Klapitaks - instructions for use, dose, side effects, contraindications

Excipients: mannitol 36.125 mg / 72.25 mg / 52.00 mg, crospovidone 20.00 mg / 40.00 mg / 52.00 mg,cellulose microcrystalline 67.00 mg / 134.00 mg / 79.50 mg, giprolose (low-substituted) 4.00 mg / 8.00 mg / 8.00 mg, macrogol-6000 8.00 mg / 16.00 mg / 20 , 00 mg, silicon colloidal dioxide 3.00 mg / 6.00 mg / 6.00 mg, zinc stearate 12.00 mg / 24.00 mg / 32.00 mg;

film sheath: Opaprai pink * (for 75 mg tablets), Opadrai white ** (for tablets 150 mg and 300 mg), carnauba wax - traces.

*Opadrai pink contains: lactose monohydrate BP 39.5%; hypromellose BP 39.25%; titanium dioxide BP (EI71) 10%; triacetin USP 10%; iron dye oxide red BP (E172) 1.25%,

** Deficient white contains: lactose monohydrate BP 40%; hypromellose BP 40%; gitanic dioxide BP (E171) 10%; triacetin USP 10%.

Description:

Tablets 75 mg: round biconvex tablets, covered with a film shell of pink color.

Tablets of 150 mg: round biconvex tablets, covered with a film shell of white color with a risk on one side.

Tablets 300 mg: round biconvex tablets, covered with a film coating of white color.

On the cross-section (for all dosages) almost white (white with a yellowish hue) mass with single dark impregnations.

Pharmacotherapeutic group:Antiaggregant agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

Pharmacodynamics:

Clopidogrel 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 (adenosine diphosphate) with P2Y12 platelet receptor and subsequent ADP-mediated activation of the complex GPIIb/IIIa, 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. Since the formation of the active metabolite occurs with the isoenzymes of the cytochrome P450 system, some of which may be polymorphic or may be inhibited by other drugs, adequate platelet suppression is not possible in all patients.

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, platelet aggregation is suppressed on average by 40-60%. After stopping the use of clopidogrel, platelet aggregation and bleeding time gradually return to the baseline level on average for 5 days.

In studying the pharmacodynamics of clopidogrel, there was less inhibition of LDF-induced platelet aggregation in women. However, there was no difference between men and women in prolonging bleeding time.

Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular damage, particularly in cases of cerebral, coronary or peripheral arteries.

In patients with recent myocardial infarction, ischemic stroke and / or diagnosed peripheral arterial occlusive disease, taking clopidogrel at a dose of 75 mg per day significantly reduces the risk of developing vascular complications (myocardial infarction, stroke, cardiovascular mortality).

In acute coronary syndrome without segment elevation ST on ECG (unstable angina, myocardial infarction), the use of clopidogrel (loading dose of 300 mg once,then 75 mg / day) in combination with acetylsalicylic acid at a dose of 75-325 mg / day and other standard therapy, reliably and independently of other treatments reduces the risk of vascular complications.

With myocardial infarction with a segment elevation ST on ECG reception of clopidogrel (loading dose of 300 mg once during the first 12 hours of the disease, then 75 mg / day) in combination with acetylsalicylic acid (loading dose of 150-325 mg, then 75-162 mg / day), fibrinolytic therapy and, by indications, heparin, reduces the incidence of occlusion of the infarct-related coronary artery (according to coronary angiography when discharged from the hospital), repeated myocardial infarction and fatal outcomes. In patients who did not undergo coronary angiography during the discharge, taking clopidogrel according to this scheme reduces the incidence of fatal outcomes and repeated myocardial infarction before the 8th day of the disease or until discharge from the hospital.

In general, with myocardial infarction, regardless of changes in the ECG (segment elevation ST, segment depression ST or the first complete blockage of the left leg of the bundle of His), the use of clopidogrel at a dose of 75 mg / day incombination with acetylsalicylic acid 162 mg per day leads to a reduction in overall mortality and the total frequency of repeated myocardial infarction, ischemic stroke and death.

In patients with atrial fibrillation who have at least one risk factor for vascular complications and who do not take indirect anticoagulants for any reason, clopidogrel at a dose of 75 mg / day in combination with acetylsalicylic acid (compared with the intake of acetylsalicylic acid only) reduces the total incidence of stroke, myocardial infarction, systemic thromboembolism outside the central nervous system and cardiovascular mortality, mainly by reducing the risk of developing a non-fatal stroke. This effect of clopidogrel was observed in studies lasting up to 5 years.

