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

Excipients: lactose monohydrate - 94.425 mg, microcrystalline cellulose - 26.20 mg, giprolase L - 22.50 mg, macrogol 6000 - 3.00 mg, hydrogenated castor oil - 6.00 mg.

Film Sheath: opadrai pink 03В54564 - 6.50 mg (hypromellose 6 сР (НРМС 2910) - 62,5%, titanium dioxide - 31,02%, macrogol 400 - 6,25%, iron dye oxide red - 0,23%).

Description:

Tablets from light pink to pink, biconvex, round, covered with a film shell with an engraving "C4" on one side and smooth on the other. Type of tablet on the fracture: homogeneous pressed mass from white to almost white.

Pharmacotherapeutic group:antiplatelet agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

Pharmacodynamics:

Clopidogrel (more precisely, its active metabolite) irreversibly binds to platelet ADP receptors (adenosine diphosphate receptors) and selectively inhibits the binding of ADP to ADP-receptor platelets and subsequent activation of the complex GPIIb/IIIa under the action of ADP, due to which ADP-induced aggregation of platelets is suppressed. Clopidogrel also inhibits platelet aggregation caused by other agonists, due to the fact that it blocks activation platelets released by ADP. In connection with the irreversibility of the binding of clopidogrel with ADP-receptors of platelets,platelets remain immune to stimulation of ADP for the rest of their life, and the restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal.

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

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.

Pharmacokinetics:

Suction

With a single and repeated oral administration at a dose of 75 mg per day clopidogrel quickly absorbed. The mean maximum concentration (C_mOh) of unchanged clopidogrel in blood plasma (approximately 2.2-2.5 ng / ml after ingestion of a single dose of 75 mg) are reached approximately 45 minutes after the drug is administered. According to excretion of metabolites of clopidogrel in urine, its absorption is approximately 50%.

Distribution

In vitro Clopidogrel and its main circulating non-active metabolite in the blood reversibly bind to plasma proteins (98% and 94%, respectively), and 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: first carried out with the help of esterases, leads to hydrolysis of clopidogrel with the formation of an inactive derivative of carboxylic acid (85% from circulating metabolites), and the second pathway is carried out using cytochrome P450 isoenzymes. Originally 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 active metabolite is formed mainly by isoenzyme CYP2C19, but some other isoenzymes also participate in its formation, including CYP1A2, CYP2B6 and CYP3A4. Active thiol metabolite of clopidogrel, which was isolated in in vitro studies, quickly and irreversibly binds to platelet receptors, thus blocking their aggregation of platelets.

The maximum concentration of the active metabolite of clopidogrel (C_mOh) after a single intake of its loading dose of 300 mg is 2 times greater than that after 4 days of taking a maintenance dose of clopidogrel 75 mg. FROM_mOh is achieved within about 30-60 minutes.

Excretion

Within 120 hours after ingestion by a human ¹⁴C-labeled clopidogrel about 50% of the radioactivity is released through the kidneys with urine and about 46% of the radioactivity is excreted through the intestine with a fecal mass. After a single oral dose of 75 mg half-life (T_1/2) of clopidogrel is approximately 6 hours. After a single administration and reception of repeated doses of clopidogrel (T_1/2) of its main circulating non-active metabolite in the blood is 8 h.

Pharmacogenetics

Using isoenzyme CYP2C19 both active metabolite and intermediate metabolite - 2-oxo-clopidogrel are formed. Pharmacokinetics and antiplatelet effect of the active metabolite clopidogrel, in the study of platelet aggregation ex vivo, vary depending on the genotype of the isoenzyme CYP2C19. Gene allele CYP2C19 * 1 corresponds to fully functional metabolism, whereas gene alleles CYP2C19 * 2 and CYP2C19 * 3 are non-functional. Alleles of genes CYP2C19 * 2 and CYP2C19 * 3 cause a decrease in metabolism in the majority of representatives of the Caucasoid (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, gene alleles CYP2C19 * 4, * 5, * 6, * 7 and * 8. Patients with low isoenzyme activity CYP2C19 should have the two alleles of the gene with loss of function. Published frequencies of occurrence of phenotypes of persons with low isoenzyme activity CYP2C19 are 2% for Caucasians, 4% for Negroid people, and 14% for Chinese. There are special tests to determine the patient's isoenzyme genotype CYP2C19.

