Plagril^® (Tablets) Instructions for Use

ATC Code

B01AC04 (Clopidogrel)

Active Substance

Clopidogrel (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiplatelet agent

Pharmacotherapeutic Group

Antiaggregant agent

Pharmacological Action

Clopidogrel is a prodrug, one of whose active metabolites is an inhibitor of platelet aggregation.

To form the active metabolite, which inhibits platelet aggregation, Clopidogrel must be metabolized by cytochrome P450 system isoenzymes (CYP450).

The active metabolite of clopidogrel selectively inhibits the binding of ADP to the P2Y12 platelet receptor and the subsequent ADP-mediated activation of the GPIIb/IIIa complex, leading to suppression of platelet aggregation.

Due to irreversible binding, platelets remain unresponsive to ADP stimulation for the remainder of their lifespan (approximately 7-10 days), and the restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal.

Pharmacokinetics

After oral administration in a dose of 75 mg, Clopidogrel is rapidly absorbed from the gastrointestinal tract.

The mean C_max of unchanged clopidogrel in blood plasma (approximately 2.2-2.5 ng/ml after a single oral dose of 75 mg) is reached approximately 45 minutes after administration.

In vitro, Clopidogrel and its main circulating inactive metabolite reversibly bind to plasma proteins (98% and 94%, respectively), and this binding is non-saturable up to a concentration of 100 mg/ml.

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, Clopidogrel is metabolized by two pathways: the first is carried out by esterases and leads to the hydrolysis of clopidogrel to form an inactive carboxylic acid derivative (85% of circulating metabolites), the C_max of this metabolite in plasma after repeated doses of clopidogrel is about 3 mg/L and is observed approximately 1 hour after administration; the second pathway is carried out by cytochrome P450 isoenzymes.

Initially, Clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of the active metabolite of clopidogrel – a thiol derivative of clopidogrel.

In vitro, this active metabolite is formed mainly by the CYP2C19 isoenzyme, but other isoenzymes, including CYP1A2, CYP2B6, and CYP3A4, are also involved in its formation.

The active thiol metabolite of clopidogrel, isolated in in vitro studies, rapidly and irreversibly binds to platelet receptors, thereby blocking platelet aggregation.

The C_max of the active metabolite of clopidogrel after a single loading dose of 300 mg is twice that after 4 days of maintenance dosing of clopidogrel 75 mg. C_max is reached within approximately 30-60 minutes.

Within 120 hours after oral administration of ¹⁴C-labeled clopidogrel to humans, approximately 50% of the administered dose is excreted by the kidneys and approximately 46% via the intestine.

After a single oral dose of 75 mg, the T_1/2 of clopidogrel is approximately 6 hours. After a single dose and repeated doses of clopidogrel, the T_1/2 of its main circulating inactive metabolite is 8 hours.

The pharmacokinetics of the main metabolite are characterized by a linear relationship in the clopidogrel dose range of 50-150 mg.

Indications

Secondary prevention of atherothrombotic complications; in adult patients after a recent myocardial infarction (from several days to 35 days old), a recent ischemic stroke (from 7 days to 6 months old), or with diagnosed occlusive peripheral arterial disease, clopidogrel reduced the incidence of the combined endpoint, which included recurrent ischemic stroke (fatal or not), recurrent myocardial infarction (fatal or not), and other cardiovascular death; in adult patients with acute coronary syndrome – acute coronary syndrome without ST-segment elevation (unstable angina/non-Q-wave myocardial infarction), including patients who are to receive medical treatment and patients for whom percutaneous coronary intervention (with or without stenting) or coronary artery bypass grafting (CABG) is indicated, acute myocardial infarction with ST-segment elevation.

Prevention of atherothrombotic and thromboembolic complications in adult patients with atrial fibrillation.

ICD codes

Dosage Regimen

Tablets

The tablets are taken orally, regardless of meals.

For the prevention of ischemic disorders in patients after myocardial infarction, ischemic stroke, or with diagnosed peripheral arterial diseases, adults (including elderly patients) are prescribed Plagril^® at a dose of 75 mg once a day.

Treatment should be initiated within 35 days after a Q-wave myocardial infarction and from 7 days to 6 months after an ischemic stroke.

For acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), treatment should be started with a single loading dose of 300 mg, then continued with the drug at a dose of 75 mg once a day (with simultaneous administration of acetylsalicylic acid at a dose of 75-325 mg/day).