Pharmacokinetics:

Suction

With a single and course administration in a dose of 75 mg per day clopidogrel quickly absorbed. The mean maximum concentration (C_mOh) of unchanged clopidogrel in blood plasma is very low (approximately 2.2-2.5 ng / ml after ingestion of a single dose of 75 mg) is reached approximately 45 minutes after administration.According to the excretion of metabolites of clopidogrel with urine, its absorption is approximately 50%. The concentration of unchanged substance in the plasma rapidly decreases and already within 2 hours after administration does not reach the measurement limit (0.025 μg / l).

Distribution

In vilro Clopidogrel and its main circulating non-active metabolite in the blood reversibly bind to plasma proteins (by 98% and 94%, respectively) and this bond is unsaturated over a wide range of concentrations.

Metabolism

Being a prodrug, clopidogrel intensively metabolized in the liver. An active metabolite is not found in the blood.

In vitro and in vivo clopidogrel is metabolized in two ways:

- through esterases and subsequent hydrolysis to form an inactive derivative of carboxylic acid (85% of circulating metabolites);

- through the cytochrome P450 system.

at first 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-thiol clopidogrel derivative. In-vitro this way of metabolism occurs with the help of cytochrome P450 - CYP3A4, CYP2C19, CYP1A2 and CYP2B6 isoenzymes.The active thiol metabolite of clopidogrel, which was isolated in studies in vitro, in conditions in vivo quickly and irreversibly binds to platelet receptors, blocking the aggregation of platelets.

FROM_mOh active metabolite of clopidogrel after receiving a loading dose of 300 mg is 2 times greater than C_mOh after taking a maintenance dose of clopidogrel 75 mg for 4 days. When taking 300 mg clopidogrel TS_mOh is approximately 30-60 minutes.

After repeated use of clopidogrel inwards at a dose of 75 mg per day C_mOh the main inactive metabolite is about 3 mg / l, TFROM_mOh the inactive metabolite is reached after 1 hour.

Excretion

Within 120 hours after ingestion by a human ¹⁴C-labeled clopidogrel approximately 50% of radioactivity is excreted in the urine and approximately 46% of radioactivity with a caloric mass.

After a single administration and reception of repeated doses, the elimination half-life (T_1/2) of the main inactive metabolite (the carboxylic acid derivative) circulating in the blood is 8 hours.

Pharmacogenetics

Several polymorphic isoenzymes of the cytochrome P450 system are involved in the activation of clopidogrel.Isozyme CYP2C19 is involved in the formation of both an active metabolite and an intermediate metabolite, 2-oxo-clopidogrel. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel, studied by platelet aggregation ex vivo, differ depending on the genotype of the isoenzyme CYP2C19.

Gene allele CYP2C19 * 1 is responsible for the normally functioning metabolism, whereas the gene alleles CYP2C19 * 2 and CYP2C19 * 3 are non-functional. These alleles are responsible for a decrease in metabolism in about 85% of the representatives of the Caucasoid race and 99% in the representatives of the Mongoloid race. Other alleles associated with a lack or decrease in metabolism - CYP2C19 * 4, * 5, * 6, * 7 and * 8, but they are rarely found in the general population. Patients with low isoenzyme activity CYP2C19, should have the two above alleles of the gene with loss of function.

Published frequencies of occurrence of phenotypes of persons with low isoenzyme activity CYP2C19 in Caucasians 2%, Negroid 4% and Chinese 14%.

There are tests to determine the genotype of the patient's SUR2C19; these tests can be used as an auxiliary tool in determining the tactics of treatment.

In a cross-sectional study of 40 healthy volunteers (10 volunteers with a very fast, extensive, intermediate and delayed metabolism), the pharmacokinetics and antiplatelet effect of clopidogrel was studied in its application in two ways: 1) 300 mg once, followed by a dose of 75 mg in day for 5 days and 2) 600 mg once with subsequent administration at a dose of 150 mg per day for 5 days (until equilibrium is reached). There were no significant differences in the effect of the active metabolite and the average level of inhibition of platelet aggregation (IAT) between groups of volunteers with very rapid, extensive and intermediate metabolism. In volunteers with a reduced metabolic rate, the effect of the active metabolite was 63-71% lower compared with volunteers, extensively metabolizing clopidogrel.

