Composition, form of production and packaging
Tablets, film-coated 1 tab.
clopidogrel 75 mg
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (2) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2012.
PHARMACHOLOGIC EFFECT
Antiaggregant agent. Selectively reduces the binding of adenosine diphosphate (ADP) to platelet receptors and the activation of Ilb / IIIa glycoprotein receptors under the action of ADP, disrupting platelet aggregation.
Reduces platelet aggregation caused by other agonists, preventing their activation by released ADP, does not affect the activity of phosphodiesterase (PDE).Irreversibly binds to ADP-receptor platelets, which remain immune to stimulation of ADP throughout the life cycle (about 7 days).
The inhibition of platelet aggregation is observed after 2 hours after administration (40% inhibition) of the initial dose of 400 mg. With the long-term administration of therapeutic doses of clopidogrel (75 mg / day), a marked inhibition of platelet aggregation is noted as early as the first day of treatment. The maximum effect (60% suppression of aggregation) develops after 4-7 days of constant admission in a dose of 50-100 mg / day. Antiaggregant effect persists throughout the life span of platelets (7-10 days). After the end of treatment, the effect of clopidogrel on aggregation and bleeding time usually decreases within 5 days.
PHARMACOKINETICS
Suction
Absorption and bioavailability of the drug is high. After a second oral dose of 75 mg / day, clopidogrel is rapidly absorbed. The concentration of the main compound in the plasma is low, after 2 hours after administration it does not reach the measurement limit (0.025 Ојg / l). Clopidogrel and its main circulating metabolite bind reversibly to plasma proteins (98% and 94%, respectively).
Metabolism
Clopidogrel is rapidly metabolized in the liver. Its main metabolite is inactive and accounts for about 85% of the compound circulating in the plasma. With mР° this metabolite in plasma (about 3 mg / l after application of repeated oral doses in 75 mg) is observed in an hour after reception. The kinetics of the main metabolite showed a linear dependence (increase in plasma concentration depending on the dose) within the dose range of 50 to 150 mg of clopidogrel. The concentration of the main metabolite in plasma after taking 75 mg / day is lower in patients with severe kidney disease (creatinine clearance 5-15 ml / min) compared with patients with moderate kidney disease (creatinine clearance from 30 to 60 ml / min) and healthy persons.
Clopidogrel is a precursor of the active substance. Its active metabolite is formed by oxidation of clopidogrel and subsequent hydrolysis. The oxidative stage is regulated, first of all, by cytochrome P450 isoenzymes: 2B6 and 3A4. The active metabolite quickly and irreversibly binds to platelet receptors and suppresses platelet aggregation. This metabolite is not detected in plasma.
Excretion
About 50% of the drug is excreted by the kidneys with urine and approximately 46% with feces within 120 hours after administration. T 1/2 of the main metabolite is 8 hours after a single and repeated administration. The concentration of kidney metabolites is 50%
Pharmacokinetics of special groups
Several polymorphic enzymes of the P450 system are involved in the activation of clopidogrel. The CYP2C19 isozyme is involved in the formation of both an active metabolite and an intermediate metabolite, 2-oxoclopidogrel. The pharmacokinetics and antiplatelet effects of the active metabolite of clopidogrel, studied by ex vivo platelet aggregation, differ depending on the genotype of the CYP2C19 isoenzyme. The allele of the CYP2C19 * 1 gene is responsible for the normally functioning metabolism, whereas the alleles of the CYP2C19 * 2 isoenzyme and the CYP2C19 * 3 isoenzyme are responsible for reduced metabolism. These alleles are responsible for a decrease in metabolism in about 85% of the representatives of the Caucasoid race and 99% in the representatives of the Mongoloid race. Other alleles associated with reduced metabolism are represented by CYP2C19 * 4, * 5, * 6, * 7 and * 8 isoenzymes, but they are rarely found in the general population. Published data on the frequency of occurrence of the phenotype and genotype of the isoenzyme CYP2C19 are presented in the table.
