Expiration date: 05/2026

The composition and form of issue:

Tablets, film-coated. 1 tablet contains active substance: 

clopidogrel hydrosulfate (equivalent to clopidogrel) 75 mg

auxiliary substances: povidone K30 croscarmellose sodium lactose monohydrate microcrystalline hydrogenated castor oil 

shell film: Opadry white (titanium dioxide, hypromellose, talc, macrogol) titanium dioxide 

in packages contour cell PVC film/aluminium foil of 7, 10 or 14 PCs. in cardboard pack for 2, 4, 8 or 12 packs of contour for 7 pieces or 3 or 9 contour cell packs in 10 pieces, or 1 or 2 packing contour cell 14 PCs.

Description pharmaceutical form:

The tablets are biconvex, round shaped, film-coated white or nearly white with a yellowish tint, scored on one side, odourless or almost odourless in cross section, the kernel white, or almost white.

Pharmacokinetics:

After a single dose and in exchange oral administration at a dose of 75 mg/day, clopidogrel is rapidly absorbed.

Absorption and bioavailability is high. However, the concentration of the original substance in the plasma is low and through 2 hours after admission does not reach the measurement limit (0,025 µg/l). Connection with plasma proteins — 98-94%. Is a prodrug.

Clopidogrel is rapidly metabolized in the liver. The active metabolite in the blood is undetectable. Define the main metabolite — inactive derivative carboxylato acid Tmax which after repeated oral doses of 75 mg of 1 h, Cmax of about 3 mg/L.

About 50% of the drug excreted by the kidney and approximately 46% intestinal within 120 h after injection. T1/2 the main metabolite after single and repeated administration is 8 h. the Amount excreted by kidney metabolites to 50%.

The concentration of the main metabolite in plasma after administration of 75 mg/day lower in patients with severe chronic renal insufficiency (Cl creatinine clearance 5-15 ml/min) compared with patients with chronic renal failure of moderate severity (creatinine Cl 30 to 60 ml/min) and healthy subjects.

Description pharmacological action:

Clopidogrel — antiplatelet drug. Selectively reduces the binding of ADP receptors on platelets and activation of the receptor glycoprotein IIb/IIIa by the action of ADP, impairing platelet aggregation.

Reduces agregatia platelets, caused by other agonists, preventing activation of the released ADP, does not affect the activity of phosphodiesterase. Irreversibly binds to ADP-receptors platelets, which remain impervious to the stimulation of ADP throughout the life cycle (about 7 days). Inhibition of platelet aggregation observed after 2 h after administration of the initial dose of 400 mg (inhibition of 40%). The maximum effect develops after 4-7 days of admission in a dose of 50-100 mg/day (suppression of aggregation — 60%). Antiplatelet effect lasts for the entire period of life of platelets (7-10 days).

Indications:

• prevention of thrombotic complications in patients with myocardial infarction, ischemic stroke or peripheral arterial occlusion
  
• prevention of thrombotic complications in acute coronary syndrome in combination with acetylsalicylic acid (ASA): with ST-segment elevation when possible, use of thrombolysis without ST-segment elevation (unstable angina or myocardial infarction without Q wave), including patients undergoing stenting.
  

Contraindications:

• hypersensitivity to any active or auxiliary component of the drug
  
• lactose intolerance, lactase deficiency syndrome glucose-galactose malabsorption
  
• severe liver failure
  
• acute bleeding (including peptic ulcer or intracranial hemorrhage)
  
• pregnancy and lactation
  
• the age of 18 years (efficacy and safety not established).
  

Caution: moderate hepatic failure, chronic liver failure, pathological conditions that increase the risk of bleeding (including trauma, surgery), bleeding tendency, concomitant use of ASA, warfarin, NSAIDs (including COX-2 inhibitors), heparin, inhibitors of the glycoprotein IIb/IIIa, genetic reduction of function of the CYP2C19 isoenzyme.

Application of pregnancy and breast-feeding:

In the absence of data, it is recommended not to take clopidogrel during pregnancy and lactation.

Side effects:

Bleeding is the most common reaction that occurs during the first month of treatment. The cases of severe bleeding was in patients receiving clopidogrel simultaneously with ASA or clopidogrel with ASA and heparin (see "precautions").

The frequency of side effects is defined as follows: very often (>,1/10) often (>,1/100, <,1 10="">,1/1000, <,1 100="">,1/10000, <,1 1000="" 1="" 10000="" p="">,

Organs of hematopoiesis: rarely — thrombocytopenia, leukopenia, eosinophilia, rarely — naturopatia, including expressed very rarely thrombotic thrombocytopenic purpura, anemia, including aplastic, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia.

From the nervous system: rare — headache, dizziness, paresthesia, intracranial hemorrhage, including fatal very rarely — confusion, hallucinations, taste disturbance.

From the sensory organs: rarely — bleeding in the conjunctiva, the eye, the retina rarely vertigo.

From the CCC: often — very rarely hematoma — heavy bleeding, bleeding from the operative wound, vasculitis, decrease in blood pressure.

