Plogrel (Tablets) Instructions for Use

Marketing Authorization Holder

Oxford Laboratories, Pvt. Ltd. (India)

ATC Code

B01AC04 (Clopidogrel)

Active Substance

Clopidogrel (Rec.INN registered by WHO)

Dosage Form

Plogrel

Film-coated tablets, 75 mg: 14, 28, 30, 56, 84 or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white with a yellowish tint, round, biconvex, with a score, odorless or almost odorless; on the cross-section, the core is white or almost white.

Excipients: povidone K30 – 6 mg, croscarmellose sodium – 5 mg, lactose monohydrate – 50.2 mg, microcrystalline cellulose – 50 mg, hydrogenated castor oil – 2 mg.

Film coating composition Opadry white – 3 mg (titanium dioxide – 12%, hypromellose – 32%, talc – 39%, macrogol – 17%), titanium dioxide – 3 mg.

7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.
14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Antiplatelet agent

Pharmacotherapeutic Group

Antiaggregant agent

Pharmacological Action

Antiplatelet agent. Selectively reduces the binding of adenosine diphosphate (ADP) to its receptors on platelets and the activation of the glycoprotein IIb/IIIa receptor complex by ADP, thereby weakening platelet aggregation.

It reduces platelet aggregation induced by other agonists by preventing their activation by released ADP, without affecting phosphodiesterase activity. It irreversibly binds to ADP receptors on platelets, which remain unresponsive to ADP stimulation for their entire lifespan (about 7 days).

Inhibition of platelet aggregation is observed 2 hours after administration (40% inhibition) of an initial 400 mg dose. The maximum effect (60% inhibition of aggregation) develops after 4-7 days of continuous administration at a dose of 50-100 mg/day. The antiplatelet effect persists throughout the platelet lifespan (7-10 days).

Pharmacokinetics

Absorption and Distribution

After a single dose and during repeated oral administration at a dose of 75 mg/day, Clopidogrel is rapidly absorbed. Absorption and bioavailability are high. However, the plasma concentration of the parent substance is low and 2 hours after administration does not reach the limit of quantification (0.025 µg/l).

Plasma protein binding is 98-94%.

It is a prodrug.

Metabolism

Clopidogrel is rapidly metabolized in the liver. The active metabolite is not detectable in blood. The main determinable metabolite is an inactive carboxylic acid derivative, whose time to reach C_max after repeated oral administration of a 75 mg dose is 1 hour, C_max is about 3 mg/l.

Excretion

Approximately 50% of the drug is excreted by the kidneys and about 46% via the intestines within 120 hours after administration. The T_1/2 of the main metabolite after single and repeated administration is 8 hours. The concentrations of metabolites excreted by the kidneys account for 50%.

Pharmacokinetics in Special Clinical Cases

The plasma concentration of the main metabolite after a 75 mg/day dose is lower in patients with severe chronic renal failure (CrCl 5-15 ml/min) compared to patients with moderate chronic renal failure (CrCl from 30 to 60 ml/min) and healthy individuals.

Indications

• Prevention of thrombotic complications in patients with myocardial infarction, ischemic stroke, or established peripheral arterial disease;
• In combination with acetylsalicylic acid for the prevention of thrombotic complications in acute coronary syndrome with ST-segment elevation when thrombolytic therapy is possible;
• In combination with acetylsalicylic acid for the prevention of thrombotic complications in acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), including in patients undergoing stenting.

ICD codes

Dosage Regimen

Take orally, regardless of meals.

For prevention of thrombotic complications in patients with myocardial infarction, ischemic stroke, or established peripheral arterial disease, 75 mg once daily is prescribed. In patients with myocardial infarction, treatment can be started from the first days up to day 35 after myocardial infarction, and in patients with ischemic stroke – within 7 days to 6 months after the ischemic stroke.

For prevention of thrombotic complications in acute coronary syndrome without ST-segment elevation (unstable angina, non-Q-wave myocardial infarction), start with a single 300 mg loading dose, then take 75 mg/day (in combination with acetylsalicylic acid at doses of 75-325 mg/day, the recommended dose is 100 mg/day). The maximum beneficial effect occurs after 3 months. The course of treatment is up to 1 year.

For prevention of thrombotic complications in acute coronary syndrome with ST-segment elevation (acute myocardial infarction with ST-segment elevation), 75 mg/day is prescribed with an initial single loading dose in combination with acetylsalicylic acid and thrombolytics (or without thrombolytics).

Combination therapy should be started as early as possible after symptom onset and continued for at least 4 weeks.

In patients over 75 years of age, clopidogrel treatment should be initiated without a loading dose.

In patients with genetically determined reduced function of the CYP2C19 isoenzyme, a reduced effect of clopidogrel is possible. The optimal dosing regimen for such patients has not been established.

Experience with use in patients with chronic renal failure or moderate hepatic impairment is limited.

Adverse Reactions

Bleeding is the most frequent reaction, occurring during the first month of taking the drug. Cases of severe bleeding have been reported in patients taking Clopidogrel concurrently with acetylsalicylic acid or Clopidogrel with acetylsalicylic acid and heparin.

The frequency of adverse effects is defined according to the following criteria: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1/10,000 and <1/1000), very rare (<1/10,000, including isolated cases). Within each frequency group, adverse effects are presented in order of decreasing severity.

Blood and lymphatic system disorders: uncommon – thrombocytopenia, leukopenia, eosinophilia; rare – neutropenia, including severe neutropenia; very rare – thrombotic thrombocytopenic purpura, anemia including aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia.

Nervous system disorders: uncommon – headache, dizziness, paresthesia, intracranial bleeding, including fatal; very rare – confusion, hallucinations.