Frequency of occurrence of the phenotype and genotype of the isoenzyme CYP2C19 Frequency%
Europeoids (n = 1356) Negroids (n = 966) Mongoloids (n = 573)
Intensive metabolism of the isoenzyme CYP2C19 * 1 / * 1 74 66 38
Interim metabolism of the isoenzyme CYP2C19 * 1 / * 2 or. * 1 / * 3 26 29 50
Reduced metabolism of the isoenzyme CYP2C19 * 2 / * 2 or * 2 / * 3 or * 3 / * 3 2 4 14
The effect of the CYP2C19 isoenzyme genotype on the pharmacokinetics of the active metabolite of clopidogrel was studied in 227 people in 7 published studies. In individuals with a reduced metabolism of the CYP2C19 isoenzyme, a decrease in C max and an area under the concentration-time curve (AUC) of the active metabolite by 30-50% after taking a loading dose of 300 mg or 600 mg and a subsequent maintenance dose of 75 mg was observed. Reduced activity of the metabolite clopidogrel may lead to a lesser degree of platelet inhibition or to their increased reactivity. A weakened antiplatelet response to clopidogrel was described for individuals with intermediate and decreased metabolism in 21 studies on 4520 subjects. The relative difference in the antiplatelet response between groups with different genotypes differed in studies due to the use of different methods of assessing the response, but was more than 30%. The relationship between the genotype of the isoenzyme CYP2C19 and the outcome of clopidogrel therapy was evaluated in two postgraduate clinical trials (CLARITY-TIMI28 (n = 465) and TRITON-TTMI38 (n = 1477) and 5 cohort studies (n = 6489) .In CLAR1TY-TIMI28 and in one of the cohort studies (Trenk, n = 765), the frequency of cardiovascular events did not differ significantly depending on the genotype.In TRITON-TIMI38 and three cohort studies (Collet, Sibbing, Giusti, n = 3516), patients with intermediate and decreased metabolism had a higher incidence of cardiovascular events (myocardial infarction, and stroke, death) or stent thrombosis compared to patients with good metabolism.In the fifth cohort study (Simon, n = 2208), an increase in the incidence of cardiovascular events was observed only in patients with reduced metabolism.
Pharmacogenetic testing allows us to determine the genotype with the variability of the activity of the isoenzyme CYP2C19.
Genetic variants of other enzymes of the P450 system with effects on the ability of formation of active metabolites of clopidogrel are also possible.
INDICATIONS
- prophylaxis of thrombotic complications in patients with myocardial infarction, ischemic stroke or occlusion of peripheral arteries;
- in combination with acetylsalicylic acid (ASA) for the prevention of thrombotic complications in acute coronary syndrome: with the elevation of the ST segment with the possibility of carrying out thrombolytic therapy; without ST segment elevation (unstable angina, myocardial infarction without Q-wave), incl. in patients undergoing stenting.
DOSING MODE
Inside, regardless of food intake.
For the prevention of thrombotic complications in patients with myocardial infarction, ischemic stroke or occlusion of peripheral arteries - 75 mg 1 time / day.
In patients with myocardial infarction, treatment can begin from the first days of the 35th day of myocardial infarction, and in patients with ischemic stroke - in the period from 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 Q wave) - begin with a single dose loading dose of 300 mg, and then take 75 mg / day (in combination with ASA in doses of 75- 325 mg / day, the recommended dose is 100 mg / day). The maximum favorable effect occurs after 3 months. The course of treatment is up to 1 year. To prevent thrombotic complications in acute coronary syndrome with ST segment elevation (acute myocardial infarction with ST-segment elevation) - 75 mg / day with initial single dose loading in combination with ASA and thrombolytic agents (or without thrombolytics).