According to a cross-sectional study (40 volunteers) that included individuals with very high, high, intermediate and low isoenzyme activity CYP2C19, no significant differences in the exposure of the active metabolite and in the mean values of platelet aggregation inhibition (ADI) induced by ADP.in volunteers with very high, high and intermediate isoenzyme activity CYP2C19 was not identified. In volunteers with low isoenzyme activity CYP2C19 the exposure of the active metabolite was reduced by 63-71% in comparison with persons with high isoenzyme activity CYP2C19. When using the treatment regimen, 300 mg loading dose / 75 mg maintenance dose (300 mg / 75 mg) in volunteers with low isoenzyme activity CYP2C19, the antiplatelet effect was reduced with mean values of the IBR of 24% (after 24 hours) and 37% (on the 5th day of treatment) compared with the IAT. 39% (24 hours) and 58% (on day 5 of treatment) in volunteers with high isoenzyme activity CYP2C19 and 37% (after 24 hours) and 60% (on the 5th day of treatment) in volunteers with intermediate isoenzyme activity CYP2C19.

When volunteers with low isoenzyme activity CYP2C19 received a treatment regimen of 600 mg loading dose / 150 mg maintenance dose (600 mg / 150 mg), the exposure of the active metabolite was higher than when taking the 300 mg / 75 mg treatment regimen. In addition, the ATI was 32% (after 24 hours) and 61% (on the 5th day of treatment), which was greater than that of individuals with low isoenzyme activity CYP2C19 who received a 300 mg / 75 mg treatment regimen and were similar to those in the higher intensity groups CYP2C 19-metabolism, receiving a treatment regimen of 300 mg / 75 mg.However, in studies with clinical outcomes, the dosing regimen of clopidogrel for patients in this group (patients with low isoenzyme activity CYP2C19) is not yet installed.

Similar to the results of this study, a meta-analysis of six studies, which included data from 335 volunteers who received clopidogrel and those in the state of attaining an equilibrium concentration, showed that in comparison with volunteers with high isoenzyme activity CYP2C19, in volunteers with intermediate isoenzyme activity CYP2C19, the exposure of the active metabolite was reduced by 28%, and in volunteers with low isoenzyme activity CYP2C19 - by 72%, while the IAB was reduced with differences in the IAT that are 5.9% and 21.4, respectively.

An evaluation of the influence of the genotype CYP2C19 on clinical outcomes in patients who received clopidogrel, in prospective, randomized, controlled trials. However, to date, 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 study TRITON-TIMI 38 and 3 cohort studies (Collet, Sibbing, Giusti) patients of the combined group with intermediate or low isoenzyme activity CYP2C19 had a higher incidence of cardiovascular complications (death, myocardial infarction and stroke) or stent thrombosis compared to those in patients with high isoenzyme activity CYP2CI9.

In the study CHARISMA and one cohort study (Simon), an increase in the incidence of cardiovascular complications was observed only in patients with low isoenzyme activity CYP2C19 (when compared with patients with high isoenzyme activity CYP2C19).

In the study CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk) there was no increase in the incidence of cardiovascular complications as a function of CYP2C19-metabolism.

Individual patient groups

The pharmacokinetics of the active metabolite of clopidogrel in these patient groups have not been studied.

Elderly patients

In elderly volunteers (over 75 years old), when compared with young volunteers, there was no difference in platelet aggregation and bleeding time. Do not require dose adjustment in the elderly.

Children

No data available.

Patients with impaired renal function

After repeated use of clopidogrel at a dose of 75 mg / day in patients with severe renal impairment (creatinine clearance from 5 ml / min to 15 ml / min), inhibition of ADP-induced platelet aggregation was lower (by 25%) 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 per day.

Patients with a violation of phFunctions liver

After daily administration of clopidogrel at a daily dose of 75 mg for patients with severe impairment of liver function during 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.

Race

Prevalence of alleles of isoenzyme genes CYP2C19, which determine the intermediate and low activity of this isoenzyme, differs among representatives of different racial groups. There are limited literature data on their prevalence in representatives of the Mongoloid race, which does not allow us to assess their values of genotyping isoenzyme CYP2C19 for the development of ischemic complications.