Eye and ear disorders: uncommon – conjunctival hemorrhage, retinal hemorrhage; rare – vertigo; very rare – taste disturbance.

Cardiac and vascular disorders: very rare – vasculitis, decreased blood pressure.

Coagulation disorders: common – hematoma; very rare – severe bleeding, surgical wound bleeding.

Respiratory, thoracic and mediastinal disorders: very common – epistaxis; very rare – bronchospasm, interstitial pneumonitis, pulmonary hemorrhage, hemoptysis.

Gastrointestinal disorders: common – diarrhea, abdominal pain, dyspepsia, gastrointestinal bleeding; uncommon – gastric and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence; rare – retroperitoneal hemorrhage; very rare – pancreatitis, colitis, including ulcerative or lymphocytic colitis, stomatitis, acute liver failure, hepatitis, abnormal liver function tests, fatal gastrointestinal bleeding.

Skin and subcutaneous tissue disorders: common – subcutaneous hemorrhage; uncommon – skin rash, pruritus, purpura; very rare – erythematous rash, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, eczema, lichen planus.

Musculoskeletal and connective tissue disorders: very rare – hemarthrosis, arthritis, arthralgia, myalgia.

Renal and urinary disorders: uncommon – hematuria; very rare – glomerulonephritis, increased blood creatinine.

Immune system disorders: very rare – angioedema, urticaria, anaphylactic reactions, serum sickness.

Investigations: uncommon – prolonged bleeding time, abnormal liver function tests, increased blood creatinine concentration.

General disorders and administration site conditions: very rare – fever.

Contraindications

• Severe hepatic impairment;
• Active bleeding (e.g., peptic ulcer or intracranial hemorrhage);
• Lactose intolerance, lactase deficiency, glucose/galactose malabsorption syndrome;
• Children and adolescents under 18 years of age (efficacy and safety not established);
• Pregnancy;
• Lactation period;
• Hypersensitivity to the components of the drug.

Use with caution in moderate hepatic impairment, chronic renal failure, pathological conditions that increase the risk of bleeding (including trauma, surgery), bleeding tendency, concurrent use of acetylsalicylic acid, warfarin, NSAIDs (including COX-2 inhibitors), heparin, glycoprotein IIb/IIIa inhibitors, hereditary reduced function of the CYP2C19 isoenzyme.

Use in Pregnancy and Lactation

Due to the lack of data, Clopidogrel should not be used during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Use with caution in moderate hepatic impairment. Contraindication: severe hepatic impairment.

Use in Renal Impairment

Use with caution in renal impairment.

Pediatric Use

Contraindication: age under 18 years (efficacy and safety not established).

Geriatric Use

In patients over 75 years of age, clopidogrel treatment should be initiated without a loading dose.

Special Precautions

During treatment, indicators of the hemostatic system (aPTT, platelet count, platelet function tests) should be monitored; liver function should be regularly examined.

Clopidogrel should be used with caution in patients at risk of significant bleeding from trauma, surgery, in patients with lesions prone to bleeding (especially gastrointestinal and intraocular), and in patients receiving acetylsalicylic acid, NSAIDs (including COX-2 inhibitors), heparin, or glycoprotein IIb/IIIa inhibitors. Patients should be carefully monitored for any signs of bleeding, including occult bleeding, especially during the first weeks of drug use and/or after invasive cardiac procedures or surgery. Concurrent use of clopidogrel and warfarin is not recommended as it may increase bleeding.

In case of surgical interventions where the antiplatelet effect is undesirable, the course of treatment should be discontinued 7 days before surgery.

Patients should be warned that since stopping bleeding that occurs during the use of clopidogrel (in combination with acetylsalicylic acid or without it) requires more time, they should report any case of bleeding to the doctor. Patients should also inform the doctor about taking the drug if they are scheduled for surgery.

After taking clopidogrel, thrombotic thrombocytopenic purpura has been detected very rarely, sometimes after short-term use. This condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia combined with neurological signs, renal impairment, or fever.

Thrombotic thrombocytopenic purpura is a potentially fatal condition requiring immediate treatment, including plasmapheresis.

Due to the lack of data, Clopidogrel cannot be recommended for acute (less than 7 days) ischemic strokes.

Experience with the use of clopidogrel in patients with impaired renal function is limited, so Clopidogrel should be prescribed with caution to these patients.

In severe hepatic impairment, the risk of hemorrhagic diathesis should be considered; experience with the drug in patients with moderate hepatic impairment is limited, so Clopidogrel should be prescribed with caution to these patients.

Effect on ability to drive vehicles and operate machinery

Clopidogrel may cause side effects from the nervous system (headache, dizziness, vertigo, confusion, hallucinations), which may affect the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms prolonged bleeding time and subsequent hemorrhagic complications.

Treatment if bleeding is detected, symptomatic hemostatic therapy is performed. No antidote to the pharmaceutical activity of clopidogrel has been found. If rapid correction of prolonged bleeding time is necessary, platelet transfusion is recommended.

Drug Interactions

Concomitant use of warfarin with clopidogrel may increase the intensity of bleeding, so the use of this combination is not recommended.

Prescription of glycoprotein IIb/IIIa inhibitors, acetylsalicylic acid, heparin together with clopidogrel increases the risk of bleeding.

When used concomitantly with NSAIDs, the risk of bleeding may increase.

Concomitant use with inhibitors of the CYP2C19 isoenzyme (e.g., omeprazole) is not recommended.

The active metabolite of clopidogrel inhibits the activity of the CYP2C9 isoenzyme, which may lead to increased plasma concentrations of phenytoin, tolbutamide, and NSAIDs.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.