Plavix 75 mg pills 100 pcs
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Active ingredients
Clopidogrel
Release form
Pills
Composition
Clopidogrel hydrosulfate (Form II) 97.875 mg, which corresponds to clopidogrel content 75 mg. Adjuvants: mannitol - 68.925 mg, macrogol 6000 - 34 mg, microcrystalline cellulose (with low water content, 90 μm) - 31 mg, low-substituted hyprolosis - 12.9 mg , hydrogenated castor oil - 3.3 mg. The composition of the film shell: opadra pink (lactose monohydrate, hypromellose, titanium dioxide (E171), triacetin, iron dye red oxide (E172)) - 7.5 mg, carnauba wax - traces.
Pharmacological effect
Antiplatelet. It is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of ADP to the P2Y12 receptor of platelets and the subsequent ADP-mediated activation of glycoprotein IIb / IIIa complex, leading to the suppression of platelet aggregation. Due to irreversible binding, platelets remain insensitive to stimulation of ADP for the remainder of their life (approximately 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal. Platelet aggregation, caused by agonists other than ADP, is also inhibited due to the blockade of enhanced activation of platelets released by ADP. Since the formation of an active metabolite occurs with the participation of isoenzymes of the P450 system, some of which differ in polymorphism or are inhibited by other drugs, not all patients can adequately suppress platelets. With daily intake of clopidogrel in a dose of 75 mg from the first day of administration, a significant suppression of ADP-induced platelet aggregation is noted, which gradually increases over 3-7 days and then goes to a constant level (when an equilibrium state is reached). In equilibrium, platelet aggregation is suppressed on average by 40-60%. After discontinuation of clopidogrel, platelet aggregation and bleeding time gradually return to the initial level on average within 5 days. Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular, in lesions of cerebral, coronary or peripheral arteries.A clinical study of ACTIVE-A showed that patients with atrial fibrillation, who had at least one risk factor for the development of vascular complications, but were unable to accept indirect anticoagulants, clopidogrel in combination with acetylsalicylic acid (compared to taking only acetylsalicylic acid alone) ) reduced the frequency of combined stroke, myocardial infarction, systemic thromboembolism outside the central nervous system 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 persisted for up to 5 years. The reduction 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 incidence of strokes. The risk of developing a stroke of any severity when taking clopidogrel in combination with acetylsalicylic acid decreased, and there was also a tendency to reduce the incidence of myocardial infarction in the group treated with clopidogrel in combination with acetylsalicylic acid, but there was no difference in the incidence of thromboembolism outside of the CNS or the pulmonary syndrome, but there was no difference in the number of pulmonary tumors or CNS or ventilatory acid. In addition, the use of clopidogrel in combination with acetylsalicylic acid reduced the total number of hospitalization days for cardiovascular reasons.
Pharmacokinetics
Absorption: With a single and repeated intake at a dose of 75 mg / day, clopidogrel is rapidly absorbed. After ingestion in a single dose of 75 mg, the mean Cmax values of unchanged clopidogrel in the blood plasma are reached in approximately 45 minutes and are approximately 2.2-2.5 ng / ml. According to the excretion of clopidogrel metabolites in urine, its absorption is approximately 50%. Distribution: In vitro clopidogrel and its main inactive metabolite circulating in the blood reversibly bind to plasma proteins (98% and 94%, respectively). This bond is unsaturated to a concentration of 100 mg / ml. Metabolism: Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, clopidogrel is metabolized in two ways: the first is through hydrolysis using esterases to form an inactive carboxylic acid derivative (85% of circulating metabolites), the second through the isoenzymes of 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 active metabolite is formed mainly by the isoenzyme CYP2C19, as well as some other isoenzymes, including CYP1A2, CYP2B6 and CYP3A4. The active thiol metabolite of clopidogrel, which was isolated in vitro studies, quickly and irreversibly binds to platelet receptors, thus blocking platelet aggregation. Cmax of the active metabolite of clopidogrel after a single dose in a loading dose of 300 mg is 2 times higher than that after 4 days of receiving a maintenance dose of clopidogrel 75 mg. Cmax is reached within about 30-60 minutes. Withdrawal: Within 120 hours after ingestion of 14C-labeled clopidogrel by human, about 50% of the radioactivity is excreted by the kidneys in the urine and approximately 46% is excreted through the intestine with feces. After a single oral dose of 75 mg T1 / 2, clopidogrel is about 6 hours. After a single dose and repeated doses of clopidogrel T1 / 2 of its main circulating inactive metabolite is 8 hours. Pharmacogenetics: They are formed as active through the CYP2C19 isoenzyme. the metabolite and the intermediate metabolite are 2-oxo-clopidogrel. