Tromborel (Tablets) Instructions for Use

Marketing Authorization Holder

Edge Pharma Private Limited (India)

ATC Code

B01AC04 (Clopidogrel)

Active Substance

Clopidogrel (Rec.INN registered by WHO)

Dosage Form

Tromborel

Film-coated tablets, 75 mg: 10, 14, 20, 28, 30, 56, 84, or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from light pink to pink in color, round; a cross-section shows two layers; the core is light yellow in color.

Excipients : mannitol – 35 mg, microcrystalline cellulose – 90 mg, sodium carboxymethyl starch – 40 mg, calcium stearate – 2 mg.

Shell composition Vinkout brown (hypromellose – 6.6 mg, triacetin – 1.56 mg, ethylcellulose – 1.875 mg, titanium dioxide – 4.125 mg, talc – 0.645 mg, iron oxide red – 0.195 mg) – 15 mg.

10 pcs. – Al/Al blisters (1) – cardboard packs.
10 pcs. – Al/Al blisters (2) – cardboard packs.
10 pcs. – Al/Al blisters (3) – cardboard packs.
10 pcs. – Al/Al blisters (10) – cardboard packs.
14 pcs. – Al/Al blisters (1) – cardboard packs.
14 pcs. – Al/Al blisters (2) – cardboard packs.
14 pcs. – Al/Al blisters (4) – cardboard packs.
14 pcs. – Al/Al blisters (6) – 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, which inhibits 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 their entire remaining 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.

The subsequent metabolism of 2-oxo-clopidogrel leads to the formation of the active metabolite of clopidogrel – the 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, 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 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 non-fatal), recurrent myocardial infarction (fatal or non-fatal), 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 ST-segment elevation myocardial infarction.

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

ICD codes

Dosage Regimen

Take orally, with or without food.

For recent myocardial infarction, ischemic stroke, or diagnosed peripheral arterial disease, administer a single daily dose of 75 mg.

In acute coronary syndrome without ST-segment elevation (unstable angina/non-Q-wave MI), initiate treatment with a single 300 mg loading dose, then continue with a 75 mg once daily regimen. Administer acetylsalicylic acid (ASA) concomitantly. Continue treatment for up to 12 months.

For patients with ST-segment elevation acute myocardial infarction, administer a 75 mg once daily dose, with an initial 300 mg loading dose in patients under 75 years of age. Initiate treatment with or without a thrombolytic agent. Administer ASA concomitantly. Continue treatment for at least four weeks.

In atrial fibrillation for prevention of thromboembolic complications, use a 75 mg once daily dose when vitamin K antagonists are unsuitable.

For patients undergoing percutaneous coronary intervention (PCI), initiate treatment with a 300 mg loading dose at least 24 hours before the procedure. If given less than 24 hours before PCI, a higher loading dose (600 mg) is recommended. After the procedure, continue with 75 mg daily in combination with ASA.

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

No dose adjustment is necessary for elderly patients or patients with renal impairment.

Use with caution in patients with moderate hepatic impairment; contraindicated in severe hepatic impairment.

Adverse Reactions

From the digestive system common – diarrhea, abdominal pain, dyspepsia; uncommon – nausea, gastritis, bloating, constipation, vomiting, gastric and duodenal ulcer; frequency unknown – colitis (including nonspecific 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), respiratory tract bleeding (hemoptysis, pulmonary hemorrhage), nosebleeds, hematuria and bleeding from postoperative wounds and cases of fatal bleeding (especially intracranial hemorrhages, gastrointestinal bleeding and retroperitoneal hemorrhages); 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 psyche: 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, 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.

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 – 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 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 for use 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, a decision should be made to discontinue breastfeeding.

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 events 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 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 any unusual (in location or duration) bleeding, they should report it to their doctor. Before any planned 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. In case of a confirmed isolated increase in aPTT, 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 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 thienopyridine group of drugs 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 partly with the help of the CYP2C19 isoenzyme, the use of medicinal products that inhibit this isoenzyme may lead to a decrease in the formation of the active metabolite of clopidogrel. The concomitant use of clopidogrel and potent or moderate inhibitors of the CYP2C19 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 (for example, repaglinide, paclitaxel) due to the risk of an increase in 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.