Indications:

Prevention of thrombotic complications in patients with myocardial infarction, ischemic stroke or peripheral arterial occlusion.

In combination with ASA (acetylsalicidic acid) for the prevention of thrombotic complications in acute coronary syndrome: with segment elevation ST (acute myocardial infarction) with the possibility of carrying out thrombolytic therapy; without segment elevation ST (unstable angina, myocardial infarction without a tooth Q), incl. in patients undergoing stenting.

Prevention of atherothrombotic and thromboembolic complications, including stroke, in patients with atrial fibrillation (atrial fibrillation), with at least one risk factor for vascular complications, with the inability to take indirect anticoagulants and a low risk of bleeding (in combination with acetylsalicylic acid).

Contraindications:

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

- tsevere hepatic impairment;

- aboutthe structure of bleeding (including bleeding from peptic ulcers or intracranial hemorrhage);

- bVariability and the period of breastfeeding;

- dUp to 18 years of age (safety and efficacy not established);

- Mr.lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome.

Carefully:

- Moderate hepatic impairment with impaired blood coagulability and increased risk of bleeding (limited clinical experience of use);

- diseases with risk of bleeding (gastrointestinal, intraocular);

- renal failure (limited clinical experience);

- trauma and surgery;

- simultaneous use of non-steroidal anti-inflammatory drugs, including selective inhibitors of cyclooxygenase-2 (COX-2), due to their ability to cause damage to the mucous membrane of the gastrointestinal tract, increasing the risk of bleeding;

- simultaneous use with selective serotonin reuptake inhibitors in connection with an increased risk of bleeding;

- simultaneous use of warfarin, heparin, glycoprotein inhibitors IIb/IIIa;

- low isoenzyme activity CYP2C19 with the use of clopidogrel in the recommended doses leads to the formation of less active metabolite of clopidogrel and the weakening of its antiaggregant effect. In connection with this, with the use of usually recommended doses of clopidogrel in acute coronary syndrome or percutaneous coronary intervention, a higher incidence of cardiovascular complications is possible than in patients with normal isoenzyme activity CYP2C19;

- allergic reactions to thienopyridine in the anamnesis (for example, ticlopidine, prasugrel) in connection with the possibility of cross-allergy;

- a recent transient impairment of cerebral circulation or ischemic stroke.

Pregnancy and lactation:

Pregnancy

Studies in animals showed no direct or indirect adverse effects on the course of pregnancy, embryonic development, childbirth and postnatal development. Since it is not always possible to predict the reaction in humans from the results of animal studies, and due to the absence of data from controlled clinical studies on the use of clopidogrel by pregnant women,As a precautionary measure, taking clopidogrel during pregnancy is not recommended, except in cases when, according to the doctor, its use is urgently needed.

Breastfeeding period

In studies on rats, it was shown that clopidogrel and / or its metabolites are excreted into breast milk. Does it penetrate clopidogrel in human breast milk is unknown. Since many drugs can be excreted into breast milk and have an adverse effect on an infant, the treating doctor, based on the importance of taking the drug for the mother, should recommend that she either stop taking the drug or take the drug, but give up breastfeeding.

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.

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 a loading dose of 300 mg. and then continued with a 75 mg dose once a day (in combination with acetylsalicylic acid in 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 optimal duration of treatment is not officially defined. Clinical trials support the use of the drug for up to 12 months, and the maximum beneficial effect was observed by the third month of treatment.

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

Clopidogrel should be taken once a day at a dose of 75 mg 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 begins as soon as possible after the onset of symptoms, and lasts 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 (atrial fibrillation)

Clopidogrel should be taken once a day at a dose of 75 mg. In combination with clopidogrel, you must start and then continue taking acetylsalicylic acid (75-100 mg / day).

Skipping the next dose

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.

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 isoenzyme activity CYP2C19

Low isoenzyme activity CYP2C19 is associated with 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 antiaggregant effect of clopidogrel (see section "Pharmacokinetics").However, at the present time in clinical studies that take into account clinical outcomes, an optimal dosing regimen for clopidogrel has not been established for patients with reduced metabolism due to genetically determined low isoenzyme activity CYP2C19.

