Active ingredient: clopidogrel hydrosulfate in the form of II97.875 mg (in terms of clopidogrel - 75 mg);
Excipients: mannitol - 68.925 mg; macrogol 6000 - 34 mg; MCC (with a low water content of 90 microns) - 31 mg; low substituted hyprolose - 12.9 mg; hydrogenated castor oil - 3.3 mg;
Film sheath: Opadry pink (lactose monohydrate, hypromellose, titanium dioxide (E171), triacetin, dye iron oxide red (E172) - 7.5 mg; carnauba wax - traces
Plavix is anti-aggregation.
Clopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. The active clopidogrel metabolite selectively inhibits the binding of ADP to the P2Y12 platelet receptor and subsequent ADP-mediated activation of the GPIIb / IIIa complex, leading to inhibition of platelet aggregation. Due to irreversible binding, platelets remain immune to ADP stimulation for the rest of their life (approximately 7–10 days), and normal platelet function is restored at a rate corresponding to platelet renewal rate.
Platelet aggregation caused by agonists other than ADP is also inhibited by the blockade of increased platelet activation by the released ADP.
Since the formation of the active metabolite occurs with the help of enzymes of the P450 system, some of which may differ in polymorphism or be inhibited by other drugs, not all patients may have adequate inhibition of platelet aggregation.
With daily intake of clopidogrel at a dose of 75 mg from the first day of administration, there is a significant suppression of ADP-induced platelet aggregation, which gradually increases over 3-7 days and then reaches a constant level (upon reaching equilibrium). In equilibrium, platelet aggregation is suppressed by an average of 40-60%. After stopping clopidogrel, platelet aggregation and bleeding time gradually return to their original level, on average over 5 days.
Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular with lesions of the cerebral, coronary or peripheral arteries.
The ACTIVE-A clinical study showed that in patients with atrial fibrillation who had at least one risk factor for vascular complications but were unable to take indirect anticoagulants, clopidogrel in combination with acetylsalicylic acid (ASA) (compared with taking only one ASA) reduced the frequency of combined stroke, myocardial infarction, systemic thromboembolism outside the central nervous system vessels or vascular death, to a greater extent by reducing the risk of stroke.
The effectiveness of clopidogrel in combination with acetylsalicylic acid was detected early and lasted up to 5 years. The decrease in the risk of major vascular complications in the group of patients taking clopidogrel in combination with acetylsalicylic acid was mainly due to a greater decrease in the frequency of strokes. The risk of developing a stroke of any severity when taking clopidogrel in combination with ASA was reduced, and there was a tendency to decrease the incidence of myocardial infarction in the group treated with clopidogrel in combination with ASA, but there was no difference in the frequency of thromboembolism outside the central nervous system vessels or vascular death. In addition, taking clopidogrel in combination with ASA reduced the total number of days of hospitalization for cardiovascular reasons.
Suction. With a single and repeated oral administration at a dose of 75 mg / day, clopidogrel is rapidly absorbed.
Average peak plasma concentrations of unchanged clopidogrel (approximately 2.2–2.5 ng / ml after ingestion of a single dose of 75 mg) are reached approximately 45 minutes after administration. According to urinary excretion of clopidogrel metabolites, its absorption is approximately 50%.
Distribution. In vitro, clopidogrel and its main inactive metabolite circulating in the blood bind reversibly to plasma proteins (by 98 and 94%, respectively), and this bond is unsaturated in a wide range of concentrations.
Metabolism. Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, clopidogrel is metabolized in two ways: the first through esterases and subsequent hydrolysis to form an inactive metabolite, a derivative of carboxylic acid (85% of the circulating metabolites), and the second route through the cytochrome P450 system. Initially, clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of an active metabolite of clopidogrel - a thiol derivative of clopidogrel. In vitro, this metabolic pathway occurs using the P450 isoenzymes CYP2C19, CYP1A2, and CYP2B6. The active thiol metabolite of clopidogrel, which was isolated in in vitro studies, quickly and irreversibly binds to receptors
platelets, blocking platelet aggregation.
Breeding. Within 120 hours after human ingestion of 14C-labeled clopidogrel, about 50% of the radioactivity is excreted in the urine and approximately 46% of the radioactivity is excreted in the feces. After a single oral dose of 75 mg T1 / 2, clopidogrel is approximately 6 hours. After a single dose and repeated doses of T1 / 2, the main inactive metabolite circulating in the blood is 8 hours.
