Koplaviks is a prodrug, one of which is an active metabolite and inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) with P2Y12 platelet receptor and the subsequent ADP-mediated activation of the glycoprotein complex IIb / IIIa, resulting in suppression of platelet aggregation.
Due to the irreversible binding of platelets remain impervious to ADP stimulation throughout the remainder of their useful life (approximately 7-10 days), and the restoration of normal functions of platelets occurs at a rate corresponding to the update rate of platelets. Platelet aggregation caused by agonists other than ADP, it was also inhibited by blocking the activation of enhanced platelet ADP releasable.
Since the formation of an active metabolite occurs by means of P450 isoenzyme system, some of which may be different or polymorphism can be inhibited by other drugs, not all patients may adequate inhibition of platelet aggregation. With daily administration of clopidogrel at a dose of 75 mg from day reception marked significant inhibition of ADP-induced platelet aggregation is gradually increased within 3-7 days, and then goes to a constant level (when reaching equilibrium).
At equilibrium, platelet aggregation is suppressed by an average of 40-60%. After cessation of clopidogrel platelet aggregation, and bleeding time gradually returned to the initial level within an average of 5 days. When comparing the pharmacodynamic properties of clopidogrel in men and women, minimal inhibition of ADP-induced platelet aggregation is observed in women, but sex differences in elongation of bleeding time is not detected.
In patients with recent myocardial infarction, stroke and diagnose peripheral arterial occlusive disease Koplaviks receiving the drug at a dose of 75 mg / day significantly reduced the risk of ischemic events (combined rate of myocardial infarction, stroke, cardiovascular death, and he has the greatest efficacy in patients with occlusive peripheral arterial disease, especially when combined with previous myocardial infarction, as well as more effective in patients younger than 75 years;
Patients with acute coronary syndromes without ST elevation ST (unstable angina, myocardial infarction) the drug Koplaviks (loading dose – 300 mg, then 75 mg / day) in combination with acetylsalicylic acid (ASA) (75 – 325 mg 1 time night) and other standard therapies, regardless of the kinds of simultaneous treatments (heparin blockers glycoprotein IIb / Sha, lipid-lowering drugs, beta-blockers, angiotensin converting enzyme (ACE) inhibitor) and the doses of ASA, significantly reduces the total risk devel ment of ischemic complications of acute myocardial infarction, stroke and cardiovascular death, with a relative risk reduction in the conservative treatment of 17%; translyuminarlnoy after percutaneous transluminal coronary angioplasty (PTCA) with stenting or without stenting is 29% and after coronary artery bypass surgery by 10%.
In patients with acute myocardial infarction (AMI) with ST-segment elevation reception Koplaviks preparation (within the first 12 hours of MI loading dose – 300 mg, then 75 mg / day) in combination with ASA (loading dose of 150-325 mg, followed by 1 75-162 mg once a day) and a fibrinolytic and, if indicated, heparin reduces the combined frequency indicator detectable by angiography at discharge from the hospital coronary artery occlusion related to myocardial zone or death or reinfarction development; while for patients who have not been angiography at discharge – death or reinfarction rate to 8 days infarction or until hospital discharge, mainly by reducing the frequency of coronary artery occlusion, myocardial relating to the area.
In patients with acute myocardial infarction segment elevation ST, decrease ST segment or blockade of the left leg His bundle receiving 75 mg / day Koplaviks drug in combination with ASA 162 mg 1 time per day reduces the frequency of deaths for any reason, and the total first frequency reinfarction, stroke, and death.
