Composition, form of production and packaging
The tablets covered with a film cover of pink color, round, biconcave, with engraving "I" on the one hand.
1 tab.
clopidogrel hydrogen sulfate 97.87 mg,
corresponding to clopidogrel base 75 mg
Auxiliary 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, opadrai II 85G34669 pink - about 8.25 mg (polyvinyl alcohol - 3.63 mg, talcum powder - 1.65 mg, titanium dioxide (E171) 1.63 mg, macrogol 3350-1.02 mg, lecithin (E322) 0.29 mg, ferric oxide red oxide (E172) 0.03 mg).
7 pcs. - blisters (strips) (1, 2, 4, 8) - packs of cardboard.
10 pieces. - blisters (strips) (1, 2, 3, 5, 6, 9, 10) - packs of cardboard.
7 pcs. - blisters (strips) (10, 20, 40, 60) - cardboard boxes (for hospitals).
10 pieces. - blisters (strips) (10, 20, 40, 60) - cardboard boxes (for hospitals).
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
PHARMACHOLOGIC EFFECT
Mechanism of action
Clopidogrel is a prodrug, one of its metabolites is active and inhibits the aggregation of platelets. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y 12 platelet receptor and subsequent ADP-mediated activation of the glycoprotein IIb / IIIa complex, leading to suppression of platelet aggregation. Due to irreversible binding, platelets remain immune to stimulation of ADP for the rest of their life (about 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal.
Aggregation of platelets caused by agonists other than ADP is also inhibited by blockade of enhanced platelet activation by the released ADP. Because the formation of an active metabolite occurs with the isoenzymes of the P450 system, some of which may differ in polymorphism or may be inhibited by other drugs, not all patients may adequately inhibit platelet aggregation.
Pharmacodynamic properties
With a daily intake of clopidogrel at a dose of 75 mg, a significant inhibition of ADP-induced platelet aggregation is noted from the first day of administration, which gradually increases for 3-7 days and then reaches a constant level (when the equilibrium state is reached). In the equilibrium state, when taking a dose of 75 mg / day, platelet aggregation is inhibited by an average of 40-60%. After stopping the use of clopidogrel, platelet aggregation and bleeding time gradually return to the baseline level on average for 5 days.
Clinical efficacy and safety
Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular, in the lesions of the 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 vascular complications but were unable to take indirect anticoagulants, clopidogrel in combination with acetylsalicylic acid (compared to taking only acetylsalicylic acid alone ) reduced the incidence of combined stroke, myocardial infarction, systemic thromboembolism outside the central nervous system or vascular mortality, largely due to a reduced risk of stroke.
The effectiveness of taking clopidogrel in combination with acetylsalicylic acid was detected early and lasted up to 5 years. Reduction of 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 stroke of any severity with the use of clopidogrel in combination with acetylsalicylic acid was reduced, and there was a tendency to decrease the incidence of myocardial infarction in the group treated with clopidogrel in combination with acetylsalicylic acid, but there was no difference in the frequency of thromboembolism outside the CNS or vascular death. In addition, the use of clopidogrel in combination with acetylsalicylic acid reduced the total number of days of hospitalization for cardiovascular reasons.
PHARMACOKINETICS
Suction
After a single dose and with oral administration at a dose of 75 mg / day clopidogrel quickly absorbed. Mean C max 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 data on excretion of metabolites of clopidogrel with kidneys, its absorption is at least 50%.
Distribution
In vitro clopidogrel and its main circulating inactive inactive metabolite bind reversibly to plasma proteins by 98% and 94%, respectively. In vitro, this bond is unsaturated over 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 derivative of carboxylic acid (85%) from circulating metabolites in the systemic circulation, and the second pathway through the cytochrome P450 system. Initially clopidogrel is metabolized to 2-oxoklopidogrel, which is an intermediate metabolite. The subsequent metabolism of 2-oxoclopidogrel leads to the formation of an active metabolite of clopidogrel-thiol metabolite of clopidogrel. In vitro metabolism along this pathway occurs with the participation of isoenzymes CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol clopidogrel metabolite, which was isolated in in vitro studies, quickly and irreversibly binds to platelet receptors, thus inhibiting their aggregation.