Pharmacogenetics. Using the CYP2C19 isoenzyme, both an active metabolite and an intermediate metabolite, 2-oxo-clopidogrel, are formed. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel, when examining platelet aggregation ex vivo, vary depending on the genotype of the isoenzyme CYP2C19.
The allele of the CYP2C19 * 1 gene corresponds to a fully functional metabolism, while the alleles of the CYP2C19 * 2 and CYP2C19 * 3 genes are non-functional. Alleles of the CYP2C19 * 2 and CYP2C19 * 3 genes are the cause of a decrease in metabolism in most representatives of the Caucasoid (85%) and Mongoloid race (99%). Other alleles associated with a lack or decrease in metabolism are less common and include, but are not limited to, alleles of the CYP2C19 * 4, * 5, * 6, * 7 and * 8 genes. Patients with low activity of the CYP2C19 isoenzyme should possess the two function alleles indicated above.
The published phenotypic frequencies of individuals with low activity of the isoenzyme CYP2C19 are 2% in persons of the Caucasian race, 4% in persons of the Negroid race, and 14% in Chinese.
To determine the patient’s genotype for the isoenzyme СYP2C19, appropriate tests exist. According to a cross-sectional study (40 healthy volunteers) and a meta-analysis of six studies (335 healthy volunteers) that took clopidogrel, which included healthy volunteers with very high, high, intermediate and low activity of the CYP2C19 isoenzyme, there were no significant differences in the exposure of the active metabolite and in the average values of inhibition of platelet aggregation (IAT) (induced by ADP) in healthy volunteers with very high, high and intermediate activity of the CYP2C19 isoenzyme was not detected. In healthy volunteers with low activity of the CYP2C19 isoenzyme, the exposure of the active metabolite was reduced compared to healthy volunteers with high activity of the CYP2C19 isoenzyme.
When healthy volunteers with low activity of CYP2C19 isoenzyme received a treatment regimen of 600 mg - loading dose / 150 mg - maintenance dose (600/150 mg), the exposure of the active metabolite was higher than when taking the treatment regimen 300/75 mg. In addition, IAT was similar to that in groups of healthy volunteers who received clopidogrel, with a higher metabolic rate using the CYP2C19 isoenzyme, receiving a 300/75 mg treatment regimen. Clopidogrel dosing regimen with low activity of CYP2C19 isoenzyme.
Prevention of atherothrombotic complications:
adult patients with myocardial infarction (from a few days to 35 days old), ischemic stroke (from 7 days to 6 months old) or diagnosed with peripheral arterial occlusion disease;
adult patients with acute coronary syndrome: without ST segment elevation (unstable angina or myocardial infarction without Q wave), including patients who underwent stenting with percutaneous coronary intervention (in combination with ASA); with an increase in the ST segment (acute myocardial infarction) with drug treatment and the possibility of thrombolysis (in combination with ASA).
Prevention of atherothrombotic and thromboembolic complications, including stroke, with atrial fibrillation (atrial fibrillation).
Patients with atrial fibrillation (atrial fibrillation), who have at least one risk factor for the development of vascular complications, cannot take indirect anticoagulants and have a low risk of bleeding (in combination with ASA).
hypersensitivity to clopidogrel or any of the excipients of the drug;
severe liver failure;
acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage;
rare hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption;
pregnancy and lactation (see. "Use during pregnancy and lactation");
children under 18 years of age (safety and efficacy have not been established).
With caution in the following conditions: moderate hepatic insufficiency, in which a predisposition to bleeding is possible (limited clinical experience); renal failure (limited clinical experience); injuries, surgical interventions (see. "Special instructions"); diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal or intraocular); concomitant use of NSAIDs, including and selective COX-2 inhibitors; concomitant use of warfarin, heparin, glycoprotein inhibitors on IIb / IIIa; patients with a genetically determined decrease in the function of the CYP2C19 isoenzyme (there is published data indicating that patients with a genetically determined decrease in the function of the CYP2C19 isoenzyme have a lower systemic exposure to the active metabolite of clopidogrel and have a less pronounced antiplatelet effect of the drug, in addition, they may have a higher heart rate -vascular complications after myocardial infarction compared with patients with normal function of the CYP2C19 isoenzyme); history of allergic reactions to thienopyridines (e.g. ticlopidine, prasugrel - the possibility of cross-allergy); recent transient cerebrovascular accident or acute ischemic stroke
From the nervous system: infrequently - headache, dizziness, paresthesia; rarely - vertigo.