When using the drug according to the 300 mg schedule, 75 mg once a day, the platelet response (with 5 μm stimulation of ADP) in volunteers with delayed metabolism of clopidogrel was reduced: the IAT was 24% (24 hours) and 37% (Day 5). For comparison, in volunteers with extensive metabolism, the IAT was 39% (24 hours) and 60% (Day 5).

When using clopidogrel 600 mg once 150 mg per day in volunteers with a reduced rate of clopidogrel metabolism, the effect of the drug was more pronounced than when the drug was administered at 300 mg once 75 mg per day: the IAT was 32% (after 24 hours) and 61 % (Day 5), which is comparable to the indices of IAT in groups of volunteers with a different metabolic rate of clopidogrel, who received the drug according to the 300 mg / 75 mg schedule. A suitable dosing regimen for a population of patients with a reduced rate of clopidogrel metabolism has not been established in clinical studies.

Similarly, a meta-analysis of six studies, which included data from 335 healthy volunteers, "who received clopidogrel and those in the state of reaching an equilibrium concentration, showed that in intermediate metabolizers the exposure of the active metabolite decreased by 28%, and in weak metabolizers by 72%. Compared to extensive metabolizers, inhibition of platelet aggregation in intermediate and weak metabolizers was reduced by 5.9% and 21.4%, respectively.

Assessment of the effect of the genotype CD002C19 on clinical outcomes in patients who received clopidogrel, in prospective randomized controlled trials was not conducted.Existing data from retrospective analyzes of clinical trials for which there are patient genotyping results do not have sufficient capacity to assess differences in clinical outcome in poor metabolizers of clopidogrel as compared with extensive metabolizers and intermediaries.

Individual patient groups

Elderly people

The volunteers elderly (over 75 years) compared with young volunteers has been received the distinction in terms of platelet aggregation and bleeding time. Correction of the dose of clopidogrel in elderly people is not required.

Age under 18 years of age

The pharmacokinetics of clopidogrel in children has not been studied.

Impaired renal function

After repeated receptions of clopidogrel 75 mg / day in patients with severe renal failure (creatinine clearance (CC) of 5-15 ml / min), inhibition of ADP-induced platelet aggregation were 25% lower than in healthy volunteers but the elongation bleeding time was not noted.

Impaired liver function

Upon receiving clopidogrel at a dose of 75 mg per day for 10 days in patients with severe liver inhibition of ADP-induced platelet aggregation did not differ from that in healthy volunteers.The average bleeding time in patients with severe liver damage and in healthy volunteers was comparable.

Race

Prevalence of alleles of isoenzyme genes CYP2C19, responsible for an intermediate or decreased metabolism, is different in representatives of different racial groups. Available literature data are insufficient to assess the importance of genotyping the isoenzyme CYP2C19 for predicting the development of ischemic complications.

Indications:

Prevention of atherothrombotic complications in adult patients with:

- myocardial infarction (with a prescription from several days to 35 days);

- ischemic stroke (with a duration of 7 days to 6 months);

- diagnosed occlusive disease of peripheral arteries;

- 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 ST segment lift (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 adult patients with at least one risk factor for vascular complications, contraindications to the use of indirect anticoagulants and a low risk of bleeding (in combination with acetylsalicylic acid).

Contraindications:

- Hypersensitivity to clopidogrel or any of the auxiliary components of the drug;

- severe hepatic impairment;

- active bleeding, eg bleeding from peptic ulcers or intracranial hemorrhage;

- hereditary intolerance to galactose, congenital deficiency of lactase and glucose-galactose malabsorption;

- pregnancy and lactation (see "Pregnancy and the period of breastfeeding");

- children under 18 years of age (safety and efficacy not established).