With a single administration of clopidogrel at a loading dose of 300 mg C max active metabolite is 2 times greater than C max when taking clopidogrel at a maintenance dose of 75 mg for 4 days. With mР° the active metabolite it is reached through 30-60 mines after reception clopidogrel.
Excretion
Within 120 hours after ingestion of 14 C-labeled clopidogrel, approximately 50% of the radioactivity is released through the kidneys and approximately 46% of the radioactivity through the intestine. After a single oral dose of 75 mg T1 / 2 clopidogrel is about 6 hours. After a single reception and taking repeated doses of T 1/2 of the main circulating inactive blood metabolite is 8 hours.
Pharmacogenetics
With the help of the CYP2C19 isoenzyme, both an active metabolite and an intermediate metabolite, 2-oxoclopidogrel, are formed. The pharmacokinetics and antiplatelet effect of the active metabolite 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 CYP2C19 * 2 and CYP2C19 * 3 gene alleles are non-functional. Alleles of CYP2C19 * 2 and CYP2C19 * 3 genes cause a decrease in metabolism in the majority of representatives of the Caucasoid (85%) and Mongoloid (99%). Other alleles that are associated with a lack or decrease in metabolism are less common and include, but are not limited to, the alleles of the CYP2C19 * 4, * 5, * 6, * 7, and * 8 genes. Patients, which are weak metabolizers, should have the two alleles of the gene with loss of function indicated above. Published frequency of phenotypes of weak metabolizers CYP2C19 is 2% for Caucasians, 4% for Negroid people and 14% for Chinese.
In a cross-sectional study of 40 volunteers, 10 patients in each group with 4 CYP2C19 isoenzyme subtypes (ultrafast metabolizers, intensive metabolizers, intermediate metabolizers, weak metabolizers) evaluated the pharmacokinetics and antiplatelet effect when taking clopidogrel at a dose of 300 mg followed by its administration at 75 mg / day and with the use of clopidogrel at a dose of 600 mg followed by its reception at 150 mg / day for 5 days (reaching the equilibrium state).There were no significant differences in the exposure of the active metabolite and the mean platelet aggregation inhibition (ADI) (induced by ADP) in ultrafast, intensive and intermediate metabolizers. In weak metabolizers, the exposure of the active metabolite was reduced by 63-71% compared to intensive metabolizers.When the 300 mg / 75 mg treatment regimen was used in weak metabolizers, the antiplatelet effect was reduced with a mean of 24% (24 hours) and 37% (on day 5), compared to a 39% and 58% (on the 5th day of treatment) in intensive metabolizers and 37% (after 24 hours) and 60% (on the 5th day of treatment) in intermediate metabolizers. If the weak metabolizers received the 600 mg / 150 mg treatment regimen, the exposure of the active metabolite was higher than with the 300 mg / 75 mg treatment regimen. In addition, the IAT was 32% (24 hours) and 61% (at day 5 of treatment), which was greater than that of the weak metabolizers receiving the 300 mg / 75 mg treatment regimen and was similar to that in the higher-intensity CYP2C19 -metabolism, receiving a treatment regimen of 300 mg / 75 mg. However, in studies with clinical outcomes, the dosage regimen of clopidogrel for patients in this group has not yet been established.
According to the results of this study, in a meta-analysis of six studies, which included data from 335 volunteers who received clopidogrel and were in the C ss state, showed that intermediate metabolizers had an exposure of 28% for the active metabolite, and for weak metabolizers 72%, although the IAB was reduced compared to the intensive metabolizers with differences in the AIT of 5.9% and 21.4%, respectively. There was no evaluation of the effect of the CYP2C19 genotype on clinical outcomes in patients receiving clopidogrel in prospective, randomized, controlled trials. However, to date, there are several retrospective analyzes. Genotyping results are available in the following clinical trials: CURE (n = 2721), CHARISMA (n = 2428), CLARITY-TIMI 28 (n = 227), TRITON-TIMI 38 (n = 1477) and ACTIVE-A (n = 601) , as well as in several published cohort studies.
