Composition
Active ingredient:
clopidogrel (in the form of clopidogrel hydrosulfate) 75 mg (97.875 mg);
Auxiliary substances:
lactose monohydrate (200 mesh) 60,0 mg,
microcrystalline cellulose (Avicel PH-101) 40,125 mg
of hyprolose 3.0 mg,
microcrystalline cellulose (Avicel PH-112) of 26.0 mg,
crospovidone 6.0 mg,
hydrogenated vegetable oil type I (Terotex-Drytex) 10.0 mg,
sodium lauryl 7,0 mg;
film cover Opadry pink IIOY-L – 34836:
lactose monohydrate 2.16 mg,
hypromellose 15 cP (E 464) 1.68 mg,
titanium dioxide (E 171) 1.53 mg,
macrogol-4000 0.60 mg,
iron oxide red dye (E 172) 0.024 mg,
Indigo Carmine 0.0030 mg,
iron oxide yellow dye (E 172) 0.0006 mg
Pharmacological action
Pharmacodynamics
Clopidogrel is a specific and active inhibitor of platelet aggregation; it has a coronary dilating effect. Selectively reduces ADP binding to platelet receptors and activation of GPI Ib/IIIa receptors by ADP, reducing platelet aggregation.
Reduces platelet aggregation caused by other agonists, preventing their activation by released ADP, does not affect the activity of phosphodiesterase (PDE). It irreversibly binds to platelet ADP receptors, which remain immune to ADP stimulation throughout the life cycle (about 7 days).
Inhibition of platelet aggregation is observed 2 hours after use (40% inhibition) of the initial dose of 400 mg. The maximum effect (60% suppression of aggregation) develops after 4-7 days of continuous use at a dose of 50-100 mg / day. The antiplatelet effect persists for the entire period of platelet life (7-10 days).
If there is an atherosclerotic lesion of the vessel, it prevents the development of atherothrombosis, regardless of the localization of the vascular process (cerebrovascular, cardiovascular or peripheral lesions).
Pharmacokinetics
Clopidogrel is rapidly absorbed with a course of oral use of 75 mg per day. Bioavailability is high. However, the concentration of the initial substance in plasma is low and does not reach the measurement limit (0.025 mcg/l) within 2 hours after use. The relationship with plasma proteins is 98-94%.
Clopidogrel is rapidly metabolized in the liver. Its main metabolite is an inactive carboxylic acid derivative, the time to reach the maximum concentration (CMAX) of which, after repeated oral doses of 75 mg, is reached in 1 hour (Cmax – about 3 mg/l).
Approximately 50% of the drug is excreted by the kidneys and approximately 46% in the faeces within 120 hours after use. The half-life of the main metabolite after single and repeated use is 8 hours. Concentrations of metabolites excreted by the kidneys are 50%. The concentration of the main metabolite in plasma after taking 75 mg / day is lower in patients with severe renal diseases (creatinine clearance ( creatinine clearance) – 5-15 ml / min) compared with patients with moderate renal diseases (creatinine clearance from 30 to 60 ml / min) and healthy individuals.
Indications
Prevention of thrombotic complications:
- after myocardial infarction (from a few days to 35 days), ischaemic stroke (from 6 days to 6 months) or when diagnosed with the disease of the peripheral arteries
- in acute coronary syndrome without ST-segment elevation (unstable angina or myocardial infarction without pathological Q-wave), including patients undergoing surgery for percutaneous coronary bypass surgery, in combination with acetylsalicylic acid;
- in acute coronary syndrome with ST-segment elevation (acute myocardial infarction) in combination with acetylsalicylic acid in patients receiving medication with possible use of thrombolytic therapy.
Use during pregnancy and lactation
Due to the lack of data, it is not recommended to take clopidogrel during pregnancy and lactation.
Contraindications
- Hypersensitivity to the active or any auxiliary component of the drug Clopidogrel;
- Severe liver failure;
- Active bleeding (including bleeding from a peptic ulcer or intracranial hemorrhage);
- Pregnancy and lactation;
- Age up to 18 years (the effectiveness and safety of its use have not been established);
- Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.
With caution: Moderate liver failure, chronic renal failure (CRF), a morbid condition that increases the risk of bleeding (including trauma, surgery), concomitant use of ASA, warfarin, nonsteroidal anti-inflammatory drugs (NSAIDs) (including COX-2 inhibitors), heparin and inhibitors of glycoprotein IIb/IIIa, an inherited decrease in the function of the isoenzyme CYP2C19.