The respiratory system: often — nasal bleeding very rarely — bronchospasm, interstitial pneumonitis, pulmonary hemorrhage, hemoptysis.

From the digestive system: often — diarrhea, abdominal pain, dyspepsia, bleeding from the digestive tract rarely, gastric ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence rare retroperitoneal bleeding very rarely — pancreatitis, colitis, including ulcerative or lymphocytic, stomatitis, acute liver failure, hepatitis, disturbance in liver function tests, bleeding from the gastrointestinal tract with a fatal outcome.

With the skin: often — bruising infrequently — skin rash, itch, purpura very rare — angioneurotic edema, urticaria, erythematous rashes, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, eczema, lichen planus.

From the side of musculoskeletal system: very rarely — hemarthrosis, arthritis, arthralgia, myalgia.

With the genitourinary system: rare — hematuria very rarely — glomerulonephritis, gipercreatininemia.

Allergic reactions: very rarely — anaphylactic reactions, serum sickness.

Laboratory parameters: rare — prolonged bleeding time, disturbances in liver function tests, increased creatinine concentration in blood.

Other: very rarely — increased body temperature.

Drug interactions:

Simultaneous reception of warfarin with clopidogrel can increase the intensity of bleeding, therefore, the use of this combination is not recommended.

The appointment of inhibitors of glycoprotein IIb/IIIa, ASA, heparin in conjunction with clopidogrel increases the risk of bleeding.

While the use of NSAIDs may increase the risk of bleeding.

Concomitant use with CYP2C19 inhibitors (e.g. omeprazole) is not recommended.

Clopidogrel active metabolite inhibits the activity of the isoenzyme CYP2C9, resulting in increase concentration of phenytoin, tolbutamide and the NSAIDs in plasma.

Method of application and dose:

Inside.

To take regardless of the meal.

For prevention of thrombotic complications in patients with myocardial infarction, ischemic stroke or peripheral arterial occlusion — 75 mg 1 time per day. In patients with myocardial infarction, the treatment can begin with the first days on the 35th day of the disease, and in patients with ischemic stroke within 7 days to 6 months after ischemic stroke.

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

To prevent thrombotic complications of acute coronary syndrome with ST-segment elevation (acute myocardial infarction with ST-segment elevation) — 75 mg/day with an initial one-time admission loading dose in combination with ASA and with thrombolytic drugs (or without thrombolytics).

Combination therapy is started as early as possible after the onset of symptoms and continued for at least 4 weeks. In patients older than 75 years, treatment with clopidogrel should be started without taking a loading dose.

In patients with a genetically determined reduced function of the CYP2C19 isoenzyme may reduce the effect of clopidogrel. The optimum dosage regimen in such patients is not installed.

Experience of use in patients with chronic liver insufficiency or moderate hepatic insufficiency is limited.

Overdose:

Symptoms: overdose with clopidogrel may lead to prolonged bleeding time and subsequent haemorrhagic complications. Upon detection of bleeding should be applied the appropriate treatment.

Not discovered antidotes pharmaceutical activity of clopidogrel.

Treatment: if you need a fast correction of the lengthening of bleeding time, it is recommended that the platelet transfusion.

Precautions:

During treatment necessary to monitor the hemostatic parameters (APTT, the number of platelets, tests of functional activity of platelets) regularly examine the functional activity of the liver.

Clopidogrel should be used with caution in patients with risk of severe bleeding in trauma, surgery, damaged, prone to bleeding (particularly gastrointestinal and intraocular), and in patients receiving ASA, NSAIDs (including COX-2 inhibitors), heparin or inhibitors of glycoprotein IIb/IIIa. The patients should be carefully monitored to detect any signs of bleeding, including hidden, especially during the first weeks of the drug and/or after invasive procedures on the heart or surgery. The simultaneous use of clopidogrel and warfarin is not recommended since it can increase bleeding.

In the case of surgery if antiplatelet effect is undesirable, the treatment should be discontinued 7 days before surgery.

Patients should be warned that because the bleeding that occurs on the background of the use of clopidogrel (in combination with ASA or not), requires more time, they should inform the doctor about each case of bleeding. Patients should also inform the doctor about the drug if they have surgery.

After taking clopidogrel thrombotic thrombocytopenic purpura (TTP) have been detected very rarely, sometimes after short-term use. This condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia in combination with neurological signs, impaired kidney function or fever. TTP is a potentially fatal condition that requires immediate treatment, including the use of plasmapheresis.

Due to the lack of data, clopidogrel cannot be recommended in acute (<,7 p="">,

Experience with the use of clopidogrel in patients with impaired renal function is limited, therefore, these patients clopidogrel should be administered with caution.

In severe liver dysfunction should be aware of the risk of developing hemorrhagic diathesis the experience of the drug in patients with moderate hepatic impairment is limited, therefore, these patients clopidogrel should be administered with caution.

Effects on ability to drive or to perform work requiring high speed physical and mental reactions. Clopidogrel may cause side effects from the nervous system (headache, dizziness, systemic dizziness, confusion, hallucinations) that may affect the ability to drive vehicles and other potentially hazardous activities, require high concentration and psychomotor speed reactions.