In a study of 38 and 3 cohort studies (Collet, Sibbing, Giusti), patients in the combined group with intermediate or weak metabolism had a higher incidence of cardiovascular events (death, myocardial infarction and stroke) or stent thrombosis compared to those in intensive metabolizers. In the CHARISMA study and one cohort study (Simon), an increase in the incidence of cardiovascular complications was observed only in weak metabolizers (when compared with intensive metabolizers).
In the study CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk), there was no increase in the incidence of cardiovascular complications depending on the intensity of CYP2C19 metabolism.
The clinical trials conducted to date did not have a sufficient sample size to detect differences in the clinical outcome in patients with a low activity of the CYP2C19 isoenzyme.
Pharmacokinetics in special clinical cases
The pharmacokinetics of the active metabolite of clopidogrel in certain groups of patients has not been studied.
In elderly volunteers (over 75 years), when compared with young volunteers, there was no difference in 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 renal damage (SC 5-15 ml / min) after repeated clopidogrel administration at a dose of 75 mg / day, the initiation of ADP-induced platelet aggregation was lower (25%) than that of healthy volunteers, but the prolongation of bleeding time was similar to that of healthy volunteers who received clopidogrel at 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, inhibition of ADP-induced platelet aggregation was similar to that of healthy volunteers. The mean bleeding time was also comparable in both groups.
The prevalence of alleles of the CYP2C9 isoenzyme genes responsible for intermediate and decreased metabolism is different in representatives of different racial groups. There are very small literature data among representatives of the Mongoloid race, which does not allow to assess the significance of genotyping of the isoenzyme CYP2C19 for the development of ischemic complications.
INDICATIONS
Prevention of atherothrombotic complications
In adult patients with myocardial infarction (with a duration of several days to 35 days), ischemic stroke (with a duration of 7 days to 6 months) or with diagnosed occlusive disease of the peripheral arteries.
In adults 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 acetylsalicylic acid);
- with the rise of the ST segment (acute myocardial infarction) with drug treatment and the possibility of carrying out thrombolysis (in combination with acetylsalicylic acid).
Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation (atrial fibrillation)
In patients with atrial fibrillation (atrial fibrillation), which have at least one risk factor for vascular complications, they can not take indirect anticoagulants and have a low risk of bleeding (in combination with acetylsalicylic acid).
DOSING MODE
Lopirel taken internally, regardless of food intake.
Adults and elderly people with normal activity of the isoenzyme CYP2C19
Myocardial infarction, ischemic stroke and diagnosed peripheral arterial occlusive disease
The drug is taken 75 mg once a day.
Acute coronary syndrome without ST segment elevation (unstable angina, myocardial infarction without Q-wave)
Treatment with clopidogrel should be started with a single dose of 300 mg, then continued with a 75 mg dose once a day (in combination with acetylsalicylic acid at doses of 75-325 mg / day). Since the use of acetylsalicylic acid in higher doses is associated with an increased risk of bleeding, the recommended dose of acetylsalicylic acid should not exceed 100 mg. The optimal duration of treatment is not officially defined.
Clinical trials support the use of the drug for up to 12 months, the maximum favorable 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 75 mg / day with the initial single dose of a loading dose of clopidogrel 300 mg in combination with acetylsalicylic acid in combination with thrombolytic agents or without combination with thrombolytics. In patients older than 75 years, 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 efficacy of using a combination of clopidogrel and acetylsalicylic acid at this indication for more than 4 weeks has not been studied.
Atrial fibrillation (atrial fibrillation)
Clopidogrel should be taken in a dose of 75 mg 1 time / day. In combination with clopidogrel, you should start and then continue taking acetylsalicylic acid (75-100 mg / day).
Skipping the next dose
1. If less than 12 hours have passed after missing the next dose, the missed dose of the drug should be taken immediately, and then the following doses should be taken at the usual time.