Carefully:

Clopidogrel should be taken with caution when:

- moderate hepatic insufficiency (7-9 on the Child-Pugh scale), in which a predisposition to bleeding is possible (limited clinical experience);

- chronic renal failure of mild and moderate severity (creatinine clearance of 60-30 ml / min) (limited clinical experience of use);

- injuries, surgical interventions (see "Special instructions");

- diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal or intraocular);

- simultaneous administration of non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2);

- simultaneous use of oral anticoagulants, heparin, glycoprotein IIb / IIIa inhibitors, selective serotonin reuptake inhibitors (SSRIs), and thrombolytic agents;

- genetically determined decrease in the function of the isoenzyme CYP2CI9. There are published data indicating that patients with a genetically determined decrease in the function of the isoenzyme CYP2C19 undergo a less systemic exposure to the active metabolite of clopidogrel and have a less pronounced antiaggregant effect of the drug, in addition they may experience a more frequent occurrence of cardiovascular complications after myocardial infarction compared to with patients with normal isoenzyme function CYP2CI9;

- presence in the anamnesis of allergic or hematological reactions to other thienopyridines (such as ticlopidine, prasugrel) due to the possibility of cross-allergic or hematological reactions (see section "Special instructions").

Pregnancy and lactation:

As a precaution, the use of clopidogrel during pregnancy is not recommended due to the lack of clinical data on its intake by pregnant women, although studies in animals have not revealed adverse effects during pregnancy, embryonic development, childbirth and postnatal development.

Breastfeeding with clopidogrel should be discontinued, as studies in rats have shown that clopidogrel and / or its metabolites are excreted into breast milk. Penetrates or not clopidogrel in human milk is not known.

Dosing and Administration:

Clopidogrel should be taken orally, regardless of food intake.

Adults and elderly people with normal isoenzyme activity CYP2C19

Myocardial infarction, ischemic stroke and diagnosed peripheral arterial occlusive disease

The drug is taken 75 mg once a day.

In patients with myocardial infarction, treatment can begin from the first days to the 35th day after myocardial infarction, and in patients with ischemic stroke - in the period from 7 days to 6 months. Due to the lack of data clopidogrel is not recommended within the first 7 days after an acute ischemic stroke.

Acute coronary syndrome without segment elevation ST (unstable angina, myocardial infarction without a tooth Q)

Treatment with clopidogrel should be started with a single dose of 300 mg, and then continued with a 75 mg dose once daily (in combination with acetylsalicylic acid at doses of 75-325 mg per day). Since the use of higher doses of acetylsalicylic acid is associated with an increased risk of bleeding, the recommended dose of acetylsalicylic acid should not exceed 100 mg. The maximum favorable effect is observed by the third month of treatment. The course of treatment is up to 1 year. The optimal duration of treatment is not established. The results of clinical studies confirm the advisability of taking the drug up to 12 months after the development of acute coronary syndrome without segment elevation S G.

Acute coronary syndrome with segment elevation ST (acute myocardial infarction with segment elevation ST)

Clopidogrel is given once in a dose of 75 mg once a day with the initial single dose loading dose (300 mg) in combination with acetylsalicylic acid and thrombolytic agents (or without 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 four weeks. The effectiveness of the use of a combination of clopidogrel and acetylsalicylic acid with this indication over 4 weeks has not been studied.

Atrial fibrillation

Clopidogrel should be taken once a day at a dose of 75 mg in combination with acetylsalicylic acid (75-100 mg / day).

If the next dose is missed, if less than 12 hours have passed, the missed dose of the drug should be taken immediately, the following doses should be taken at the usual time; if more than 12 hours have passed, the patient should take the next dose at the usual time (do not double the dose).

Patients with a genetically determined decrease in the activity of the isoenzyme CYP2C19

Weakening of metabolism with the help of isoenzyme CYP2C19 can lead to a decrease in the antiplatelet effect of clopidogrel. The mode of application of higher doses (600 mg - loading dose, then 150 mg once a day daily) in patients with low isoenzyme activity CYP2C19 increases the antiplatelet effect of clopidogrel. However, the optimal dosing regimen for patients with a weakened metabolism by isoenzyme CYP2C19 is not yet installed.

Special patient groups

Elderly people

In elderly volunteers (over 75 years old), when compared with young volunteers, there was no difference in platelet aggregation and bleeding time. For the elderly, correction of the dose of clopidogrel is not required.

Children

The experience of using the drug in children is absent.

Patients with impaired renal function

The experience with clopidogrel in patients with chronic renal failure is limited. After repeated use of clopidogrel at a dose of 75 mg per day in patients with severe renal disease (creatinine clearance from 5 to 15 ml / min), inhibition of ADP-induced platelet aggregation was 25% lower than that of healthy volunteers,However, the lengthening of bleeding time did not differ from that in healthy volunteers who received clopidogrel in a dose of 75 mg per day.