Since the use of acetylsalicylic acid in high doses is associated with a higher risk of bleeding, the recommended dose should not exceed 100 mg. The course of treatment is up to 1 year.

For acute coronary syndrome with ST-segment elevation (acute myocardial infarction), the drug is prescribed at a dose of 75 mg once a day using an initial loading dose in combination with acetylsalicylic acid, with or without thrombolytics.

For patients over 75 years of age, treatment with clopidogrel should be carried out without the use of a loading dose. Combined therapy should be started as early as possible after the onset of symptoms and continued for at least 4 weeks.

Adverse Reactions

From the digestive system common – diarrhea, abdominal pain, dyspepsia; uncommon – nausea, gastritis, abdominal distension, constipation, vomiting, gastric and duodenal ulcer; frequency unknown – colitis (including ulcerative colitis or lymphocytic colitis), pancreatitis, stomatitis.

From the liver and biliary tract: frequency unknown – hepatitis (non-infectious), acute liver failure.

From the hematopoietic system uncommon – increased bleeding time, decreased platelet count in peripheral blood, leukopenia, decreased neutrophil count in peripheral blood, eosinophilia; frequency unknown – cases of serious bleeding, predominantly subcutaneous, musculoskeletal, ocular hemorrhages (conjunctival, tissue and retinal), bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage), epistaxis, hematuria and bleeding from postoperative wounds and cases of fatal bleeding (especially intracranial hemorrhage, gastrointestinal bleeding and retroperitoneal hemorrhage); agranulocytosis, granulocytopenia, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura, acquired hemophilia A.

From the nervous system uncommon – headache, paresthesia, dizziness; rare – vertigo; frequency unknown – taste disorders, ageusia.

From the psychiatric system: frequency unknown – confusion, hallucinations.

From the cardiovascular system frequency unknown – Kounis syndrome (vasospastic allergic angina/allergic myocardial infarction), caused by a hypersensitivity reaction to Clopidogrel, vasculitis, decreased blood pressure.

From the respiratory system frequency unknown – bronchospasm, interstitial pneumonia, eosinophilic pneumonia.

From the immune system frequency unknown – anaphylactoid reactions, serum sickness; cross-allergic and hematological reactions with other thienopyridines (such as ticlopidine, prasugrel).

From the skin and subcutaneous tissues uncommon – skin rash, pruritus; frequency unknown – maculopapular erythematous or exfoliative rash, urticaria, skin itching, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), acute generalized exanthematous pustulosis, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), eczema, lichen planus.

From the musculoskeletal system frequency unknown – arthralgia (joint pain), arthritis, myalgia.

From the urinary system frequency unknown – glomerulonephritis.

From the reproductive system frequency unknown – gynecomastia.

From laboratory parameters: frequency unknown – abnormal liver function tests, increased blood creatinine concentration.

Other frequency unknown – fever.

Contraindications

Hypersensitivity to clopidogrel; acute bleeding (including peptic ulcer or intracranial hemorrhage), severe hepatic impairment, pregnancy, lactation (breastfeeding), children and adolescents under 18 years of age.

With caution: in moderate hepatic impairment, where there may be a predisposition to bleeding; in renal impairment; in diseases where there is a predisposition to bleeding (particularly gastrointestinal or intraocular), and especially with the simultaneous use of drugs that can cause damage to the gastrointestinal mucosa (such as acetylsalicylic acid (ASA) and NSAIDs) ; in patients who have an increased risk of bleeding: due to trauma, surgery or other pathological conditions, as well as in patients receiving treatment with ASA, heparin, warfarin, glycoprotein IIb/IIIa inhibitors, NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, as well as other drugs whose use is associated with a risk of bleeding, selective serotonin reuptake inhibitors (SSRIs); with simultaneous use with drugs that are substrates of the CYP2C8 isoenzyme (repaglinide, paclitaxel); in patients with low activity of the CYP2C19 isoenzyme; with a history of allergic and hematological reactions to other thienopyridines (such as ticlopidine, prasugrel) due to the possibility of cross-allergic and hematological reactions; with a recent transient ischemic attack or ischemic stroke (when combined with ASA).

Use in Pregnancy and Lactation

Clopidogrel is contraindicated during pregnancy, except in cases where, in the physician’s opinion, its use is strongly indicated.

It is not known whether Clopidogrel is excreted in human breast milk. If use during lactation is necessary, the issue of discontinuing breastfeeding should be decided.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment. Use with caution in moderate hepatic impairment, where there may be a predisposition to bleeding (limited clinical experience).