2. If more than 12 hours have passed after missing 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
The low activity of the isoenzyme CYP2C19 is associated with a decrease in the antiplatelet effect of clopidogrel. The regimen at 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 the present time in clinical studies that take into account clinical outcomes, the optimal dosage regimen of clopidogrel has not been established for patients with its reduced metabolism due to the genetically caused low activity of the CYP2C19 isoenzyme.
Special patient groups
In elderly volunteers over 75 years of age, when compared with young volunteers, there was no difference in platelet aggregation and bleeding time. For elderly patients, dose adjustment is not required.
Lopirel should not be used in children ; there is no experience of its use in this group of patients.
After repeated use of clopidogrel at a dose of 75 mg / day in patients with severe renal disease (SC from 5 to 15 ml / min), inhibition of ADP-induced platelet aggregation (25%) was lower than that of healthy volunteers, but prolongation of bleeding time было подобным таковому у здоровых добровольцев, получавших клопидогрел в дозе 75 мг/сут. In addition, all patients was well tolerated.
After daily administration of clopidogrel for 10 days at a daily dose of 75 mg in patients with severe liver inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean bleeding time was also comparable in both groups.
Prevalence isozyme alleles CYP2C19, responsible for interim and decreased metabolism of clopidogrel to its active metabolite varies in different ethnic groups .Limited data are available for the representatives of the Mongoloid race to assess the impact of CYP2C19 genotype on clinical isoenzyme resulting events.
In a small study comparing the pharmacodynamic properties of clopidogrel in both men and women , women had less inhibition of ADP-induced platelet aggregation, but the difference in prolongation of bleeding time was not. In a large controlled study CAPRIE (clopidogrel compared with aspirin in patients at risk of ischemic complications), the frequency of clinical outcome, side effects, and other abnormalities of clinical and laboratory parameters were similar in both men and women.
SIDE EFFECT
Security clopidogrel has been studied in more than 44,000 patients, including have more than 12 000 patients treated for one year or longer. The overall tolerability of clopidogrel was similar tolerability of acetylsalicylic acid, regardless of age, sex and race of patients belonging. Listed below are clinically meaningful adverse effects observed in clinical trials: CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A. Tolerability clopidogrel 75 mg / day in CAPRIE study corresponded tolerability acetylsalicylic acid 325 mg / day. Including reported adverse drug reactions in spontaneous messages.
Most often in clinical trials, and during post-marketing use of clopidogrel was reported bleeding, most of which are developed in the first month of treatment.
In a clinical study CAPRIE overall incidence of bleeding in patients treated with clopidogrel or acetylsalicylic acid was 9.3%. The frequency of severe bleeding in clopidogrel was similar to that of the value in the application of acetylsalicylic acid.
In a clinical study CUREno increased incidence of severe bleeding in clopidogrel with aspirin for 7 days after CABG in patients withhold therapy for more than 5 days before surgery. Patients who continued therapy for 5 days prior to coronary artery bypass surgery, the frequency of this event was 9.6% for the combination of clopidogrel and acetylsalicylic acid 6.3% - placebo in combination with acetylsalicylic acid.
In a clinical study, CLARITYobserved general increase in the frequency of bleeding in clopidogrel + acetylsalicylic acid compared to placebo + acetylsalicylic acid. Major bleeding rates were similar in both groups and practically independent of the baseline characteristics of patients and the type of heparin or fibrinolytic therapy.
In a clinical COMMIT study, the overall frequency of non-cerebral major bleeding or cerebral bleeding was low and did not differ significantly in both groups.
In a clinical study ACTIVE-Athe incidence of major bleeding in clopidogrel + acetylsalicylic acid was higher than the placebo group + aspirin (6.7% vs. 4.3%). Major bleeding were mainly extracranial in both groups (5.3% vs. 3.5%), mainly observed gastrointestinal bleeding (3.5% vs. 1.8%). Under clopidogrel + acetylsalicylic acid intracranial hemorrhage was greater compared to placebo + aspirin (1.4% vs. 0.8%, respectively). There were no statistically significant differences between the treatment groups in the incidence of fatal bleeding (1.1% vs. 0.7%), and hemorrhagic stroke (0.8% vs. 0.6%).