Acetylsalicylic acid, Clopidogrel
Adults are prescribed by a doctor
1 tablet contains clopidogrel hydrogensulfate in form II – 97,875 mg (converted to 75 mg of clopidogrel), acetylsalicylic acid – 100 mg.
mannitol 68.925 mg,
macrogol-6000 34,000 mg
-144.764 mg microcrystalline cellulose,
giproloza nizkozame-schennaya – 19,567 mg
Hydrogenated Castor Oil – 3,300 mg,
stearic acid – 1,161 mg,
colloidal silica -0.631 mg,
-11.111 mg corn starch
For the prevention of thrombosis, prevention of heart attacks and strokes
Preventing atherothrombotic complications (in combination with aspirin) in patients with acute coronary syndromes:
- segment elevation ST (unstable angina or myocardial infarction without tooth Q), including patients who underwent stenting for percutaneous coronary intervention;
- segment elevation ST (acute myocardial infarction)
Hypersensitivity to clopidogrel or any of the excipients of the drug.
Severe hepatic insufficiency.
Acute bleeding, e.g., hemorrhage from peptic ulcer or intracranial hemorrhage.
Rare hereditary intolerance to lactose, lactase deficiency and malabsorption syndrome glucose-galactose.
Pregnancy and lactation.
Children under 18 years of age (safety and efficacy have not been established).
• In a clinical study CURE Use of a combination of clopidogrel with aspirin compared with placebo combination with acetylsalicylic acid does not result in a statistically significant increase in the frequency of life-threatening bleeding (2.2% and 1.8%, respectively) and fatal bleeding (0, 2% and 0.2%, respectively).
However, with the combination of clopidogrel + acetylsalicylic acid risk of major, minor and other bleedings was significantly higher: non-hazardous to life major bleeding mainly gastrointestinal and puncture site (1.6% – clopidogrel + acetylsalicylic acid versus 1.0 % – placebo + acetylsalicylic acid) and minor bleedings (5.1% – clopidogrel + acetylsalicylic acid against 2.4% – placebo + acetylsalicylic acid).
The frequency of intracranial hemorrhage in both groups was 0.1%. Frequency major bleeding with the combination of clopidogrel + acetylsalicylic acid was dependent on the dose of the latter (200 mg – 4.9%), as well as their frequency in the application of one of acetylsalicylic acid (200 mg – 4.0%). During the study bleeding risk (representing a danger to life, large, small, others) decreased when receiving a combination of clopidogrel and acetylsalicylic acid, and at the reception of only one of acetylsalicylic acid, constituting respectively 9.6% (599/6259) n 6 6% (413/6303) (0-1 month treatment), 4.5% (276/6123) and 2.3% (144/6168) (1-3 month treatment), 3.8% (228/6037 ) and 1.6% (99/6048) (3-6 month treatment), 3.2% (162/5005) n 1.5% (74/4972) (6-9 month treatment), 1.9% (73/3841) n, 1.0% (40/3844) (9 – 12 months of treatment).
Patients who discontinued taking the drug for more than 5 days before coronary artery bypass surgery, there was no higher incidence of major bleeding within 7 days after the intervention (4.4% – while taking clopidogrel + acetylsalicylic acid versus 5.3% – when receiving audio acetylsalicylic acid). Patients who remained on antiplatelet therapy during the last five days before coronary artery bypass grafting, incidence of these events was 9.6% after intervention (clopidogrel + acetylsalicylic acid) and 6.3% (one acetylsalicylic acid).
• In a clinical study CARPIE overall incidence of bleeding in patients receiving or clopidogrel or acetylsalicylic acid was 9.3%. heavy bleeding rate with clopidogrel was 1.4% and the application acetylsalicylic acid -1.6%. Patients treated with clopidogrel and in patients treated with aspirin, gastrointestinal bleeding occurred in 2.0%, respectively, and 2.7% of cases, hospitalization is required and the 0.7% and 1.1% of cases.
other bleeding was higher for patients receiving Clopidogrel than in patients treated with aspirin (7.3% vs. 6.5%, respectively). However, the incidence of severe bleeding in both groups was the same (0.6% vs. 0.4%). The most frequently observed in both groups purpura / bruising and nosebleeds.