From the digestive tract: often - dyspepsia, abdominal pain, diarrhea; infrequently - nausea, gastritis, bloating, constipation, vomiting, stomach ulcer, duodenal ulcer.
From the skin and subcutaneous tissue: infrequently - rash, itching.
On the part of the blood and lymphatic system: infrequently - an increase in bleeding time, a decrease in the number of platelets in the peripheral blood, leukopenia, a decrease in the number of neutrophils in the peripheral blood, eosinophilia.
Post-marketing experience with the drug
On the part of the blood and lymphatic system: unknown frequency - cases of serious bleeding, mainly subcutaneous, musculoskeletal, ocular hemorrhage (conjunctival, in the tissue and retina), bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage), nosebleeds, hematuria and bleeding from postoperative wounds and cases of fatal bleeding (especially intracranial hemorrhage, gastrointestinal bleeding and retroperitoneal hemorrhage), agranulocytosis, granulocytopenia, plastic anemia / pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A.
From the side of the immune system: unknown frequency - anaphylactoid reactions, serum sickness, cross-allergy with other thienopyridines (such as ticlopidine, prasugrel - see "Special Instructions").
Mental disorders: unknown frequency - confusion, hallucinations.
From the side of the nervous system: unknown frequency - impaired taste perception.
On the part of the vessels: unknown frequency - vasculitis, decreased blood pressure.
From the respiratory system, chest and mediastinal organs: unknown frequency - bronchospasm, interstitial pneumonia, eosinophilic pneumonia.
From the gastrointestinal tract: unknown frequency - colitis (including ulcerative or lymphocytic), pancreatitis, stomatitis.
From the liver and biliary tract: unknown frequency - hepatitis (non-infectious), acute liver failure.
On the part of the skin and subcutaneous tissues: unknown frequency - maculopapular erythematous or exfoliative rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), drug hypersensitivity syndrome and drug syrup and drug syrup (DRESS syndrome), eczema, lichen planus.
From the side of musculoskeletal and connective tissue: unknown frequency - arthralgia (joint pain), arthritis, myalgia.
From the side of the kidneys and urinary tract: an unknown frequency is glomerulopathy (including glomerulonephritis).
General disorders and disorders at the injection site: unknown frequency - fever.
Laboratory and instrumental data: unknown frequency - a deviation from the norm of laboratory indicators of the functional state of the liver, an increase in the concentration of creatinine in the blood.
Warfarin: although taking clopidogrel at a dose of 75 mg / day did not change the pharmacokinetics of warfarin (a substrate of the CYP2C9 isoenzyme) or INR in patients receiving long-term treatment with warfarin, concomitant use of clopidogrel increases the risk of bleeding due to its independent additional effect on blood coagulability. Therefore, caution should be exercised while taking warfarin and clopidogrel.
IIb / IIIa receptor blockers: the administration of IIb / IIIa receptor blockers together with clopidogrel requires caution in patients who are at increased risk of bleeding (with injuries and surgical interventions or other pathological conditions) (see "Special Instructions").
ASA does not alter the effect of clopidogrel, which inhibits ADP-induced platelet aggregation, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. However, simultaneous administration of ASA at a dose of 500 mg 2 times a day with clopidogrel 2 times a day for 1 day did not cause an additional increase in bleeding time due to clopidogrel. Between clopidogrel and ASA, a pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, at their simultaneous apply caution should be used, although in clinical trials, patients received combination therapy with clopidogrel and ASA for up to one year.
Heparin: according to a clinical trial conducted with healthy individuals, when taking clopidogrel, there was no need to change the dose of heparin and its anticoagulant effect did not change. The simultaneous use of heparin did not change the antiplatelet effect of clopidogrel. Pharmacodynamic interaction is possible between Plavix® and heparin, which can increase the risk of bleeding, so the simultaneous use of these drugs requires caution.
Thrombolytics: the safety of the combined use of clopidogrel, fibrin-specific or fibrin-specific thrombolytic 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 the combined use of thrombolytic agents and heparin with ASA.
NSAIDs: in a clinical study conducted with healthy volunteers, the combined use of clopidogrel and naproxen increased latent blood loss through the digestive tract. However, due to the lack of studies on the interaction of clopidogrel with other NSAIDs, it is currently unknown 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 carried out with caution (see "Special Instructions").
Other drug interactions. Since clopidogrel is metabolized to the formation of its active metabolite in part by the isoenzyme CYP2C19, the use of drugs that inhibit this isoenzyme can lead to a decrease in the level of the active metabolite of clopidogrel. The clinical significance of this interaction has not been established.