The following are adverse reactions observed in clinical trials or received in the form of spontaneous messages. The frequency of the reactions represented by the following classification: very common (1/10?), Common (1/100, <1/10?), Rare (1/1000, <1/100?), Rarely (1/10 000? <1/1000), very rare (<1/10 000), frequency not known (can not be established from the available data). In each of the sub-classification of organs and organ systems adverse reactions are presented in order of decreasing seriousness.
From the blood and lymphatic system: rarely - thrombocytopenia, leukopenia, eosinophilia; rarely - neutropenia, including severe neutropenia; very rarely - thrombotic thrombocytopenic purpura (TTP) ,aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired hemophilia type A, granulocytopenia, anemia.
Immune system: very rarely - serum sickness, anaphylactoid reactions; frequency is unknown - cross hypersensitivity reaction thienopyridine (such as ticlopidine, prasugrel) .
Mental disorders: very rarely - hallucinations, confusion.
From the nervous system: rare - intracranial bleeding (some cases have been fatal), headache, paresthesia, dizziness; very rarely - a violation of taste.
From a sight organ: seldom - ocular hemorrhage (in the conjunctiva, the tissue in the eye, the retina).
On the part of the organ of hearing and labyrinth disorders: rare - vertigo.
On the part of the vessels: often - bruises, very rarely - severe bleeding, bleeding from surgical wounds, vasculitis, decreased blood pressure.
On the part of the respiratory, thoracic and mediastinal disorders: often - nosebleeds; very rarely - bleeding from the respiratory system (haemoptysis, pulmonary haemorrhage), bronchospasm, intestinal pneumonitis, eosinophilic pneumonia.
On the part of the gastrointestinal tract:often - bleeding from the gastrointestinal tract, diarrhea, abdominal pain, dyspepsia; infrequently - gastric ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence; rarely - retroperitoneal bleeding; very rarely - gastrointestinal and retroperitoneal haemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic), stomatitis.
Of the liver and biliary tract: very rarely - acute hepatic failure, hepatitis, abnormalities in laboratory tests the functional state of the liver.
Skin and subcutaneous tissue disorders:often - bruises; infrequently - rash, pruritus, purpura (melkopyatnistye capillary bleeding in the skin, under the skin or mucous membrane); very rarely - bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), angioneurotic edema, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS-syndrome), erythematous or Exfoliative rash, urticaria, eczema, lichen planus .
On the part of the musculoskeletal and connective tissue disorders: very rarely - a hemorrhage in the musculoskeletal system (haemarthrosis), arthritis, arthralgia, myalgia.
On the part of the kidney and urinary tract: rarely - hematuria; very rarely - glomerulonephritis, increased creatinine concentration in blood.
General disorders and administration in the system: often - bleeding from the puncture site; very rarely - a fever.
Laboratory and instrumental data: infrequently - prolongation of bleeding time, reduced neutrophil count, reduced platelet counts.
CONTRAINDICATIONS
severe hepatic impairment;
- acute bleeding (including peptic ulcer bleeding or intracranial haemorrhage);
- pregnancy and the period of breastfeeding;
- Children up to age 18 years (effectiveness and safety have not been established);
- a rare hereditary intolerance to lactose, lactase deficiency and malabsorption syndrome glucose-galactose;
- increased sensitivity to clopidogrel or any excipient the formulation.
With caution:
- at moderate hepatic failure, at which possible predisposition to bleeding (limited clinical experience);
- in renal failure (limited clinical experience);
- trauma, surgical interventions (risk of increased bleeding);
- in diseases in which there is a predisposition to bleeding (especially gastrointestinal or intraocular);
- with concomitant administration of serotonin reuptake (SSRI) inhibitors;
- while taking NSAIDs, including and selective inhibitors of COX-2;
- with concomitant administration of warfarin, heparin, inhibitors of glycoprotein IIb / IIIa;
- with a history of guidance and hematologic allergic reactions to other thienopyridines (such as ticlopidine, prasugrel) with regard to the possibility of cross-allergic and hematological reactions;
- in patients with genetically determined reduction isoenzyme CYP2C19 function (in patients who are weak SYR2S19-metabolizers, with clopidogrel at recommended doses produce less active metabolite of clopidogrel and weaker expressed its antiplatelet effect; poor metabolisers receiving clopidogrel at recommended doses for acute coronary syndrome or percutaneous coronary intervention, may have a higher incidence of cardiovascular complications than patients with normal function izoferm NTA CYP2C19).