Patients with impaired hepatic function

The experience with clopidogrel in patients with hepatic insufficiency is limited. After daily administration of clopidogrel at a dose of 75 mg per day for 10 days in patients with severe liver damage, inhibition of ADP-induced platelet aggregation was similar to that of healthy volunteers. The average bleeding time in both groups was also comparable.

Patients of different ethnicity

Prevalence of alleles of isoenzyme genes CYP2C19, responsible for the intermediate and decreased metabolism of clopidogrel to its active metabolite, is different in representatives of different ethnic groups (see section "Pharmacogenetics"). There are only limited data for members of the Mongoloid race to assess the effect of the isoenzyme genotype CYP2C19 on the clinical outcome events.

Female and male patients

In a small study comparing the pharmacodynamic properties of clopidogrel in men and women,in women, there was less inhibition of ADP-induced platelet aggregation, but there was no difference in bleeding time elongation. In a controlled clinical trial CAPRIE (clopidogrel in comparison with acetylsalicylic acid in patients at risk of development of ischemic complications), the frequency of clinical outcomes, side effects and clinical and laboratory deviations from the norm was the same for men and women. Correction of the dose is not required.

Side effects:

The incidence of adverse events is determined according to the WHO classification: very often >1/10 (more than 10%), often from ≥ 1/100 to <1/10, infrequently from a 1/1000 to <1/100, rarely from ≥ 1/10000 to <1/1000, very rarely from <1/10000, unknown frequency (it is impossible to determine the frequency of occurrence of an undesired reaction from available data).

Violations of the blood and lymphatic system

Infrequently: thrombocytopenia, leukopenia, eosinophilia.

Rarely: neutropenia, including severe.

Rarely: thrombotic thrombocytopenic purpura (see section "Special instructions"), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anemia, frequency unknown - acquired hemophilia.

Immune system disorders

Rarely: anaphylactoid reactions, serum sickness, cross-allergic and hematologic reactions with other thienopyridines (such as ticlopidine, prasugrel).

Mental disorders

Rarely: hallucinations, confusion.

Disturbances from the nervous system

Infrequently: intracranial hemorrhage (including fatal), headache, paresthesia, dizziness.

Rarely: violation of taste perception.

Disturbances on the part of the organ of sight

Infrequently: eye hemorrhage (conjunctival, in the tissue and retina of the eye).

Hearing disorders and labyrinthine disorders

Rarely: Vertigo.

Vascular disorders

Often: hematoma.

Rarely: serious bleeding from the operating wound, vasculitis, lowering blood pressure.

Disturbances from the respiratory system, chest and mediastinal organs

Often: nose bleed.

Rarely: bronchospasm, interstitial pneumonia, pulmonary hemorrhage, hemoptysis, eosinophilic pneumonia.

Disorders from the digestive system

Often; gastrointestinal bleeding, diarrhea, abdominal pain, indigestion.

Infrequently: stomach ulcer and duodenal ulcer, vomiting, nausea, constipation, bloating.

Rarely: retroperitoneal hemorrhage.

Rarely: gastrointestinal bleeding and retroperitoneal hemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative colitis and lymphocytic colitis), stomatitis.

Disturbances from the liver and bile ducts

Rarely: acute hepatic insufficiency, hepatitis, deviation from the norm of indicators of liver function.

Disturbances from the skin and subcutaneous tissues

Often: "bruises" (local subcutaneous hemorrhage).

Infrequently: rash, itching, purpura, (small-capillary hemorrhage into the skin, under the skin or in the mucous membranes).

Unknown frequency: maculopapular or erythematous rash, hives, itching, angioedema, bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), drug hypersensitivity syndrome. drug rash with eosinophilia and systemic manifestations (DRESS-syndrome), eczema, red flat lichen.

Disturbances from musculoskeletal and connective tissue

Rarely: hemorrhages in muscles and joints (hemarthrosis), arthritis, arthralgia, myalgia.

Disorders from the kidneys and urinary tract

Infrequently: hematuria.

Rarely: glomerulonephritis.

General disorders and disorders at the site of administration

Often: bleeding from the point of vascular puncture.

Rarely: fever.