Less commonly encountered hematoma, hematuria and ocular hemorrhages (mainly conjunctival). The frequency of intracranial hemorrhage was 0.4% in patients treated with clopidogrel and 0.5% – in patients who received aspirin. • In a clinical study CLARITY observed general increase in bleeding in clopidogrel + acetylsalicylic acid (17.4%) compared with placebo + acetylsalicylic acid (12.9%).
major bleeding rates were similar in both groups (1.3% and 1.1% groups Clopidogrel + acetylsalicylic acid and acetylsalicylic acid + placebo, respectively) and substantially independent of the baseline characteristics of patients and the type of heparin or fibrinolytic therapy. Frequency fatal bleeding (0.8% and 0.6% in the groups Clopidogrel + acetylsalicylic acid and acetylsalicylic acid + placebo, respectively) and intracranial hemorrhage (0.5% and 0.7% in the groups clopidogrel and acetylsalicylic acid + placebo + acetylsalicylic acid, respectively) was low and did not differ significantly in both treatment groups. • In a clinical study SOMMIT
The overall frequency of large non-cerebral bleeding or cerebral bleeding was low and was not significantly different in both groups (0.6% and 0.5% in the groups clopidogrel and acetylsalicylic acid + placebo + acetylsalicylic acid, respectively).
Hematologic disorders • In a clinical study SAPRIE Severe neutropenia (frequency of severe thrombocytopenia
• In clinical studies, CLARITY and CURE The number of patients with thrombocytopenia or neutropenia in both groups was similar. Other clinically important side effects.
Side effects observed in clinical trials SAPRIE, CURE, CLARITY and SOMMIT with a frequency > 0.1%, and any serious side effects are presented below in accordance with the WHO classifications of side effects. Their frequency is defined as follows: frequent (> 1/100, 1/1000, 1/10000,
Violations of the central and peripheral nervous system: Uncommon: headache, dizziness, and paresthesia. Rare: vertigo.
Disorders of the gastrointestinal tract: Common: diarrhea, abdominal pain, dyspepsia. Uncommon: nausea, gastritis, flatulence, constipation, vomiting, gastric and duodenal ulcers.
Violations by the hemostasis: Uncommon: prolonged bleeding time.
Blood disorders: Uncommon: thrombocytopenia, leukopenia, neutropenia, and eosinophilia.
Violations of the skin and subcutaneous tissue disorders: Uncommon: rash and pruritus. Undesirable effects observed in post-marketing period, clopidogrel monotherapy and in combination with acetylsalicylic acid: Bleeding: The most frequently reported adverse events were reports of bleeding, which is most often observed in the first month of treatment.
It has been several cases of bleeding with a fatal outcome, mainly intracranial, gastrointestinal and retroperitoneal. There are reports of severe cases, bleeding in the tissues of the skin (purpura), bleeding in joints and muscles (haemarthrosis, hematoma), eye haemorrhage (conjunctival, in the tissue and the retina), nosebleeds, bleeding from the respiratory system (hemoptysis, pulmonary hemorrhage) hematuria and bleeding from the surgical wound.
Patients taking Clopidogrel simultaneously with acetylsalicylic acid, or simultaneously with acetylsalicylic acid and heparin, there were cases of severe bleeding (cm. ‘Interaction with other drugs, “and” special instructions “).
Other side effects: In addition to the adverse effects identified in clinical studies and listed above, as a result of spontaneous reports submitted following side effects have been reported, divided into groups according to the classification of adverse reactions in accordance with lesions of the organs and organ systems, presented at the medical dictionary for regulatory activities MedDRA). The frequency of spontaneous reports of side effects observed with clopidogrel, was very low (they are classified as very rare blood disorders: – Anemia (due to clopidogrel or acetylsalicylic acid) – thrombotic thrombocytopenic purpura (1:. 200,000 treated patients), severe thrombocytopenia (platelet count < 30×109 / l), agranulocytosis, granulocytopenia, aplastic anemia (pancytopenia) (due to clopidogrel)
Disorders of immune system: – Angioneurotic edema, urticaria, anaphylactoid reaction, serum sickness (caused by clopidogrel), anaphylactic shock, weighting symptoms of food allergy (caused by acetylsalicylic acid).