PREGNANCY AND LACTATION
Pregnancy
As a precautionary measure contraindicated Lopirel receiving the drug during pregnancy due to lack of clinical data on its acceptance by pregnant women, although studies of clopidogrel in animals did not reveal any direct or indirect harmful effects on pregnancy, fetal development, parturition and postnatal development.
Lactation
Breastfeeding in the case of drug treatment should be discontinued Lopirel because in studies in rats have shown that clopidogrel and / or its metabolites are excreted in breast milk. It penetrates whether clopidogrel in human breast milk is not known.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution should be used in formulation with moderate renal failure.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution should be used in formulation with moderate hepatic failure patients.
The drug is contraindicated in severe hepatic impairment.
APPLICATION FOR CHILDREN
Contraindicated in children and adolescents under 18 years.
SPECIAL INSTRUCTIONS
Bleeding and haematological disorders
Due to the risk of bleeding and haematological undesirable effects in case of occurrence in the course of treatment of clinical symptoms of suspected occurrence of bleeding, should urgently make a complete blood count to determine the APTT, platelet count, indicators of platelet functional activity and conduct other necessary investigations .
Clopidogrel, as well as other anti-platelet drugs should be used with caution in patients who have an increased risk of bleeding associated with trauma, surgery or other pathological conditions and in patients receiving aspirin, other NSAIDs, including COX-2 inhibitors, heparin, SSRIs or inhibitors of glycoprotein Ilb / IIIa.
In the treatment with clopidogrel, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgery, it is necessary to conduct a thorough monitoring of patients in order to exclude signs of bleeding, including hidden.
The combined use of clopidogrel with warfarin may intensify the bleeding , therefore, except for special rare clinical situations (such as the presence of floating thrombus in the left ventricle, stenting for patients with atrial fibrillation) combined use of warfarin and clopidogrel is not recommended.
If the patient will have a planned surgery, and thus there is no need for antiplatelet effect, then 7 days prior to surgery clopidogrel should be discontinued.
Before any forthcoming operation and before starting any new drug, patients must inform the doctor (including dental) for admission of clopidogrel.
Clopidogrel prolongs bleeding time, so the drug should be used with caution in patients with diseases predisposing to the development of bleeding (particularly gastrointestinal and intraocular).
Patients should be warned that while taking clopidogrel (alone or in combination with acetylsalicylic acid) to stop the bleeding may take more time, and that in case they have an unusual (for location or duration), they should inform the bleeding tell your doctor.
Thrombotic thrombocytopenic purpura
Very rarely after administration of clopidogrel (sometimes even short) have been reported cases of TTP, 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.
Acquired hemophilia
with clopidogrel reported acquired hemophilia. If confirmed aPTT prolongation of bleeding with or without to consider the possibility of developing acquired haemophilia. In the case of diagnosis of acquired haemophilia should start appropriate treatment and stop taking clopidogrel.
Recent myocardial ischemic stroke
Receiving Lopirel drug is not recommended in acute ischemic stroke with prescription of at least 7 days (since there is no data on its application in this condition).
In patients with recent ischemic stroke or transient ischemic attack and high risk of recurrent atherothrombotic events combination therapy with clopidogrel and aspirin did not demonstrate higher efficacy compared to monotherapy with clopidogrel, but may increase the risk of major bleeding.
isoenzyme CYP2C19
Pharmacogenetics: patients with sustained CYP2C19-mediated metabolism of clopidogrel when receiving the recommended doses of clopidogrel active metabolite is formed in smaller amounts and observed weaker effect on platelet aggregation. Tests are available to determine the genotype CYP2C19 isoenzyme in patients.
Since Clopidogrel is metabolized to active metabolites partially CYP2C19 isozyme involving the use of drugs that inhibit the activity of the farm
