Clopilet (Tablets) Instructions for Use

Marketing Authorization Holder

Sun Pharmaceutical Industries, Ltd. (India)

ATC Code

B01AC04 (Clopidogrel)

Active Substance

Clopidogrel (Rec.INN registered by WHO)

Dosage Form

Clopilet

Film-coated tablets, 75 mg: 30 pcs.

Dosage Form, Packaging, and Composition

10 pcs. – non-cell contour packs (3) – cardboard packs.

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 that suppresses platelet aggregation, Clopidogrel must be metabolized by cytochrome P450 (CYP450) system isoenzymes.

The active metabolite of clopidogrel selectively inhibits the binding of ADP to the platelet P2Y12 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 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 administration 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.

The 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 approximately within 30-60 minutes.

Within 120 hours after oral administration of ¹⁴C-labeled clopidogrel to humans, about 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 single and repeated doses of clopidogrel, the T_1/2 of its main circulating inactive metabolite is 8 hours.

The pharmacokinetics of the main metabolite is 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 a few 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

Take orally, with or without food.

For acute coronary syndrome without ST-segment elevation (unstable angina/non-Q-wave myocardial infarction): initiate with a single 300 mg loading dose. Follow with a 75 mg once daily maintenance dose. Administer in combination with acetylsalicylic acid (75-100 mg/day). Continue treatment for up to 12 months.

For ST-segment elevation myocardial infarction: initiate with a 300 mg loading dose. Follow with 75 mg once daily. In patients over 75 years of age, initiate treatment without a loading dose. Administer in combination with acetylsalicylic acid. Continue treatment for at least four weeks.

For recent myocardial infarction, recent ischemic stroke, or established peripheral arterial disease: administer 75 mg once daily as monotherapy.

For atrial fibrillation (when vitamin K antagonists are unsuitable): administer 75 mg once daily in combination with acetylsalicylic acid.

If a dose is missed and remembered within 12 hours, take the missed dose immediately. If more than 12 hours have passed, take the next dose at the usual time. Do not take a double dose to make up for a forgotten one.

Discontinue therapy 5-7 days prior to elective surgery if an antiplatelet effect is not desired.

No dose adjustment is required for elderly patients or those with renal impairment. Use is contraindicated in severe hepatic impairment.

Adverse Reactions

Digestive system common – diarrhea, abdominal pain, dyspepsia; infrequent – nausea, gastritis, flatulence, constipation, vomiting, gastric and duodenal ulcer; frequency unknown – colitis (including nonspecific ulcerative colitis or lymphocytic colitis), pancreatitis, stomatitis.

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

Hematopoietic system infrequent – 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), respiratory tract bleeding (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.

Nervous system infrequent – headache, paresthesia, dizziness; rare – vertigo; frequency unknown – taste disorders, ageusia.

Psychiatric: frequency unknown – confusion, hallucinations.

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

Respiratory system frequency unknown – bronchospasm, interstitial pneumonia, eosinophilic pneumonia.

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

Skin and subcutaneous tissues infrequent – skin rash, itching; 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.

Musculoskeletal system frequency unknown – arthralgia (joint pain), arthritis, myalgia.

Urinary system frequency unknown – glomerulonephritis.

Reproductive system frequency unknown – gynecomastia.

Laboratory parameters: frequency unknown – deviation from the norm of liver function laboratory parameters, 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, in which there may be a predisposition to bleeding; in renal impairment; in diseases where there is a predisposition to bleeding (in particular 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 the 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 for use during pregnancy, except in cases where, in the opinion of the physician, its use is strongly indicated.

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

Use in Hepatic Impairment

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

Use in Renal Impairment

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

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 of bleeding occur during treatment, a complete blood count, activated partial thromboplastin time (aPTT), platelet count, platelet functional activity 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 there is no need for an antiplatelet effect, 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 can 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 unusual (in location or duration) bleeding, 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 carried out with caution and only in case 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 activity of the CYP2C19 isoenzyme.

Patients should be questioned about a history of previous 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 the 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 partly by the CYP2C19 isoenzyme, the use of drugs that inhibit this isoenzyme may lead to a decrease in the formation of the active metabolite of clopidogrel. Simultaneous 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 simultaneous use of clopidogrel and drugs metabolized by the CYP2C8 isoenzyme (for example, repaglinide, paclitaxel) due to the risk of increasing their 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.