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. Do not require dose adjustment for the elderly.

Children

There is no experience of using the drug in children.

Patients with impaired renal function

After repeated use of clopidogrel at a dose of 75 mg / day in patients with severe renal disease (creatinine clearance from 5 to 15 ml / min), inhibition of ADP-induced platelet aggregation (25%) was lower than that of healthy volunteers, however, lengthening bleeding time was similar to that of healthy volunteers who received clopidogrel in a dose of 75 mg per day. In addition, all patients had good tolerability of the drug.

Patients with impaired hepatic function

After daily administration of clopidogrel at a daily dose of 75 mg for 10 days in patients with severe liver disease, inhibition of ADP-induced platelet aggregation was similar to that of healthy volunteers. The mean bleeding time was also comparable in both groups.

Patients of different ethnicity

Prevalence of alleles of isoenzyme genes CYP2C19 in charge of 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 clinical outcome events.

Female and male patients

In a small study comparing the pharmacodynamic properties of clopidogrel in men and women, women had less inhibition of ADP-induced platelet aggregation, but there was no difference in bleeding time elongation. In a large controlled study CAPRIE (clopidogrel in comparison with acetylsalicylic acid in patients with a risk of developing ischemic complications),the frequency of clinical outcomes, other side effects and deviations from the norm of clinical and laboratory indicators was the same for both men and women.

Side effects:

Data from clinical trials

The safety of clopidogrel was studied in more than 44,000 patients, including more than 12,000 patients who received treatment for a year or more. In general, the tolerability of clopidogrel at a dose of 75 mg / day in the study CAPRIE corresponded to the tolerability of ASA at a dose of 325 mg / day, regardless of the age, sex and race of patients. The following are clinically significant adverse effects observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT and ACTIVE A.

Bleeding and hemorrhage

Comparison of monotherapy with clopidogrel and ASA

In a clinical study CAPRIE the total frequency of all bleeding in patients taking clopidogrel, and in patients taking ASA, was 9.3%. The incidence of severe bleeding with clopidogrel and ASA was comparable: 1.4% and 1.6%, respectively.

In general, the incidence of gastrointestinal bleeding in patients taking clopidogrel(2.0% and 2.7%, respectively), including the incidence of gastrointestinal bleeding that required hospitalization was 0.7% and 1.1%, respectively.

The overall incidence of bleeding from another site with clopidogrel in comparison with ASA was higher (7.3% against 6.5% respectively). However, the incidence of severe bleeding with clopidogrel and ASA was comparable (0.6% or 0.4%, respectively). The most frequently reported development of the following bleeding: purpura / bruising. nose bleed. Less commonly reported on the development of hematomas, hematuria and ocular hemorrhage (mainly conjunctival). The incidence of intracranial hemorrhages with clopidogrel and ASA was comparable (0.4% or 0.5%, respectively).

Comparison of combination therapy clopidogrel + ASA and placebo + ASA

In a clinical study CURE in patients taking clopidogrel + ASA, compared to patients taking placebo + ASA, there was an increase in the incidence of major bleeding (3.7% vs. 2.7%), and minor bleeding (5.1% vs. 2.4%).Basically, the sources of large bleeding were the gastrointestinal tract and the sites of arterial puncture.

The frequency of life-threatening bleeding in patients who took clopidogrel + ASA compared with patients taking placebo + ASA did not differ significantly (2.2% and 1.8%, respectively), the frequency of fatal bleeding was the same (0.2% for both therapies).

The incidence of non-life-threatening large bleeding was significantly higher in patients taking clopidogrel + ASA, compared with patients taking placebo + ASA (1.6% and 1%, respectively), but the incidence of intracranial hemorrhage was similar for both therapies.

The frequency of major bleeding in the group clopidogrel + ASA depended on the dose of ASA (<100 mg: 2.6%, 100-200 mg: 3.5%,> 200 mg: 4.9%), as well as the incidence of major bleeding in the placebo + ASA group (<100 mg: 2.0%, 100-200 mg: 2.3%,> 200 mg: 4.9%).

