Lopirel coated pills 75mg N28
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Active ingredients
Clopidogrel
Release form
Pills
Composition
Clopidogrel hydrogensulphate 97.87 mg, equivalent to the contents of clopidogrel base 75 mg.Vspomogatelnye substances: lactose, - 78.13 mg, Microcrystalline Cellulose - 68.75 mg Crospovidone (Type A) - 13.75 mg Glyceryl dibehenate - 8.25 mg talc - 8.25 mg Opadry II 85G34669 pink - about 8.25 mg (polyvinyl alcohol - 3.63 mg, talc - 1.65 mg, titanium dioxide (E171) - 1.63 mg, macrogol 3350 - 1.02 mg, lecithin (E322) - 0.29 mg, iron dye red oxide (E172) - 0.03 mg ).
Pharmacological effect
Mechanism of action: Clopidogrel is a prodrug, one of the metabolites of which is active and inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y12 platelet receptor 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 using the isoenzymes of the P450 system, some of which may differ in polymorphism or may be inhibited by other drugs, not all patients may have adequate inhibition of platelet aggregation. Pharmacodynamic properties: 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 observed, which gradually increases over 3-7 days and then goes to a constant level (when an equilibrium state is reached). At equilibrium, with a dose of 75 mg / day, 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. Clinical efficacy and safety: Clopidogrel can 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 in 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 ) reduced the frequency of combined stroke, myocardial infarction, systemic thromboembolism outside the central nervous system or vascular mortality, 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 were no differences in the incidence of thromboembolism outside of the CNS or the pulmonary syndrome, and there was no difference in the number of pulmonary tumors compared with CNS or acetylsalicylic acid In addition, the use of clopidogrel in combination with acetylsalicylic acid reduced the total number of days of hospitalization for cardiovascular reasons.
Pharmacokinetics
Absorption: After a single dose and during oral intake at a dose of 75 mg / day, clopidogrel is rapidly absorbed. The mean Cmax values in plasma of unchanged clopidogrel are about 2.2-2.5 ng / ml and are reached approximately 45 minutes after administration. According to the metabolism of clopidogrel metabolites by the kidneys, its absorption is at least 50%. Distribution: In vitro clopidogrel and its main inactive metabolite circulating in the blood reversibly bind to plasma proteins at 98% and 94%, respectively. In vitro, 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 is through esterases and subsequent hydrolysis to form an inactive carboxylic acid derivative (85%) of metabolites circulating in the systemic circulation, and the second way is through the cytochrome P450 system.Initially, clopidogrel is metabolized to 2-oxoclopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxoclopidogrel leads to the formation of the active metabolite of clopidogrel, the thiol metabolite of clopidogrel. In vitro metabolism along this path occurs with the participation of the isoenzymes CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite of clopidogrel, which was isolated in vitro studies, quickly and irreversibly binds to platelet receptors, thus inhibiting their aggregation. With a single dose of clopidogrel in a loading dose of 300 mg Cmax, the active metabolite is 2 times higher than Cmax when receiving clopidogrel in a maintenance dose of 75 mg for 4 days. Cmax of the active metabolite is reached within 30-60 minutes after taking clopidogrel. Withdrawal: Within 120 hours after ingestion of a 14C-labeled clopidogrel by human, about 50% of the radioactivity is excreted through the kidneys and about 46% of the radioactivity through the intestines. After a single oral dose of 75 mg T1 / 2 clopidogrel is about 6 hours. After a single dose and repeated doses of T1 / 2 of the main inactive metabolite circulating in the blood is 8 hours. Pharmacogenetics: Both the active metabolite and the intermediate metabolism are formed with the CYP2C19 isoenzyme. metabolite - 2-oxoclopidogrel. 