Use in Renal Impairment

Use with caution in renal impairment (limited clinical experience).

Pediatric Use

Use in children and adolescents under 18 years of age is contraindicated (safety and efficacy have not been established).

Geriatric Use

No dose adjustment is required.

Special Precautions

During treatment with clopidogrel, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients should be carefully monitored for signs of bleeding, including occult bleeding.

Due to the risk of bleeding and adverse reactions from the hematopoietic system, if clinical symptoms suspicious for bleeding occur during treatment, a complete blood count, activated partial thromboplastin time (aPTT), platelet count, platelet function indicators, and other necessary tests should be urgently performed.

Clopidogrel, like other antiplatelet agents, should be used with caution in patients who have an increased risk of bleeding associated with trauma, surgery, or other pathological conditions, as well as in patients taking ASA, NSAIDs, including COX-2 inhibitors, heparin, or glycoprotein IIb/IIIa inhibitors.

If a patient is scheduled for elective surgery and the antiplatelet effect is not required, clopidogrel should be discontinued 5-7 days before surgery.

Clopidogrel prolongs bleeding time and should be used with caution in patients with conditions predisposing to bleeding (especially gastrointestinal and intraocular). Drugs that may cause damage to the gastrointestinal mucosa (such as ASA, NSAIDs) in patients taking Clopidogrel should be used with caution.

Patients should be warned that when taking clopidogrel (as monotherapy or in combination with ASA) it may take longer to stop bleeding, and also that if they experience any unusual bleeding (in location or duration), they should report it to their doctor. Before any upcoming surgery and before starting any new medication, patients should inform their doctor (including dentist) about taking clopidogrel.

Very rarely, after the use of clopidogrel (sometimes even short-term), cases of thrombotic thrombocytopenic purpura (TTP) have been reported, which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function, and fever. TTP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

It has been shown that in patients with a recent transient ischemic attack or stroke, who are at high risk of recurrent ischemic complications, the combination of ASA and clopidogrel increases the incidence of major bleeding. Therefore, such combination therapy should be used with caution and only in cases of proven clinical benefit from its use.

Cases of acquired hemophilia have been reported with clopidogrel use. If a confirmed isolated increase in aPTT is observed, with or without bleeding, the possibility of acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be managed and treated by specialists in this disease and discontinue clopidogrel.

In patients with low activity of the CYP2C19 isoenzyme, when using clopidogrel at recommended doses, less of the active metabolite of clopidogrel is formed and its antiplatelet effect is weaker, therefore, when taking the usually recommended doses of clopidogrel for acute coronary syndrome or percutaneous coronary intervention, a higher frequency of cardiovascular complications is possible than in patients with normal CYP2C19 isoenzyme activity.

Patients should be questioned about a history of allergic and/or hematological reactions to other thienopyridines (such as ticlopidine, prasugrel), as cross-allergic and/or hematological reactions between thienopyridines have been reported. Patients who have previously experienced allergic and/or hematological reactions to one of the drugs in the thienopyridine group may have an increased risk of developing similar reactions to another drug in this group. Monitoring for cross-allergic and/or hematological reactions is recommended.

During treatment, liver function should be monitored. In severe liver damage, the risk of hemorrhagic diathesis should be considered.

The use of clopidogrel is not recommended for acute stroke of less than 7 days duration (as there are no data on its use in this condition).

Drug Interactions

With simultaneous use of clopidogrel and drugs whose use is associated with a risk of bleeding (warfarin, IIb/IIIa receptor blockers, acetylsalicylic acid, heparin, fibrin-specific or fibrin-nonspecific thrombolytic agents, NSAIDs, selective serotonin reuptake inhibitors) there is an increased risk of bleeding due to their potential additive effect with clopidogrel. Treatment should be carried out with caution.

Since Clopidogrel is metabolized to form its active metabolite partially via the CYP2C19 isoenzyme, the use of medicinal products that inhibit this isoenzyme may lead to a reduction in the formation of the active metabolite of clopidogrel.

The concomitant use of clopidogrel and potent or moderate inhibitors of the CYP2C9 isoenzyme (omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol) should be avoided.

Caution should be exercised with the concomitant use of clopidogrel and medicinal products metabolized by the CYP2C8 isoenzyme (e.g., repaglinide, paclitaxel) due to the risk of increased plasma concentrations.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.