Psychiatric disorders: – Confusion, hallucinations (due to klopdogrelom).
Disorders of the nervous system: – changes in taste (arising with clopidogrel).
Violations by the organ of hearing and labyrinth disorders – Tinnitus, hearing loss (caused by acetylsalicylic acid and usually arise in her overdose).
Violations of the vascular system: – Vasculitis, lowering blood pressure (caused by clopidogrel).
Disorders of the respiratory system: – Bronchospasm (due to clopidogrel or acetylsalicylic acid), interstitial pneumonitis (due to clopidogrel).
Disorders of the gastrointestinal tract: – pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis (caused by clopidogrel). – peptic ulcer or perforation of the stomach or duodenum, defeat the symptoms of upper gastrointestinal (GI) tract, such as gastralgia (caused by acetylsalicylic acid).
Violations of the hepato-biliary system: – Acute liver failure, hepatitis (arising clopidogrel).
Disorders of the skin and subcutaneous tissue – or erythematous maculopapular rash, pruritus, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), eczema, and lichen planus (due clopidogrel).
Violations of the musculoskeletal system: – arthralgia, arthritis, myalgia (due clopidogrel).
Violations of the kidneys and urinary tract: – glomerulopathy (caused clopidogrel), acute renal failure (particularly in patients with pre-existing kidney disease, congestive heart failure, nephritic syndrome or simultaneous use of diuretics) (caused by acetylsalicylic acid).
Violations of the metabolism: – Hypoglycemia, gout (caused by acetylsalicylic acid).
General disorders: – Fever (due to clopidogrel).
Changes in laboratory parameters: – Abnormal biochemical indicators of liver functional state, increasing the concentration of creatinine in the blood (due to clopidogrel).
How to accept, acceptance rate and dosage
Adults and the elderly
Koplaviks taken orally, regardless of the meal. The tablet containing 300 mg of clopidogrel, intended for use as a loading dose patients with acute coronary syndrome.
Acute coronary syndromes without ST segment lift (unstable angina, myocardial infarction without tooth Q)
clopidogrel treatment should be initiated with a single dose of a loading dose of 300 mg, and then continue taking a dose of 75 mg once daily (in combination with acetylsalicylic acid at doses of 75-325 mg per day). Because the use of higher doses of acetylsalicylic acid associated with increased bleeding risk, the recommended dose in this indication acetylsalicylic acid should not exceed 100 mg. The maximum beneficial effect is observed for the third month of treatment. The course of treatment up to 1 year.
Acute coronary syndrome segment elevation ST (acute myocardial infarction segment elevation ST)
Clopidogrel is assigned a single dose of 75 mg once a day with an initial loading dose of a single dose of 300 mg in combination with acetylsalicylic acid, thrombolytics (or without thrombolysis). Combination therapy is started as early as possible after the onset of symptoms and continued for at least four weeks. In patients older than 75 years treated with clopidogrel should start without receiving a loading dose of it.
With regard to the maintenance dose of clopidogrel is 75 mg for the tablets produced its reception Plavike 75 mg.
Patients with genetically determined reduction function isoenzyme CYP2CJ9
Status SYP2C19 poor-metaboliser associated with a reduced antiplatelet action of clopidogrel. Mode of high doses (600 mg -nagruzochnaya dose followed by 150 mg once a day every day) have poor metabolizers increases antiplatelet effect of clopidogrel. However, the optimal dosing regimen for patients with a decreased metabolism via CYP2C19 isoenzyme in clinical studies on clinical outcomes is not yet installed.
Store at a temperature not higher than 30 ° C.
Acetylsalicylic acid, Clopidogrel
Warfarin: simultaneous reception with clopidogrel may increase the intensity of bleeding, so the use of this combination is not recommended.