The simultaneous use of strong or moderate inhibitors of the CYP2C19 isoenzyme with clopidogrel should be avoided (for example, omeprazole or esomeprazole - see "Pharmacokinetics", subsection, "Pharmacogenetics"; "Special instructions"). If proton pump inhibitors should be taken concurrently with clopidogrel, proton pump inhibitors with the least inhibition of the CYP2C19 isoenzyme, such as pantoprazole or lansoprazole, should be used.
A number of clinical studies were conducted with clopidogrel and other drugs used simultaneously, in order to study possible pharmacodynamic and pharmacokinetic interactions, which showed that:
- when using clopidogrel together with atenolol, nifedipine, or a combination of these, no clinically significant pharmacodynamic interaction was observed;
- the simultaneous use of phenobarbital, cimetidine and estrogens did not significantly affect the pharmacodynamics of clopidogrel;
- pharmacokinetic parameters of digoxin and theophylline did not change when they were used together with clopidogrel;
- antacids did not reduce the absorption of clopidogrel;
- phenytoin and tolbutamide can be used safely with clopidogrel (CAPRIE study). It is unlikely that clopidogrel can affect the metabolism of other drugs, such as phenytoin and tolbutamide, as well as NSAIDs, which are metabolized using the CYP2C9 isoenzyme of the P450 cytochrome family.
- ACE inhibitors, diuretics, beta-blockers, CCL, lipid-lowering drugs, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, hormone replacement therapy and GPIIb / IIIa-receptor blockers: no clinical studies have been identified significant unwanted interactions.
How to take, course of administration and dosage
Oral administration, regardless of food intake.
Adults and the elderly with normal activity of the CYP2C19 isoenzyme
Myocardial infarction, ischemic stroke, and diagnosed peripheral arterial occlusion disease. The drug is taken at 75 mg 1 time per day.
Acute coronary syndrome without ST segment elevation (unstable angina, myocardial infarction without Q wave). Clopidogrel treatment should be started with a single dose of a loading dose of 300 mg, and then continued with a dose of 75 mg once a day (in combination with ASA in doses of 75–325 mg / day). Since the use of higher doses of ASA is associated with an increased risk of bleeding, the recommended dose for this indication should not exceed 100 mg. The optimal duration of treatment has not been formally determined. Clinical studies support the use of the drug for up to 12 months, and the maximum beneficial effect was observed by the 3rd month of treatment.
Acute coronary syndrome with ST segment elevation (acute myocardial infarction with ST segment elevation). Clopidogrel should be taken once a day at a dose of 75 mg with an initial single dose of a loading dose of 300 mg of clopidogrel in combination with ASA in combination with thrombolytics or without a combination with thrombolytics. In patients older than 75 years of age, treatment with clopidogrel should begin without taking its loading dose. Combination therapy is started as soon as possible after the onset of symptoms and continues for at least 4 weeks. The effectiveness of the combination of clopidogrel and ASA with this indication over 4 weeks has not been studied.
Atrial fibrillation (atrial fibrillation). Clopidogrel should be taken 1 time per day at a dose of 75 mg. In combination with clopidogrel, one should start and then continue taking ASA (75–100 mg / day).
Skipping the next dose
1. If less than 12 hours have passed after skipping the next dose, you should immediately take the missed dose of the drug, and then take the next dose at the usual time.
2. If more than 12 hours have passed after skipping the next dose, the patient should take the next dose at the usual time (do not take a double dose).
Patients with Genetically Decreased CYP2C19 Isoenzyme Activity
The low activity of the CYP2C19 isoenzyme is associated with a decrease in the antiplatelet effect of clopidogrel. The regimen for the use of higher doses (600 mg is the loading dose, then 150 mg once a day daily) in patients with low activity of the CYP2C19 isoenzyme increases the antiplatelet effect of clopidogrel (see "Pharmacokinetics"). However, at the moment, in clinical trials that take into account clinical outcomes, the optimal dosage regimen of clopidogrel for patients with its reduced metabolism is not established due to the genetically determined low activity of the CYP2C19 isoenzyme.
Special patient groups
The elderly. In elderly volunteers (over 75 years old), when compared with young volunteers, there were no differences in platelet aggregation and bleeding time. No dose adjustment is required for the elderly.
Children. There is no experience with the use of the drug in children.