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 who are weak metabolisers should have the two alleles of the gene indicated above with loss of function. The published frequencies of occurrence of phenotypes of weak metabolizers of CYP2C19 are 2% for people of the Caucasian race, 4% for people of the Negroid race, and 14% for the Chinese. In a cross-sectional study of 40 volunteers, 10 people in each group with 4 subtypes of the CYP2C19 isoenzyme (ultra-fast metabolizers, intensive metabolizers, intermediate metabolizers, weak metabolizers),pharmacokinetics and antiplatelet effects were evaluated when clopidogrel was taken at a dose of 300 mg followed by taking 75 mg / day and clopidogrel was taken at a dose of 600 mg followed by taking 150 mg / day for 5 days (reaching equilibrium). There were no significant differences in the exposure of the active metabolite and the mean values of inhibition of platelet aggregation (IAT) (induced by ADP) in ultrafast, intensive and intermediate metabolizers. In weak metabolizers, the exposure of the active metabolite was reduced by 63–71% compared with intensive metabolizers. When using the 300 mg / 75 mg treatment regimen in weak metabolizers, the antiplatelet effect decreased with average IAT values of 24% (after 24 hours) and 37% (on the 5th day of treatment) compared with IAT of 39% (after 24 hours) and 58% (on the 5th day of treatment) in intensive metabolisers and 37% (after 24 hours) and 60% (on day 5 of treatment) in intermediate metabolisers. If the weak metabolisers received a treatment regimen of 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 more than that of weak metabolisers 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 the 300 mg / 75 mg treatment regimen. However, in studies taking into account clinical outcomes, the dosage regimen of clopidogrel for patients in this group has not yet been established. In accordance with the results of this study, a meta-analysis of six studies, which included data from 335 volunteers who received clopidogrel and were able to achieve Css, showed that intermediate metabolisers had an active metabolite exposure decreased by 28%, and in weak metabolisers - by 72 %, although IAT was reduced compared with intensive metabolisers 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 (n = 2721), CHARISMA (n = 2428), CLARITY-TIMI 28 (n = 227), TRITON-TIMI 38 (n = 1477) and ACTIVE-A (n = 601) and also in several published cohort studies.In the TRITON-TIMI 38 and 3 cohort studies (Collet, Sibbing, Giusti), patients of the combined group with an intermediate or weak metabolism had a higher incidence of cardiovascular complications (death, myocardial infarction and stroke) or stent thrombosis compared to those of intensive metabolizers. In the CHARISMA study and one cohort study (Simon), an increase in the incidence of cardiovascular complications was observed only in weak metabolisers (when compared with intensive metabolizers). In the CURE, CLARITY, ACTIVE-A study and one of the cohort studies (Trenk), no increase in the frequency of cardiovascular complications was observed, depending on the intensity of the CYP2C19 metabolism. Clinical studies conducted to date have not had enough sample size to detect differences in clinical outcome in patients with low CYP2C19 isoenzyme activity. Pharmacokinetics in special clinical situations: The pharmacokinetics of the active metabolite of clopidogrel in some groups of patients has not been studied. Elderly volunteers (over 75 years old) compared with young volunteers did not show differences in terms of platelet aggregation and bleeding time. No dose adjustment is required in elderly patients. The pharmacokinetics of clopidogrel in children has not been studied. In patients with severe kidney damage (CK 5–15 ml / min), after repeated doses of clopidogrel at a dose of 75 mg / day, the initiation of ADP-induced platelet aggregation was lower (25%) than in healthy volunteers, but the lengthening of bleeding time was similar to that in healthy volunteers who received clopidogrel in a dose of 75 mg / day. Clopidogrel was well tolerated in all patients. In patients with severe liver damage after daily administration of clopidogrel at a dose of 75 mg / day for 10 days, the inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The average bleeding time was also comparable in both groups. The prevalence of alleles of the CYP2C9 isoenzyme genes, which are responsible for intermediate and reduced metabolism, is different in representatives of different racial groups. There is very little literature data among members of the Mongoloid race, which does not allow us to estimate the significance 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), ischemic stroke (with prescription from 7 days to 6 months) or diagnosed with occlusive peripheral arterial disease. In adult patients with acute coronary syndrome: - without ST-segment elevation (unstable angina or myocardial infarction without Q wave), including patients who underwent stenting for percutaneous coronary intervention (in combination with acetylsalicylic acid) - with ST segment elevation (acute myocardial infarction) with drug treatment and the possibility of thrombolysis (in combination with acetylsalicylic acid). 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 acetyl alicylic acid).