Blockers glycoprotein IIb / IIIa: appointment blockers glycoprotein IIb / IIIa in conjunction with clopidogrel requires caution in patients who have an increased risk of bleeding (trauma and surgery or other pathological conditions) (see “Cautions”.).
Acetylsalicylic acid: acetylsalicylic acid, clopidogrel modifies non effect inhibiting ADP-induced platelet aggregation, clopidogrel but potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, simultaneous with receiving clopidogrel aspirin 500 mg two times a day does not cause a substantial increase in bleeding time for 1 day, the local reception clopidogrel. Between clopidogrel and acetylsalicylic acid may pharmacodynamic interaction, which leads to increased risk of bleeding. Therefore, when simultaneous application of caution, although clinical trials of patients received a combination therapy with clopidogrel and acetylsalicylic acid up to one year.
Heparin: according to clinical trials conducted in healthy individuals, while taking clopidogrel did not need to change the dose of heparin and did not change its anticoagulant effect. The simultaneous use of heparin did not alter the antiplatelet effect of clopidogrel. Between clopidogrel and heparin possible pharmacodynamic interactions, which may increase the risk of bleeding, so simultaneous use of these preparations requires caution.
Thrombolytics: joint application of the safety of clopidogrel fibrinspetsificheskih fibrinnespetsificheskih or thrombolytic agents and heparin was studied in patients with acute myocardial infarction. The incidence of clinically relevant bleeding was similar to that observed in the case of joint use of thrombolytic agents and heparin, acetylsalicylic acid.
Nonsteroidal anti-inflammatory drugs (NSAIDs): in a clinical study conducted in healthy volunteers, the combined use of clopidogrel and naproxen increased occult blood loss from the gastrointestinal tract. However, due to the lack of research on the interaction of clopidogrel with other NSAIDs, it is not known the time, whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel with other NSAIDs. Therefore, the appointment of NSAIDs, including COX-2 inhibitors, in combination with clopidogrel should be undertaken with caution.
Another combination therapy
Since Clopidogrel is metabolized to form its active metabolite partially by isoenzyme CYP2C19, use of drugs inhibiting this system can reduce the concentration of the active metabolite of clopidogrel. The clinical significance of this interaction is not established. simultaneous application should be avoided with clopidogrel strong or moderate CYP2C19 inhibitors (e.g. omeprazole). If the proton pump inhibitors should be administered simultaneously with clopidogrel, use of proton pump inhibitor with the smallest inhibitory activity isoenzyme CYP2C19, such as pantoprazole.
Due to the presence of two antiplatelet drug Koplaviks® substances it should be used with caution in patients at high risk of bleeding caused by trauma, surgery or other pathological conditions, as well as in patients receiving non-steroidal anti-inflammatory drugs (including, COX-2 inhibitors), heparin, inhibitors of glycoprotein II / Sha and thrombolytic agents.
It is necessary to conduct a thorough monitoring of patients in order to exclude signs of bleeding, including the hidden, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgery.
The combined use of clopidogrel with warfarin can enhance the intensity of bleeding (cm. ‘Interaction with other drugs “), however, except for special rare clinical situations (such as the presence of floating thrombus in the left ventricle, stenting for patients with atrial fibrillation or other indications for anticoagulation indirect action), and the combined use of Koplaviksa varfariia not recommended.
If the patient will have elective surgery, and thus there is no need for an antithrombotic effect, then 7 days prior to surgery Koplaviks® should be abolished. Koplaviks® increases bleeding time and should be used with caution in patients with lesions predisposing to the development of bleeding (especially gastrointestinal and intraocular hemorrhage).
Due to the risk of bleeding and hematologic adverse effects (see., “Side effects”) in the case of during the treatment of clinical symptoms suspicious for occurrence of bleeding, it is necessary to urgently make CBC determine APTT (activated partial thromboplastin time), the number of platelets , indicators of the functional activity of platelets and conduct other necessary investigations.