Patients with impaired renal function. After repeated doses of clopidogrel at a dose of 75 mg / day in patients with severe kidney damage (Cl creatinine from 5 to 15 ml / min), the inhibition of ADP-induced platelet aggregation (25%) was lower compared to that in healthy volunteers, however, the bleeding time was longer was similar to that in healthy volunteers who received clopidogrel at a dose of 75 mg / day. In addition, all patients had good tolerance to the drug.
Patients with impaired liver function. After daily daily intake of 75 mg of clopidogrel daily in patients with severe liver damage, inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. Mean bleeding time was also comparable in both groups.
Patients of different ethnicity. The prevalence of alleles of the CYP2C19 isoenzyme genes responsible for intermediate and decreased metabolism of clopidogrel to its active metabolite varies among representatives of various ethnic groups (see Pharmacogenetics). There is only limited data for members of the Mongoloid race to assess the effect of the CYP2C19 isoenzyme genotype on clinical outcome events.
Male and female patients. In a small study comparing the pharmacodynamic properties of clopidogrel in men and women, women showed less inhibition of ADP-induced platelet aggregation, but there was no difference in lengthening bleeding time. In a large, controlled study of CAPRIE (clopidogrel versus ASA in patients at risk of developing ischemic complications), the incidence of clinical outcomes, other side effects, and abnormal clinical and laboratory parameters was the same in both men and women.
Symptoms: an overdose of clopidogrel can lead to an increase in bleeding time with subsequent complications in the form of bleeding.
Treatment: when bleeding occurs, appropriate medical measures are required. If rapid correction of an extended bleeding time is needed, platelet transfusion is recommended. Clopidogrel antidote not established.
When treating with clopidogrel, especially during the first weeks of treatment and / or after invasive cardiological procedures / surgical intervention, careful monitoring of patients should be carried out to exclude signs of bleeding, including hidden.
Due to the risk of bleeding and hematological undesirable effects (see “Side effects”), if clinical symptoms that are suspected of causing bleeding appear during treatment, an urgent clinical blood test should be done to determine APTT, platelet count, platelet functional activity and conduct other necessary research.
Clopidogrel, like other antiplatelet drugs, should be used with caution in patients who have an increased risk of bleeding associated with injuries, surgical interventions or other pathological conditions, as well as in patients receiving ASA, other N
PVA, including COX-2 inhibitors, heparin or glycoprotein IIb / IIIa inhibitors.
The combined use of clopidogrel with warfarin can increase the intensity of bleeding (see “Interaction”), therefore caution should be exercised when the combined use of clopidogrel and warfarin.
If the patient has planned surgery, and there is no need for an antiplatelet effect, then 5–7 days before surgery, clopidogrel should be discontinued.
Clopidogrel prolongs bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (especially gastrointestinal and intraocular). Drugs that can cause damage to the gastrointestinal mucosa (NSAIDs, including ASA) in patients taking clopidogrel should be used with caution.
Patients should be warned that when taking clopidogrel (alone or in combination with ASA), it may take longer to stop the bleeding, and that if they have unusual (by location or duration) bleeding, they should be informed this to your doctor. Before any upcoming surgery and before starting to take any new drug, patients should inform the doctor (including the dentist) about taking clopidogrel.
Very rarely, after the use of clopidogrel (sometimes even short-lived), there have been cases of TTP, which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever. TTP is a potentially life-threatening condition that requires immediate treatment, including plasmapheresis.
It has been shown that in patients with a recent transient cerebrovascular accident or stroke who have a high risk of recurring ischemic complications, a combination of ASA and clopidogrel increases the risk of major bleeding. Therefore, such combination therapy should be carried out with caution and only in the case of clinical evidence of the benefits of its use.
Cases of the development of acquired hemophilia when taking clopidogrel have been reported. With a confirmed isolated increase in APTT, with or without the development of bleeding, consideration should be given to the possibility of developing acquired hemophilia. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated by specialists in this disease and stop taking clopidogrel.
Patients should be interviewed for an allergy to thienopyridines (such as ticlopidine, prasugrel) in the anamnesis, as Cross allergies between thienopyridines and clopidogrel have been reported.
During the treatment period, it is necessary to monitor the functional state of the liver. In severe liver damage, remember the risk of developing hemorrhagic diathesis. Clopidogrel is not recommended for acute stroke with a duration of less than 7 days (because there is no data on its use in this condition).
Influence on the ability to drive a car and work with mechanisms. Plavix® does not have a significant impact on the abilities required to drive a car or work with machinery.
At a temperature not exceeding 30 °C