Patients who stopped antiplatelet therapy more than 5 days before coronary artery bypass grafting did not experience a higher incidence of major bleeding within 7 days after the intervention (4.4% in the group clopidogrel + ASA and 5.3% in the placebo + ASA group).Patients who continued antiplatelet therapy for the last five days before aortocoronary bypass surgery, the incidence of these events after intervention was 9.6% (in the group clopidogrel + ASA) and 6.3% (in the placebo + ASA group).

In a clinical study CLARITY frequency of major bleeding (defined as intracranial hemorrhage or hemorrhage with a decrease in hemoglobin> 5 g / dl) in both groups (clopidogrel + ASA and placebo + ASA) was comparable in both treatment groups (1.3% against 1.1% in the group clopidogrel + ASA and placebo + ASA group, respectively). It was the same in subgroups of patients divided by baseline characteristics and by types of fibrinolytic therapy or heparin therapy.

The incidence of fatal bleeding (0.8% vs. 0.6%) and intracranial hemorrhage (0.5% vs. 0.7%) in the treatment clopidogrel + ASA and placebo + ASA, respectively, was low and comparable in both treatment groups.

In a clinical study COMMIT the overall incidence of non-cerebral large bleeding or cerebral bleeding was low and the same (0.6% in the group clopidogrel + ASA and 0.5% in the placebo + ASA group).

In a clinical study ACTIVE-A frequency of major bleeding in the group clopidogrel + ASA was higher than in the placebo + ASA group (6.7% against 4.3% respectively). The large bleeding was mainly extracranial in both groups (5.3% vs. 3.5%), mainly from the gastrointestinal tract (3.5% vs. 1.8%). In a group clopidogrel + ASA of intracranial hemorrhages was greater in comparison with the placebo + ASA group (1.4% against 0.8%, respectively). There were no statistically significant differences between these treatment groups in the incidence of fatal bleeding (1.1% versus 0.7%) and hemorrhagic stroke (0.8% against 0.6%).

Blood disorders

In the study CAPRIE, severe neutropenia (<0.45 10⁹/ l) was observed in 4 patients (0.04%) who received clopidogrel, and in 2 patients (0.02%) who received ASA.

In two of the 9599 patients who took clopidogrel, there was a complete absence of neutrophils in the peripheral blood, which was not observed in any of the 9586 patients taking ASA. Despite the fact that the risk of developing myelotoxic action when taking clopidogrel is low enough, if the patient taking clopidogrel, there is a fever or other signs of infection, the patient should be examined for possible neutropenia.

In the treatment of clopidogrel in one case, development of aplastic anemia was observed.

The incidence of severe thrombocytopenia (<80-107 l) was 0.2% in patients taking clopidogrel and 0.1% in patients taking ASA, very rare cases of a platelet count decrease of <30-10% were reported.

In studies CURE and CLARITY There was a comparable number of patients with thrombocytopenia or neutropenia in both treatment groups

Other clinically significant adverse reactions observed in clinical trials CAPRIE, CURE, CLARITY COMMIT and ACTIVE-A

The following classification of the World Health Organization (WHO) was used to estimate the incidence of adverse reactions: very often (≥1/10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1000 and <1/100) , rarely (≥1 / 10000 and <1/1000), very rarely (<1/10000, including isolated cases).

Disturbances from the nervous system

Infrequent: headache, dizziness, paresthesia.

Rarely: vertigo.

Disorders from the gastrointestinal tract

Often: indigestion, abdominal pain, diarrhea.

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

Disturbances from the skin and subcutaneous tissue

Infrequent: rash, itching.

Violations of the blood and lymphatic system

Infrequent: an increase in bleeding time, a decrease in the number of platelets in peripheral blood: leukopenia, a decrease in the number of neutrophils in peripheral blood, eosinophilia.

Postmarketing experience with the drug

Violations of the blood and lymphatic system

Frequency is unknown: cases of serious bleeding, mainly subcutaneous, musculoskeletal, ocular hemorrhage (conjunctival, in tissue and retina), bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage), epistaxis, haematuria and bleeding from postoperative wounds and bleeding episodes with lethal outcome (especially intracranial hemorrhage, gastrointestinal bleeding and retroperitoneal hemorrhage); agranulocytosis, granulocytopenia, aplastic anemia / pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A.