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel, in the study of platelet aggregation ex vivo, vary depending on the genotype of the CYP2C19 isoenzyme. The allele of the CYP2C19 * 1 gene corresponds to a fully functional metabolism, whereas the alleles of the CYP2C19 * 2 and CYP2C19 * 3 genes are non-functional. Alleles of the CYP2C19 * 2 and CYP2C19 * 3 genes are responsible for the decrease in metabolism in the majority of Caucasians (85%) and Mongoloid race (99%). Other alleles that are associated with a lack or decrease in metabolism are less common and include, but are not limited to, the CYP2C19 * 4, * 5, * 6, * 7, and * 8 gene alleles. Patients with low CYP2C19 isoenzyme activity should have the two gene alleles indicated above with loss of function. The published frequency of phenotypes for people with low CYP2C19 isoenzyme is 2% for Caucasians, 4% for Negroids, and 14% for Chinese. There are specific tests to determine whether the patient has a genotype of CYP2C19 isoenzyme. According to a cross-sectional study (40 volunteers), which included individuals with a very high, high, intermediate, and low activity of the isoenzyme CYP2C19,no significant differences in the exposure of the active metabolite and in the mean values of inhibition of platelet aggregation (IAT) induced by ADP were found in volunteers with very high, high and intermediate isoenzyme CYP2C19. In volunteers with a low activity of the CYP2C19 isoenzyme, the exposure of the active metabolite was reduced by 63-71% compared with individuals with a high activity of the CYP2C19 isoenzyme. When using the 300 mg treatment regimen, the loading dose / 75 mg maintenance dose (300 mg / 75 mg) in volunteers with a low activity of the CYP2C19 isoenzyme, the antiplatelet effect decreased with average IAT values of 24% (after 24 hours) and 37% (on day 5 treatment) compared with an IAT of 39% (after 24 hours) and 58% (on day 5 of treatment) in volunteers with high activity of the isoenzyme CYP2C19 and 37% (in 24 hours) and 60% (on day 5 of treatment) in volunteers intermediate activity of the isoenzyme CYP2C19. When volunteers with a low activity of the CYP2C19 isoenzyme received a treatment regimen of 600 mg loading dose / 150 mg maintenance dose (600 mg / 150 mg), the active metabolite exposure was higher than with the 300 mg / 75 mg treatment regimen. In addition, IAT was 32% (after 24 hours) and 61% (on the 5th day of treatment), which was greater than that of people with low CYP2C19 isoenzyme who received the 300 mg / 75 mg treatment regimen, and was similar to that in groups of patients with higher intensity of CYP2C19 metabolism, treated with 300 mg / 75 mg treatment regimen. However, in studies taking into account clinical outcomes, the dosage regimen of clopidogrel for patients of this group (patients with low activity of the isoenzyme CYP2C19) has not yet been established. Similar to the results of this study, a meta-analysis of 6 studies, which included data from 335 volunteers who received clopidogrel and were able to reach equilibrium concentrations, showed that, compared with volunteers with high CYP2C19 isoenzyme, in volunteers with intermediate activity of CYP2C19 isoenzyme, the active metabolite exposure decreased by 28%, and in volunteers with low activity of the CYP2C19 isoenzyme - by 72%, while IAT was reduced with differences in IAT of 5.9% and 21.4%, respectively. There was no assessment of the effect of the CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel in prospective, randomized, controlled studies. However, at the moment there are several retrospective analyzes.The results of genotyping are available in the following clinical studies: CURE, CHARISMA, CLARITY-TIMI 28, TRITON-TIMI 38 and ACTIVE-A, as well as in several published cohort studies. In the TRITON-TIMI study of 38 and 3 cohort studies (Collet, Sibbing, Giusti), patients of the combined group with intermediate or low activity of the CYP2C19 isoenzyme had a higher incidence of cardiovascular complications (death, myocardial