Side effects
From the side of the blood coagulation system: Â often-bleeding (in most cases – during the first month of treatment), purpura, hematomas; infrequently-conjunctival bleeding; rarely-intracranial bleeding; prolongation of bleeding time, leukopenia, decreased neutrophil count and eosinophilia, decreased platelet count.
From the hematopoietic system: Â very rare – thrombocytopenic thrombohemolytic purpura, severe thrombocytopenia (platelet count
Nervous system disorders: Â infrequently-headache, dizziness, paresthesia; rarely-vertigo; very rarely-confusion, hallucinations.
From the cardiovascular system: Â often-hematoma; very rarely-severe bleeding, bleeding from an operating wound, vasculitis, low blood pressure.
Respiratory system disorders: Â very often – nosebleeds; very rarely – bronchospasm, interstitial pneumonitis, pulmonary hemorrhage, hemoptysis.
From the digestive system: Â often – diarrhea, abdominal pain, dyspepsia, bleeding from the gastrointestinal tract; rarely, gastric ulcer and duodenal ulcer, gastritis, vomiting, nausea, flatulence, constipation; rarely – retroperitoneal bleeding; rarely – colitis (including ulcerative or lymphocytic), pancreatitis, change in taste, stomatitis, hepatitis, acute liver failure, increased liver enzymes,
Musculoskeletal disorders: Â very rarely – arthralgia, arthritis, myalgia.
From the urinary system: Â infrequently-hematuria; very rarely-glomerulonephritis, hypercreatininemia.
Dermatological reactions: Â very rarely – bullous rash (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), erythematous rash, eczema, lichen planus.
Allergic reactions: Â very rarely – angioedema, urticaria, anaphylactoid reactions, serum sickness.
 Other services:  very rarely – an increase in body temperature.
Interaction
Warfarin: concomitant use with clopidogrel may increase the intensity of bleeding, so the use of this combination is not recommended. IIb/IIIa-receptor blockers: the use of IIb/IIIa-receptor blockers in combination with clopidogrel requires caution in patients who have an increased risk of bleeding (due to injuries and surgical interventions or other pathological conditions).
Acetylsalicylic acid: acetylsalicylic acid does not alter the effect of clopidogrel, which inhibits ADP-induced platelet aggregation, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, concomitant use of 500 mg acetylsalicylic acid twice daily for 1 day with clopidogrel did not significantly increase the bleeding time caused by clopidogrel. There may be a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid, which leads to an increased risk of bleeding. Therefore, caution should be exercised when using them simultaneously. Although in clinical trials, patients received combination therapy with clopidogrel and acetylsalicylic acid for up to one year.
Heparin: according to a clinical trial conducted in healthy subjects, clopidogrel did not require a change in the dose of heparin and did not change its anticoagulant effect. Concomitant use of heparin did not alter the antiplatelet effect of clopidogrel. There may be a pharmacodynamic interaction between clopidogrel and heparin, which may increase the risk of bleeding, so the simultaneous use of these drugs requires caution.
Thrombolytics: The safety of co-use of clopidogrel, fibrin-specific or fibrin-specific drugs, and heparin has been studied in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the case of combined use of thrombolytics and heparin with acetylsalicylic acid.
Nonsteroidal anti-inflammatory drugs (NSAIDs): in a clinical study conducted in healthy volunteers, the combined use of clopidogrel and naproxen increased hidden blood loss through the gastrointestinal tract. However, due to the lack of studies on the interaction of clopidogrel with other NSAIDs, it is currently not known whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel together with other NSAIDs. Therefore, the use of NSAIDs, including COX-2 inhibitors in combination with clopidogrel, should be carried out with caution.Other combination therapies: Since clopidogrel is partially metabolized to its active metabolite by the CYP2C19 system, the use of drugs that inhibit this system (for example, omeprazole) is not recommended.
A number of clinical studies have been conducted with clopidogrel and other concomitant medications to investigate possible pharmacodynamic pharmacokinetic interactions, which have shown that:
- when using clopidogrel together with atenolol, nifedipine or both drugs simultaneously clinically significant pharmacodynamic interactions were observed
- concurrent use of phenobarbital, cimetidine and estrogen had no significant effect on the pharmacodynamics of clopidogrel,
- the pharmacokinetic parameters of digoxin or theophylline was not altered in their joint application with clopidogrel
- antacids did not reduce the absorption of clopidogrel,
- phenytoin and tolbutamide can be safely administered concomitantly with clopidogrel (CAPRIE study), despite the fact that the data obtained in studies with human liver microsomes show what carboxyl metabolite of clopidogrel may inhibit the activity of isozyme 2 From 9 families of cytochrome P-450, which may lead to increased plasma concentrations of certain drugs (phenytoin, tolbutamide, and some NSAIDs), which are metabolized with help of isoenzyme 2 From 9 families of cytochrome P450.