Laboratory and instrumental data

Infrequently: prolongation of bleeding time, decrease in the number of neutrophils, a decrease in the number of platelets in the peripheral blood, impaired functional tests of the liver, an increase in the concentration of creatinine in the blood plasma.

Overdose:

Symptoms

An overdose of clopidogrel may lead to prolonged bleeding time and subsequent hemorrhagic complications.

Treatment

Symptomatic. The antidote of clopidogrel is not established. If a fast correction of the prolonged bleeding time is necessary, transfusion of the platelet mass is recommended.

Interaction:

Oral anticoagulants

Simultaneous use of clopidogrel and oral anticoagulants may increase the intensity of bleeding, and therefore the use of this combination is not recommended, Clopidogrel at a dose of 75 mg per day does not affect the pharmacokinetics of warfarin and does not change the values of the International Normalized Ratio (INR) in patients taking long-term warfarin. However, simultaneous administration of warfarin with clopidogrel may increase the risk of bleeding due to the independent effect of these drugs on hemostasis (see section "Special instructions").

Inhibitors of glycoprotein IIb/IIIa

Purpose of glycoprotein inhibitors IIb/IIIa together with clopidogrel requires caution in patients who have an increased risk of bleeding (with trauma and surgical interventions or other pathological conditions) (see "Special instructions").

Acetylsalicylic acid

Acetylsalicylic acid does not alter the effect of clopidogrel, an inhibitor of ADP-induced platelet aggregation, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, simultaneous with clopidogrel, the intake of acetylsalicylic acid 500 mg twice a day for 1 day did not cause a significant lengthening of bleeding time caused by the use of clopidogrel.Between clopidogrel and acetylsalicylic acid, pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, although in clinical trials patients will receive combined therapy with clopidogrel and acetylsalicylic acid for up to one year, caution should be exercised when using them simultaneously.

Heparin

According to a clinical study conducted with the participation of healthy volunteers, when taking clopidogrel did not require a change in the dose of heparin and did not change its anticoagulant effect. The simultaneous use of heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation. Between clopidogrel and heparin, pharmacodynamic interaction is possible, which may increase the risk of bleeding, so the simultaneous use of these drugs requires caution.

Thrombolytics

The safety of the joint use of clopidogrel, fibrin-specific or fibrin-specific thrombolytic drugs and heparin was investigated in patients with acute myocardial infarction.The frequency of clinically significant bleeding was similar to that observed in the joint use of thrombolytic agents and heparin with acetylsalicylic acid.

Non-steroidal anti-inflammatory drugs (NSAIDs)

With the simultaneous use of clopidogrel with NSAIDs, the risk of bleeding may increase. In a clinical study conducted with the participation of healthy volunteers, the combined use of clopidogrel and naproxen increased latent blood loss through the gastrointestinal tract. However, due to the lack of research on the interaction of clopidogrel with other NSAIDs, it remains to this day unknown whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel together with other NSAIDs. Therefore, the use of NSAIDs, including COX-2 inhibitors, should be performed with caution in combination with clopidogrel (see "Specific guidance").

Selective serotonin reuptake inhibitors (SSRIs)

As SSRIs disrupt the activation of platelets and increase the risk of bleeding, simultaneous use of SSRI with clopidogrel should be carried out with caution.

Inhibitors CYP2C19

As clopidogrel metabolized to the formation of its active metabolite in part by means of CYP2C19, the use of drugs that inhibit this system can lead to a decrease in the level of the active metabolite of clopidogrel and a decrease in its clinical efficacy. The clinical significance of this interaction remains unknown, however, as a precautionary measure, it is recommended to avoid simultaneous reception of clopidogrel with drugs that inhibit CYP2C19 (omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol).

Proton Pump Inhibitors

Omeprazole at a dose of 80 mg once a day, taken simultaneously with clopidogrel or at an interval of 12 hours after taking clopidogrel reduces the effect of the active metabolite by 45% after taking the loading dose and 40% after taking a maintenance dose. This decrease leads to a decrease in inhibition of platelet aggregation by 39% and 21%, respectively. It is assumed that esomeprazole has a similar effect on the activity of clopidogrel.In observational and controlled clinical trials, conflicting evidence was obtained regarding the clinical significance of this interaction (assessed for the risk of major cardiovascular complications). As a precautionary measure, it is not recommended to apply clopidogrel together with omeprazole and esomeprazole.