infarction and stroke) or stent thrombosis compared to with those in patients with high activity of the isoenzyme CYP2C19. In the CHARISMA study and one cohort study (Simon), an increase in the incidence of cardiovascular complications was observed only in patients with low CYP2C19 isoenzyme activity (when compared with patients with high CYP2C19 isoenzyme activity). In the CURE, CLARITY, ACTIVE-A study and one of the cohort studies (Trenk), there was no increase in the incidence of cardiovascular complications depending on the intensity of the CYP2C19 metabolism. Pharmacokinetics in special clinical situations: The pharmacokinetics of the active metabolite of clopidogrel have not been studied in these groups of patients. Elderly patients. Older volunteers (over 75 years old) compared with young volunteers did not show differences in platelet aggregation and bleeding time. Dose adjustment is not required in the elderly. Children. No data available. Patients with impaired renal function. After repeated doses of clopidogrel at a dose of 75 mg / day in patients with severe renal dysfunction (CC from 5 ml / min to 15 ml / min), the inhibition of ADP-induced platelet aggregation was lower (by 25%) compared with that in healthy volunteers however, the lengthening of the bleeding time was similar to that of healthy volunteers who received clopidogrel in a dose of 75 mg / day. Patients with impaired liver function. After taking clopidogrel daily for 10 days at a daily dose of 75 mg in patients with severely impaired liver function, the inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The average bleeding time was also comparable in both groups. Race. The prevalence of alleles of the CYP2C19 isoenzyme genes, which determine the intermediate and low activity of this isoenzyme, differs in representatives of different racial groups.There are limited literature data on their prevalence among members of the Mongoloid race, which does not allow them to estimate the values of the genotyping of the CYP2C19 isoenzyme for the development of ischemic complications.
Indications
Prevention of atherothrombotic complications: - in adult patients with myocardial infarction (with prescription from several days to 35 days), with ischemic stroke (with prescription from 7 days to 6 months), with diagnosed occlusive peripheral artery disease - in adult patients with acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without a Q wave), including patients who underwent stenting for percutaneous coronary intervention (in combination with acetylsalicylic acid) - in patients with acute coronary syndrome with ST-segment elevation (acute myocardial infarction) with drug treatment and the possibility of thrombolysis (in combination with acetylsalicylic acid). with atrial fibrillation (atrial fibrillation), which have at least one risk factor for the development of vascular complications, cannot take indirect anticoagulants and have a low s risk of bleeding (in combination with acetylsalicylic acid).
Contraindications
- hypersensitivity to clopidogrel or any of the auxiliary components of the drug — severe liver failure — acute bleeding, for example, bleeding from a peptic ulcer or intracranial hemorrhage — rare hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome; ) - children and adolescents under 18 years of age (safety and efficacy have not been established). With caution- With moderate liver intraocular insufficiency, in which a predisposition to bleeding is possible (limited clinical experience of use) .- In renal failure (limited clinical experience of use) .- In diseases in which there is a predisposition to the development of bleeding (in particular gastrointestinal or intraocular),and especially with the simultaneous use of drugs that can cause damage to the gastrointestinal mucosa (such as ASA and NSAIDs) .- In patients who have an increased risk of bleeding (due to injury, surgery or other pathological conditions), and in patients receiving ASK, heparin, warfarin, glycoprotein IIb / IIIa inhibitors, NSAIDs, incl. selective COX-2 inhibitors, as well as other drugs whose use is associated with the risk of bleeding, selective serotonin reuptake inhibitors (SSRIs) .- When used simultaneously with drugs that are substrates of the CYP2C8 isoenzyme (repaglinide, paclitaxel) .- In patients with low activity of the isoenzyme CYP2C19.- With indications in the history of allergic and hematological reactions to other thienopyridines, such as ticlopidine, prasagrel (the possibility of cross-allergenic their and hematological reactions) .- After a recent history of transient cerebral circulation or ischemic stroke (when combined with ASA).