Combination therapy is started as soon as possible after the onset of symptoms and continues for at least 4 weeks. In patients older than 75 years, treatment with clopidogrel should begin without taking its loading dose. In patients with a genetically determined decrease in the function of the isoenzyme CYP2C19, the effect of clopidogrel may be reduced. The optimal dosage regimen in these patients is not established.
SIDE EFFECT
Clopidogrel, as a rule, is well tolerated. Undesirable effects rarely require withdrawal of clopidogrel treatment.
On the part of the organs of hematopoiesis: infrequently - thrombocytopenia, leukopenia, eosinophilia; rarely - neutropenia, incl. expressed; very rarely - thrombotic thrombocytopenic purpura, anemia, incl. aplastic, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia.
Allergic reactions: very rarely - anaphylactic reactions, serum sickness.
From the nervous system: infrequently - headache, dizziness, paresthesia, intracranial hemorrhage, incl. with lethal outcome; very rarely - confusion, hallucinations, a taste disorder.
From the sense organs: infrequently - hemorrhage in the conjunctiva of the eye, retina; rarely - vertigo.
From the cardiovascular system: often - hematoma; very rarely - heavy bleeding, bleeding from the operating wound, vasculitis, lowering blood pressure.
On the part of the respiratory system: very often - nosebleeds; very rarely - bronchospasm, interstitial pneumonitis, pulmonary hemorrhage, hemoptysis.
On the part of the digestive system: often - diarrhea, abdominal pain, indigestion, bleeding from the gastrointestinal tract; infrequently - stomach ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence; rarely - retroperitoneal bleeding; very rarely - pancreatitis, colitis, incl. ulcerative or lymphocytic, stomatitis, acute hepatic insufficiency, hepatitis, a violation of functional liver tests, bleeding from the gastrointestinal tract with lethal outcome.
From the skin: often - subcutaneous hemorrhage; infrequently - skin rash, itching, purpura; very rarely - angioedema, urticaria, erythematous rash, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, eczema, lichen planus.
From the side of the musculoskeletal system: very rarely - hemarthrosis, arthritis, arthralgia, myalgia.
From the genitourinary system: infrequently - hematuria; very rarely - glomerulonephritis, hypercreatininaemia.
Local reactions: often - bleeding at the injection site.
Laboratory indicators: infrequent - prolongation of bleeding time.
Other: very rarely - fever.
CONTRAINDICATIONS
hypersensitivity;
severe hepatic impairment;
- Acute bleeding (including bleeding from peptic ulcers or intracranial hemorrhage);
- Pregnancy and the period of breastfeeding;
- Children and adolescence under 18 years.
With caution : moderate hepatic insufficiency, chronic renal failure (CRF), pathological conditions that increase the risk of bleeding (including trauma, surgery), a tendency to bleed, concurrent administration of ASA, warfarin, NSAIDs (including cyclooxygenase-2 inhibitors) , heparin and glycoprotein IIb / IIIa inhibitors, a hereditary decrease in the isoenzyme function of CYP2C19.
PREGNANCY AND LACTATION
The use of clopidogrel is contraindicated in pregnancy. For the duration of treatment, breastfeeding should be discontinued.
APPLICATION FOR FUNCTIONS OF THE LIVER
The experience of using in patients with chronic renal failure (CRF) is limited.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Contraindicated in severe hepatic insufficiency.
The experience of using in patients with moderate degree of hepatic insufficiency is limited.
APPLICATION FOR CHILDREN
Contraindicated in children and adolescents under 18 years.
APPLICATION IN ELDERLY PATIENTS
In patients older than 75 years, treatment with clopidogrel should begin without taking its loading dose.
SPECIAL INSTRUCTIONS
In the case of surgical interventions, if antiaggregant effect is undesirable, the course of treatment should be discontinued 7 days before the operation.
Patients should be warned that because the stoppage of the bleeding that occurs when the drug is used requires more time, they should inform the doctor about every case of unusual bleeding. Patients should also inform the doctor about taking the medication if they are undergoing surgery (including dental surgery) or if the doctor prescribes a new medication for the patient.