If it becomes necessary to prescribe proton pump inhibitors simultaneously with clopidogrel, the drug with the lowest inhibition CYP2C19 (pantoprazole or lansoprazole). When used simultaneously with pantoprazole at a dose of 80 mg once a day, the concentration of the active metabolite of clopidogrel in the blood plasma is reduced by 20% after taking the loading dose and by 14% after taking a maintenance dose of clopidogrel. At the same time, inhibition of platelet aggregation decreases by 15% and 11%, respectively.

Other combination therapy

As clopidogrel metabolized to the formation of its active metabolite partially by means of the system CYP2C19, the use of drugs that inhibit this system (for example, omeprazole) can lead to a decrease in the level of the active metabolite of clopidogrel and a decrease in its clinical effectiveness. Simultaneous reception of drugs that inhibit the system CYP2C19, is not recommended. If proton pump inhibitors are to be taken concomitantly with clopidogrel, a proton pump inhibitor with the least inhibition of isoenzyme should be used CYP2CI9, such as pantoprazole.

A number of clinical studies with clopidogrel and other concomitant medications have been conducted to study possible pharmacodynamic and pharmacokinetic interactions that have shown that:

- when clopidogrel was used together with atenolol, nifedipine, or with both drugs, clinically significant pharmacodynamic interaction was not observed;

- with simultaneous administration of phenobarbital, cimetidine or estrogens, no significant effects on the pharmacodynamics of clopidogrel were found;

- pharmacokinetic indices of digoxin or theophylline did not change when combined with clopidogrel;

- antacids did not reduce the absorption of clopidogrel;

- according to the study CAPRIE, phenytoin and tolbutamide can be safely used concomitantly with clopidogrel, even though data from studies with human liver microsomes suggest that the carboxylic metabolite of clopidogrel can inhibit isoenzyme activity CYP2C9.

It is unlikely that clopidogrel can influence the metabolism of other medicines, such as phenytoin and tolbutamide, as well as NSAIDs, which are metabolized with the participation of isoenzyme CYP2C9.

Angiotensin converting enzyme (ACE) inhibitors, diuretics, beta-blockers, slow calcium channel blockers, hypolipidemic drugs, hypoglycemic agents (including insulin), coronary vasodilators, antiepileptics, hormone replacement therapy and glycoprotein inhibitors IIb/IIIa - Clinical studies did not reveal clinically significant undesirable interactions.

Special instructions:

In the treatment of clopidogrel, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgical intervention, careful monitoring of patients should be conducted to exclude signs of bleeding, including latent.

In connection with the risk of bleeding and hematological adverse effects (see "Side Effects"), if clinical symptoms that are suspect for bleeding occur during treatment, it is urgent to do a clinical blood test, determine activated partial thromboplastin time (APTT), platelet count , indicators of the functional activity of platelets and conduct other necessary studies. Clopidogrel as well as other antiplatelet agents, should be used with caution in patients with an increased risk of bleeding associated with trauma, surgery or other pathological conditions, as well as in patients receiving acetylsalicylic acid, NSAIDs, including COX- 2, heparin, glycoprotein inhibitors IIb/IIIa , SSRIs or thrombolytic drugs.

Joint use of clopidogrel with warfarin increases the risk of bleeding (see section "Interaction with other drugs"), so care should be taken when they are used together.

In case of the forthcoming planned surgical operation and if there is no need for an antiaggregant effect for 5-7 days before the operation, the use of clopidogrel should be discontinued. If the therapy is discontinued more than 5 days before the operation of aortocoronary shunting, the frequency of large bleeding in patients receiving clopidogrel and placebo, was comparable (4.4% in patients who received clopidogrel and acetylsalicylic acid, and 5.3% in patients receiving acetylsalicylic acid and placebo).

Clopidogrel prolongs bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (especially, gastrointestinal and intraocular).

Patients should be warned that when taking clopidogrel (alone or in combination with acetylsalicylic acid), it may take longer to stop bleeding, and that if they have unusual bleeding (localization or duration), they should be informed about this to your doctor. Before any future operation (including dental manipulations) and before starting any new drug, patients should inform the doctor about taking clopidogrel.

Very rarely, after the use of clopidogrel (sometimes even briefly), there have been cases of thrombotic thrombocytopenic purpura (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 requiring immediate treatment, including plasmapheresis.