Dosage and administration
The drug is taken orally, regardless of the meal. Adults and elderly patients with normal activity of the isoenzyme CYP2C19 Myocardial infarction, ischemic stroke and diagnosed occlusive peripheral artery disease: The drug is prescribed at a dose of 75 mg 1 time / day. Acute coronary syndrome without ST segment elevation (unstable angina, myocardial infarction without a Q wave): Treatment with clopidogrel should be started with a single dose of 300 mg and then continued at a dose of 75 mg 1 time / day (in combination with acetylsalicylic acid at 75 - 325 mg / day). Since the use of acetylsalicylic acid in higher doses is associated with an increased risk of bleeding, the dose of acetylsalicylic acid recommended for this indication does not exceed 100 mg. The optimal duration of treatment is not officially defined. These clinical studies support the drug to 12 months, and the maximum beneficial effect was observed by 3 months of treatment. Acute coronary syndrome with ST-segment elevation (acute myocardial infarction with ST-segment elevation): Clopidogrel should be taken once at a dose of 75 mg 1 time / day with an initial single dose of clopidogrel 300 mg in combination with acetylsalicylic acid and thrombolytics and without combination with thrombolytics .In patients over the age of 75, treatment with clopidogrel should be started without taking a 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 acetylsalicylic acid in this indication over 4 weeks has not been studied. Atrial fibrillation (atrial fibrillation): Clopidogrel should be taken 1 time / day in a dose of 75 mg. In combination with clopidogrel should begin and then continue taking acetylsalicylic acid (75-100 mg / day). Skipping the next dose: 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. If more than 12 hours have passed after skipping the next dose, the patient should take the next dose at the usual time (double dose should not be taken). Patients with genetically determined reduced activity of the isoenzyme CYP2C19 Low activity of the isoenzyme CYP2C19 is associated with a decrease in the antiplatelet effect of clopidogrel. The mode of use of the drug in higher doses (600 mg - loading dose, then 150 mg 1 time / day) in patients with low activity of the isoenzyme CYP2C19 increases the antiplatelet effect of clopidogrel. However, at present, clinical studies that take into account clinical outcomes have not established the optimal dosage regimen of clopidogrel for patients with its reduced metabolism due to the genetically determined low activity of the CYP2C19 isoenzyme. Special patient groups: Elderly volunteers (older than 75 years) compared with young volunteers did not show differences in platelet aggregation and bleeding time. Elderly patients dose adjustment is not required. There is no experience of using the drug in children. After repeated doses of clopidogrel at a dose of 75 mg / day in patients with severe kidney damage (CC from 5 to 15 ml / min), the inhibition of ADP-induced platelet aggregation (25%) was lower compared to that in healthy volunteers, but the lengthening of bleeding time was similar to that of healthy volunteers who received clopidogrel in a dose of 75 mg / day. In addition, all patients had good tolerability.After taking clopidogrel in a daily dose of 75 mg daily for 10 days in patients with severe liver damage, the inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The average bleeding time was also comparable in both groups. Patients of different ethnicity. The prevalence of alleles of the CYP2C19 isoenzyme genes, which are responsible for the intermediate and reduced metabolism of clopidogrel to its active metabolite, differs in representatives of different ethnic groups. Only limited data are available for representatives of the Mongoloid race to assess the effect of the CYP2C19 isoenzyme genotype on the clinical outcomes. Patients are female and male. In a small comparative study of the pharmacodynamic properties of clopidogrel in men and women, women experienced less inhibition of ADP-induced platelet aggregation, but there were no differences in the lengthening of bleeding time. In a large controlled study of CAPRIE (clopidogrel versus acetylsalicylic acid in patients at risk of developing ischemic complications), the frequency of clinical outcomes, other side effects and abnormal clinical and laboratory parameters was the same in both men and women.