Contraindications
- severe liver failure - acute bleeding (including bleeding from peptic ulcers or intracranial hemorrhage) - pregnancy and breastfeeding period — children under 18 years of age (efficacy and safety have not been established) - rare hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome — hypersensitivity to clopidogrel or any excipient of the drug. With caution: - with mild hepatic insufficiency, in which predisposition to bleeding (limited clinical experience) - with renal failure (limited clinical experience) - with injuries, surgical interventions (risk of increased bleeding) - with diseases that have a predisposition to the development of bleeding (especially gastrointestinal or intraocular) - with the simultaneous appointment of serotonin reuptake inhibitors (SSRIs) - while taking NSAIDs, including and selective COX-2 inhibitors — with simultaneous administration of warfarin, heparin,glycoprotein IIb / IIIa inhibitors — with indications of a history of allergic and hematological reactions to other thienopyridines (such as ticlopidine, prasugrel) due to the possibility of cross-allergic and hematological reactions — in patients with a genetically determined decrease in function of the CYP2C19 isoenzyme (in patients who are weak CYP2C19 metabolisers; when using clopidogrel in recommended doses, less active metabolite of clopidogrel is produced and its antiaggregant effect is weaker; weak metabolites congestion receiving clopidogrel in recommended doses, with acute coronary syndrome or percutaneous coronary intervention, may have a higher frequency of cardiovascular complications than patients with normal function of an isoenzyme CYP2C19).
Dosage and administration
Lopirel take orally, regardless of the meal. Adults and the elderly with normal activity of the isoenzyme CYP2C19: Myocardial infarction, ischemic stroke and diagnosed occlusive peripheral artery disease: The drug is taken 75 mg 1 time / day. Acute coronary syndrome without ST segment elevation (unstable angina, myocardial infarction without a tooth Q) Treatment with clopidogrel should be started with a single dose of 300 mg, then continued with a dose of 75 mg 1 time / day (in combination with acetylsalicylic acid in doses 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 should not exceed 100 mg. The optimal duration of treatment is not officially defined. These clinical studies support the drug to 12 months, the maximum beneficial effect was observed by the third month of treatment. Acute coronary syndrome with ST-segment elevation (acute myocardial infarction with ST-segment elevation) Clopidogrel should be taken once at 75 mg / day with an initial single dose of clopidogrel 300 mg in combination with acetylsalicylic acid in combination with thrombolytic or without thrombolytic. In older patients over 75 years, treatment with clopidogrel should begin without taking its loading dose.Combination therapy is started as early as possible after the onset of symptoms, and continued for at least 4 weeks. The effectiveness of the combination of clopidogrel and acetylsalicylic acid in this indication for more than 4 weeks has not been studied. Atrial fibrillation (atrial fibrillation): Clopidogrel should be taken at a dose of 75 mg 1 time / day. In combination with clopidogrel should begin and then continue taking acetylsalicylic acid (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 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 regimen of administration in higher doses (loading dose - 600 mg, then 150 mg 1 time / day daily) 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 when compared with young volunteers, there were no differences in terms of platelet aggregation and bleeding time. For elderly patients, dose adjustment is not required. Lopirel should not be used in children, because there is no experience of its use in this group of patients. 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 daily administration of clopidogrel for 10 days at a daily dose of 75 mg 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. 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 among members 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. 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 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 incidence of clinical outcomes, other side effects and abnormal clinical and laboratory parameters was the same in both men and women.