and severity of bleeding (see section "Special warnings and precautions for use"). Although administration of clopidogrel 75 mg once daily does not alter the pharmacokinetic profile of S-warfarin or the international normalized ratio (INR) in patients receiving long-term warfarin therapy, concomitant use of clopidogrel and warfarin increases the risk of bleeding due to their independent effects on haemostasis.

GLYCOPROTEIN IIb/IIIa INHIBITORS. Clopidogrel should be used with caution in patients receiving glycoprotein IIb/IIIa inhibitors (see section "Special warnings and precautions for use").

ACETYLSALICYLIC ACID (ASA). Acetylsalicylic acid does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but 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 the prolonged bleeding time caused by clopidogrel. Since a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid with an increased risk of bleeding is possible, concomitant use of these agents requires caution (see section "Special warnings and precautions for use"). Despite this, clopidogrel and ASA have been co-administered for up to one year in clinical trials.

HEPARIN. Clinical data from a study in healthy volunteers indicate that clopidogrel does not require dose adjustment of heparin and does not alter heparin's effect on coagulation. Concomitant administration of heparin did not affect the inhibitory effect of clopidogrel on platelet aggregation. However, since a pharmacodynamic interaction between clopidogrel and heparin with an increased risk of bleeding is possible, concomitant use of these agents requires caution.

THROMBOLYTIC AGENTS. Data are available on the safety of concomitant use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic agents, and heparin 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 (see section "Undesirable effects").

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs). Clinical data from a study in healthy volunteers show that concomitant use of clopidogrel and naproxen increases 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 cyclooxygenase-2 (COX-2) inhibitors, concomitantly with clopidogrel (see section "Special warnings and precautions for use").

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 OF OTHER DRUGS. Since clopidogrel is partially converted to its active metabolite via CYP2C19, concomitant use of drugs that reduce the activity of this enzyme is likely to decrease plasma concentrations of the active metabolite of clopidogrel. The clinical significance of this interaction is not fully established. Therefore, as a precautionary measure, concomitant use of strong and moderate CYP2C19 inhibitors should be avoided (see section "Special warnings and precautions for use").

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 between doses of these two drugs, reduced plasma concentrations of the active metabolite by 45% (loading dose) and 40% (maintenance dose). This reduction was associated with a decrease in platelet aggregation inhibition by 39% (loading dose) and 21% (maintenance dose). A similar interaction with clopidogrel is expected with esomeprazole.

Observational and clinical trial data on the clinical consequences of these pharmacokinetic (PK) and pharmacodynamic (PD) interactions in terms of major cardiovascular events are conflicting. As a precautionary measure, omeprazole or esomeprazole should not be used concomitantly with clopidogrel (see section "Special warnings and precautions for use").

A less pronounced reduction in metabolite concentrations in blood was observed with 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 reduction was associated with a decrease in mean platelet aggregation inhibition by 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 production, such as H2-receptor antagonists or antacids, affect the antiplatelet activity of clopidogrel.

COMBINATION WITH OTHER MEDICINAL PRODUCTS. Data from several clinical studies with clopidogrel and other drugs have been conducted to investigate 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 essentially unchanged when administered concomitantly with phenobarbital and estrogen.

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

ANTACIDS did not affect the absorption of clopidogrel.

Data from human liver microsome studies indicate that clopidogrel carboxylic acid metabolites may inhibit the activity of cytochrome P450 2C9. This may potentially increase plasma levels of drugs such as phenytoin, tolbutamide, and NSAIDs, which are metabolized by cytochrome P450 2C9. Nevertheless, data indicate that phenytoin and tolbutamide can be safely co-administered with clopidogrel.

MEDICINAL PRODUCTS THAT ARE SUBSTRATES OF THE CYP2C8 ENZYME. Clopidogrel has been shown to increase exposure to repaglinide in healthy volunteers. In vitro studies have demonstrated that this increased exposure to repaglinide 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 with medicinal products that are primarily eliminated via CYP2C8-mediated metabolism (such as repaglinide, paclitaxel) requires caution (see section "Special warnings and precautions for use").

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 clopidogrel clinical trials were concurrently 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 effects.

In HIV-infected patients receiving ritonavir- or cobicistat-boosted antiretroviral therapy (ART), a significant reduction in the effect of the active metabolite of clopidogrel and reduced platelet inhibition has been demonstrated. Although the clinical significance of these findings is uncertain, spontaneous reports of recurrent occlusive events after revascularization or thrombotic events in HIV-infected patients receiving boosted ART during clopidogrel treatment have been reported. The effect of clopidogrel and mean platelet inhibition may be reduced when administered concomitantly with ritonavir. Therefore, concomitant use of clopidogrel and boosted ART is not recommended.

Special precautions.