- ACE inhibitors, diuretics, beta-blockers, slow calcium channel blockers, hypolipidemic agents, coronary vasodilators, hypolipidemic agents (including insulin), antiepileptic drugs, hormone replacement therapy, and GPIIb/IIIa receptor blockers: no clinically significant adverse interactions were identified in clinical studies.
How to take, course of use and dosage
Clopidogrel is taken orally, regardless of food intake. For the prevention of ischemic disorders in patients after myocardial infarction, ischemic stroke and diagnosed peripheral artery disease-75 mg 1 time/day. Treatment should begin within a few days to 35 days after a myocardial infarction and from 7 days to 6 months after an ischemic stroke.
Non-ST-segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction)Â treatment should begin with a single loading dose of 300 mg, and then continue using the drug at a dose of 75 mg 1 time/day (with simultaneous use of acetylsalicylic acid at a dose of 75-325 mg/day). Since the use of acetylsalicylic acid in high doses is associated with a high risk of bleeding, the recommended dose should not exceed 100 mg. The course of treatment is up to 1 year.
In acute myocardial infarction with ST segment elevation, the drug is prescribed at a dose of 75 mg 1 time/day using an initial loading dose in combination with acetylsalicylic acid in combination or without thrombolytics. For patients over 75 years of age, treatment with clopidogrel should be performed without the use of a loading dose. Combination therapy should be initiated as early as possible after the onset of symptoms and continued for a minimum of 4 weeks.
Overdose
Overdose with clopidogrel can lead to prolonged bleeding time and hemorrhagic complications.
If bleeding is detected, appropriate treatment should be applied.
No antidotes to the pharmaceutical activity of clopidogrel were found.
If a rapid correction of prolonged bleeding time is required, platelet transfusion is recommended.
Special instructions
During treatment, it is necessary to monitor indicators of the hemostatic system (activated partial thromboplastin time (APTT), platelet count, tests of platelet functional activity); regularly examine the functional activity of the liver. Patients should be carefully monitored for any signs of bleeding, including latent bleeding, especially during the first weeks of use of the drug and/or after invasive heart procedures or surgical operations.
Clopidogrel should be used with caution in patients with increased risk of bleeding in trauma, surgery, other pathological conditions, diseases of, predisposing to the development of bleeding (especially gastrointestinal and ocular), and in patients receiving ASA, NSAIDs (including COX-2 inhibitors), heparin, or inhibitors of glycoprotein IIb/IIIa.
Concomitant use of clopidogrel and warfarin is not recommended, as it may increase the intensity of bleeding (except in very rare clinical situations).
In the case of surgical interventions, if the antiplatelet effect is undesirable, the course of treatment should be stopped 7 days before the operation. Clopidogrel prolongs the bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (especially gastrointestinal and intraocular).
Patients should be warned that since stopping bleeding that occurs with clopidogrel (in combination with ASA or without it) requires more time, they should inform the doctor about each case of bleeding. Patients should also inform the doctor (including the dentist) about taking the drug if they are going to undergo surgery, dental procedures, and before starting any new medication.
Very rarely, thrombotic thrombocytopenic purpura (TTP) was observed after taking clopidogrel (including short-term use). This condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia in combination with neurological signs, impaired renal function, or fever. TTP is a potentially life-threatening disease that requires immediate treatment, including plasmapheresis.
Experience with the use of clopidogrel in patients with impaired renal function is limited, so these patients should be prescribed clopidogrel with caution.
Patients with severe hepatic impairment should be aware of the risk of hemorrhagic diathesis, experience with the drug in patients with moderate hepatic impairment is limited, so these patients should be prescribed clopidogrel with caution.
Clopidogrel should not be taken in patients with rare hereditary problems of galactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome.
Influence on the ability to drive a vehicle or other mechanisms.
Due to the possibility of dizziness when taking clopidogrel, caution should be exercised when driving vehicles and engaging in other potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.
Form of production
Film-coated tablets
Storage conditions
At a temperature not exceeding 25 °C
Shelf life
2 years
Active ingredient
Clopidogrel
Conditions of release from pharmacies
By prescription
Dosage form
Tablets
Purpose
Adults as prescribed by a doctor
Indications
Thromboembolism prevention, Acute Myocardial infarction Prevention, Stroke Prevention, Thrombosis Prevention, Angina
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