During the treatment period, it is necessary to monitor the parameters of the hemostatic system (active partial thromboplastin time (APTT), the number of platelets, tests of the functional activity of thrombocytes); regularly investigate the functional activity of the liver. In case of severe violations of liver function, one should remember about the risk of hemorrhagic diathesis.
It is not recommended to prescribe to patients with ischemic stroke less than 7 days old. Preparations containing hydrogenated castor oil can induce dyspepsia and diarrhea.
Very rarely, when taking clopidogrel, thrombotic thrombocytopenic purpura developed, sometimes after short-term use. The condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia, associated with neurologic disorders, kidney damage and fever. Thrombotic thrombocytopenic purpura is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.
In the absence of violations of the kidneys should follow the usual dosage regimen. The experience of using in patients with chronic renal failure (CRF) and / or moderate degree of hepatic insufficiency is limited.
Features of the drug at the first admission or when it is canceled
No features of the action when the first reception or withdrawal of clopidogrel is registered. No special actions by the doctor (paramedic) or the patient while skipping one or more doses of the drug are required.
Impact on the ability to drive vehicles and manage mechanisms
Clopidogrel does not significantly affect the abilities necessary for driving or working with machinery.
OVERDOSE
Symptoms: lengthening bleeding time, hemorrhagic complications.
Treatment: stop bleeding, transfusion of platelet mass.
DRUG INTERACTION
Joint use of clopidogrel with warfarin may increase the intensity of bleeding, so this combination is not recommended.
Acetylsalicylic acid does not alter the ADP-induced platelet aggregation caused by clopidogrel. Clopidogrel enhances the effect of acetylsalicylic acid on collagen-induced platelet aggregation, so when using these drugs together, care must be taken.
The appointment of IIb / IIIa receptor blockers in conjunction with clopidogrel requires caution in patients who have an increased risk of bleeding (with trauma and surgical interventions or other pathological conditions).
The simultaneous use of heparin does not alter the inhibitory effect of clopidogrel on platelet aggregation. Clopidogrel with co-administration does not change the need for heparin and the action of heparin on blood coagulation. However, the simultaneous use of these drugs requires caution.
NSAIDs: In a clinical study conducted with the participation of healthy volunteers, the combined use of clopidogrel and naproxen increased hidden blood loss through the gastrointestinal tract. However, due to the lack of research on the interaction of clopidogrel with other NSAIDs, it is not currently known whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel together with other NSAIDs. Therefore, the appointment of NSAIDs, including COX-2 inhibitors, in combination with clopidogrel should be done with caution.
Combined use with other drugs: no significant clinical interactions were detected with simultaneous administration of clopidogrel and such drugs as atenolol, angiotensin converting enzyme (ACE) inhibitors, lipid-lowering agents, nifedipine, digoxin, phenobarbital, cimetidine, estrogens, theophylline, phenytoin, tolbutamide. Clopidogrel inhibits the activity of the enzyme CYP2C9 of the cytochrome P450 system with simultaneous use with drugs that are metabolized with the participation of this enzyme (phenytoin, tolbutamine), so it is possible to increase them in blood plasma. Since clopidogrel is metabolized prior to the formation of its active metabolite in part by the CYP2C19 system, the use of drugs that inhibit this system can lead to a decrease in the level of the active metabolite of clopidogrel and a decrease in its clinical effectiveness. Simultaneous administration of drugs that inhibit the CYP2C19 system (eg, omeprazole) is not recommended . Antacids do not affect the absorption of clopidogrel.
Simultaneous reception of clopidogrel with food and drink: eating does not have any effect. Clopidogrel can be taken regardless of food intake.
TERMS OF RELEASE FROM PHARMACY
On prescription.
TERMS AND CONDITIONS OF STORAGE
Store in a dry place inaccessible to children at a temperature not exceeding 25 В° C.
Shelf life - 2,5 years.