Bleeding and hematological disorders. Due to the risk of bleeding and hematological adverse effects, 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 nonsteroidal anti-inflammatory drugs, including COX-2 inhibitors, or selective serotonin reuptake inhibitors (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"). Close monitoring for signs of bleeding, including occult bleeding, is required, especially 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 the case of planned surgery, when temporary discontinuation of antiplatelet therapy is required, clopidogrel treatment should be discontinued 7 days before the procedure. Patients should inform their physician (including dentists) that they are taking clopidogrel prior to any surgical procedure or before starting a new 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 warned that bleeding may take longer than usual to stop during treatment with clopidogrel (alone or in combination with ASA), and they should inform their physician of any unusual bleeding (in site or duration).

Thrombotic thrombocytopenic purpura (TTP). Cases of thrombotic thrombocytopenic purpura (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 result in death and therefore requires immediate treatment, including plasma exchange.

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

Recent ischemic stroke. Due to insufficient data, clopidogrel is not recommended within the first 7 days following an 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 standard recommended doses of clopidogrel are administered.

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 lead to decreased plasma concentrations of the active metabolite of clopidogrel. However, the clinical significance of this interaction has not been fully established. Therefore, as a precautionary measure, concomitant use of strong and moderate CYP2C19 inhibitors should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

CYP2C8 substrates. Caution is advised in patients receiving clopidogrel concomitantly with medicinal products that are substrates of the CYP2C8 enzyme (see section "Interaction with other medicinal products and other forms of interaction").

Cross-sensitivity with thienopyridines. Patients should be evaluated for a history of hypersensitivity to other thienopyridines (such as ticlopidine, prasugrel), as cross-hypersensitivity among thienopyridines has been reported. Thienopyridine use may lead to mild to severe allergic reactions such as rash, angioedema (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 similar or different reactions 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 the use of clopidogrel 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. If a patient has known intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

Special precautions for disposal of unused medicine and waste. Unused medicine 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 clopidogrel use during pregnancy, the drug should not be used in pregnant women (as a precautionary measure).

Animal studies have not shown any direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development.

Breastfeeding. 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 clopidogrel.

Fertility. No adverse effects of clopidogrel on fertility were observed in animal studies.

Ability to drive and use machines. Clopidogrel has no effect or has a negligible effect on the ability to drive vehicles or operate machinery.

Method of Administration and Dosage.

Adults and elderly patients. Clopidogrel should be administered at a dose of 75 mg once daily, independent of food intake.

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

For patients with acute ST-elevation myocardial infarction, clopidogrel should be administered at 75 mg once daily, starting with a single 300 mg loading dose, in combination with ASA, with or without thrombolytic agents. In patients aged 75 years and older, treatment should be initiated without a loading dose of clopidogrel. Combined therapy should be initiated as early as possible after symptom onset and continued for at least 4 weeks. The benefit of using clopidogrel in combination with ASA beyond 4 weeks in this condition has not been studied.

Patients with atrial fibrillation should receive clopidogrel at a single daily dose of 75 mg. Acetylsalicylic acid (ASA) (at a dose of 75–100 mg daily) should be initiated and continued together 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 for hemorrhagic diathesis is limited.

Children. Clopidogrel should not be used in children, as there is no data on the efficacy of the medicinal product.

Overdose. Prolongation of bleeding time with subsequent complications may occur in case of clopidogrel overdose. If bleeding occurs, symptomatic treatment is recommended.

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 transfusion of platelet concentrate.

Adverse reactions.

The adverse effects observed during clinical trials or during the use of the medicinal product in clinical practice are listed in the table below. Adverse reactions are classified by "Organ-Class" system, and their frequency is defined as follows: common (from ≥ 1/100 to <1/10), uncommon (from ≥ 1/1000 to <1/100), rare (from ≥ 1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known. Within each organ system class, adverse effects are listed in order of decreasing severity.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions through 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 the reach of children.

Packaging. Tablets, 10, 10×2, 10×3 in blisters, in a carton.

Prescription status. Prescription only.

Manufacturer.

Limited Liability Company "Research Plant "GNCLC", or

Limited Liability Company "FARMEKS GROUP", or

Limited Liability Company "Pharmaceutical Company "Zdorov'ya".

Address of manufacturer and its place of business.

8 Vorobiova Street, Kharkiv, Kharkiv region, 61057, Ukraine.

(Limited Liability Company "Research Plant "GNCLC")

100 Shevchenka Street, Boryspil, Kyiv region, 08301, Ukraine.

(Limited Liability Company "FARMEKS GROUP")

22 Shevchenka Street, Kharkiv, Kharkiv region, 61013, Ukraine.

(Limited Liability Company "Pharmaceutical Company "Zdorov'ya")