Very rarely, after application of clopidogrel (sometimes even short) have been reported cases of thrombotic thrombocytopenic purpura (THP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, renal dysfunction and fever. TTP is a potentially life-threatening condition that requires immediate treatment including plasmapheresis.
It was clearly shown that in patients with a recent transient ischemic attack or brain stroke, have an increased risk of recurrent ischemia, the combination of aspirin and clopidogrel increases the possibility of major bleeding. Therefore, when applying Koplaviks® the drug in such patients, in all cases, including those where the beneficial effect of the combination has been proven to be careful.
Perhaps the relationship between aspirin and the emergence of a life-threatening syndrome Reye at the prodromal infection in children. Koplaviks® should be used with caution in patients with peptic ulcer or gastrointestinal bleeding history or in patients with even mild symptoms of upper gastrointestinal tract, which can be symptoms of ulcerative lesions of the stomach that can lead to gastric bleeding. When treating drug Koplaviks® at any time may have symptoms from the upper gastrointestinal tract, such as gastralgia, heartburn, nausea, vomiting and gastrointestinal bleeding.
Despite the fact that the treatment of drug Koplaviks® minor side effects from the gastrointestinal tract, such as dyspepsia, are common, the attending physician is always in these cases, should exclude gastrointestinal ulceration and bleeding of mucous membranes, even in the absence of disease history with the gastrointestinal tract.
Patients should be informed about the symptoms of adverse reactions from the gastrointestinal tract. Patients should also be warned that when receiving Koplaviks® drug to stop bleeding it may take longer than usual, and that, in case they have any unusual (for location or duration) of bleeding, they should report it to your doctor . Before any forthcoming operation and before you proceed to the acceptance of any new drug, patients should inform the physician (including dentists) on the treatment of drug Koplaviks®.
Patients with impaired metabolic function izofsrmenta CYP2C19 with clopidogrel at recommended doses produce less active metabolite of clopidogrel decreases its effect on platelet function. Therefore, patients with acute coronary syndrome or undergoing percutaneous coronary intervention and receiving clopidogrel may have a greater incidence of cardiovascular events than patients with normal isoenzyme CYP2C19.
This preparation should not accept patients with the rare genetic disorders galactose tolerability, with lactase deficiency syndrome or glucose-galactose malabsorption (see. “Composition”).
Effects on ability to drive and engage in other potentially hazardous activities that require high concentration and speed of psychomotor reactions
Koplaviks® usually has no significant effect on the ability to drive and engage in other potentially hazardous activities that require high concentration and psychomotor speed reactions. However, in case of patient adverse reactions in the nervous system and psyche (see. Section “Side effects”) may reduce the concentration of attention and speed of psychomotor reactions, which may hinder engage in such activities. In such cases, the possibility of a class of potentially hazardous activities should be decided by the attending physician.
Pregnancy and lactation
Clopidogrel Overdose can lead to increased bleeding time and subsequent complications in the form of bleeding. If bleeding appears appropriate treatment was required.
An antidote to clopidogrel is not installed. If you need a quick correction to lengthen bleeding time, it is recommended that a platelet transfusions.
Data concerning overdose Koplaviks®, no drug.
Symptoms and treatment of overdosage clopidogrel
Symptoms and Treatment of overdoses of acetylsalicylic acid
Moderate degree of overdose: ringing in the ears, sensation of hearing loss, headaches, vertigo.
Heavy overdose: fever, hyperventilation, ketosis, respiratory alkalosis, metabolic acidosis, coma, cardiovascular collapse (collapse), respiratory failure, severe hypoglycemia.
In the case of acetylsalicylic acid severe overdosage should take the following steps: monitoring the acid-base equilibrium, intravenous administration of sodium bicarbonate (to alkalinization of forced to accelerate excretion of urine salicylates), if necessary, can apply hemodialysis or peritoneal dialysis.