It is reported that cases of development of acquired hemophilia with the use of clopidogrel. With the confirmed isolated increase in activated partial thromboplastin time (APTT), accompanied or not accompanied by the development of bleeding, the possibility of developing acquired hemophilia should be suspected. Patients with a confirmed diagnosis of acquired hemophilia should be observed and treated by specialists in this disease. The use of clopidogrel must be discontinued.

It should be clarified the presence in the anamnesis in patients of allergic and / or hematological reactions to other thienopyridine derivatives (such as ticlopidine and prasugrel), t.cases of cross-allergic and / or hematological reactions between thienopyridines are described. Tienopyridines can cause mild or severe allergic reactions (rash, angioedema) or hematologic reactions (thrombocytopenia, neutropenia). Patients who have previously experienced allergic and / or hematologic reactions to one of the drugs - thienopyridine derivatives, may have an increased risk of developing such reactions when taking another drug from the group of thienopyridines. Such patients require careful observation during the entire period of therapy to detect signs of hypersensitivity to clopidogrel.

During the treatment it is necessary to monitor the functional activity of the liver. With severe liver damage should be remembered about the risk of hemorrhagic diathesis.

Taking clopidogrel is not recommended for an acute stroke less than 7 days old (as there is no data on its use in this condition).

In patients with recent ischemic stroke or transient ischemic attack and high risk of recurrent atherothrombotic events, combined therapy with clopidogrel and acetylsalicylic acid has not demonstrated morehigh efficacy in comparison with monotherapy with clopidogrel, but may increase the risk of major bleeding.

It should be clarified the presence in the patient's history of hypersensitivity to other derivatives of thienopyridine (ticlopidine, prasugrel), t. cases of cross-allergic reactions between thienopyridines are described. Patients who have previously experienced hypersensitivity to other thienopyridine require careful follow-up throughout the treatment period to identify signs of hypersensitivity to clopidogrel.

The experience of using clopidogrel in patients with chronic renal failure is limited, in connection with which clopidogrel in this category of patients should be used with caution.

With severe violations of liver function, the use of clopidogrel is contraindicated because of the high risk of hemorrhagic diathesis. The experience of using the drug in patients with moderate violations of the liver is limited, so these patients clopidogrel should be administered with caution.

Clopidogrel should not be taken to patients with a rare hereditary intolerance to galactose, a deficiency of lactase and a glucose-galactose malabsorption syndrome (see "Composition").

Effect on the ability to drive transp. cf. and fur:

Clopidogrel does not significantly affect the ability to drive vehicles and other mechanisms.

Form release / dosage:Pills, coated with film, 75 mg, 150 mg and 300 mg.

Packaging:

Tablets, film-coated, 75 mg: 7 or 14 tablets per aluminum strip or contour-cell packaging; 1, 2, 4, 6, 8 or 12 strips or contour-cell packages together with instructions for use in a cardboard pack;

Tablets, film-coated, 150 mg: 7 or 10 tablets per aluminum strip or contour-cell packaging, 1,2, 3, 4, 6, 8, 10 or 12 strips or contour-cell packs together with instructions for use in a cardboard package;

Film-coated tablets, 300 mg: 10 tablets per aluminum strip or contour-cell packaging; 1, 2, 3, 6 or 10 strips or contour-box packages together with instructions for use in a cardboard pack;

Combined packaging: 1 film-coated tablet, 300 mg + 28 tablets, film-coated 75 mg: 7 or 14 75 mg tablets per aluminum strip or contour-cell packaging; 1 tablet 300 mg peraluminum strip or contour-cell packaging; on 2 or 4 strips or contour-cell packs with 75 mg tablets and 1 strip or contour-cell packaging with a 300 mg tablet along with instructions for use in a cardboard pack.

Storage conditions:

Keep in dry the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date stated on the package

Terms of leave from pharmacies:On prescription

Registration number:LP-002947

Date of registration:07.04.2015 / 30.05.2017

Expiration Date:07.04.2020

The owner of the registration certificate:ESCO PHARMA, LLCESCO PHARMA, LLC

Manufacturer: & nbsp

NOVALEK PHARMACEITICAL, Pvt. Ltd. India

Representation: & nbspJodas Expoim, Open CompanyJodas Expoim, Open Company

Information update date: & nbsp11.01.2018

Illustrated instructions

Instructions

Klapitax (Klapitax)