Immune system disorders

The frequency is unknown: anaphylactoid reactions, serum sickness: cross-allergic and hematologic reactions with other thienopyridines (such as ticlopidine. prasugrel) (see section "Special instructions").

Disorders of the psyche

The frequency is unknown: confusion, hallucinations.

Disturbances from the nervous system

The frequency is unknown: a violation of taste perception.

Vascular disorders

The frequency is unknown: vasculitis, lowering blood pressure.

Disturbances from the respiratory system, organs of the chest and mediastinum

The frequency is unknown: bronchospasm, interstitial pneumonia, eosinophilic pneumonia.

Disorders from the gastrointestinal tract

The frequency is unknown: colitis (including ulcerative colitis or lymphocytic colitis), pancreatitis, stomatitis.

Disturbances from the liver and bile ducts

The frequency is unknown: hepatitis (non-infectious), acute hepatic insufficiency.

Disturbances from the skin and subcutaneous tissues

The frequency is unknown: maculopapular erythematous or exfoliative rash, hives, itching, angioedema, bullous dermatitis (erythema multiforme,Stevens-Johnson syndrome, toxic epidermal necrolysis), acute generalized exanthematous pustulosis, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations (DRESS-syndrome)

Disturbances from musculoskeletal and connective tissue

The frequency is unknown: arthralgia (joint pain), arthritis, myalgia.

Disorders from the kidneys and urinary tract

Frequency unknown: glomerulonephritis.

Violations of the genitals and mammary gland

The frequency is unknown: gynecomastia.

General disorders and disorders at the site of administration

Frequency unknown: fever.

Laboratory and instrumental data

The frequency is unknown: deviation from the norm of laboratory indicators of the functional state of the liver, increasing the concentration of creatinine in the blood, eczema, flat lichen.

Overdose:

With a single oral administration of 600 mg of clopidogrel, no side effects were noted in healthy individuals. The bleeding time was extended 1.7 times, which corresponds to the value recorded after taking a therapeutic dose (75 mg per day).

Symptoms: prolonged bleeding time, hemorrhagic complications.

Treatment: stop bleeding, transfusion of platelet mass. There is no specific antidote.

Interaction:

Warfarin

Although taking clopidogrel 75 mg / day did not change the pharmacokinetics of warfarin (substrate isoenzyme CYP2C9) or MNO (an internationally normalized relationship), in patients receiving long-term treatment with warfarin, concurrent administration of clopidogrel increases the risk of bleeding due to its additional independent effect on blood clotting. Therefore, care should be taken while taking warfarin and clopidogrel.

Blockers IIb/IIIa-receptors

The use of blockers IIb/IIIa-receptors together with clopidogrel requires caution in patients who have an increased risk of bleeding (with trauma and surgical interventions or other pathological conditions.

Acetylcalicyclic acid

Acetylsalicylic acid does not alter the inhibitory 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 one day did not cause a significant increase in 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, with their simultaneous use, care should be taken, although in clinical trials patients received combined therapy with clopidogrel and acetylsalicylic acid for up to 1 year.

Heparin

According to a clinical study conducted with the participation of healthy individuals, 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 antiplatelet effect of clopidogrel. Between clopidogrel and heparin, pharmacodynamic interaction is possible, which can increase the risk of bleeding, so the simultaneous use of clopidogrel and heparin requires caution.

Thrombolytics

The safety of the combined use of clopidogrel, fibrin-specific or fibrin-nonspecific thrombolytic agents, and heparin was studied 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.

NSAIDs

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 is currently 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, in combination with clopidogrel, should be performed with caution.

Selective serotonin uptake inhibitors (SSRIs)

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

Other drug interactions

With strong and moderate inhibitors of isoenzyme CYP2C19

As clopidogrel metabolized to its active metabolite in part by isoenzyme CYP2C19, the use of drugs that inhibit this isoenzyme may lead to a decrease in the formation of an active metabolite of clopidogrel. The clinical significance of this interaction is not established. As a precaution, simultaneous use of clopidogrel and strong or moderate isoenzyme inhibitors should be avoided CYP2C19. Strong or moderate isoenzyme inhibitors CYP2C19 are omeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol.

It should be avoided simultaneous use of proton pump inhibitors that are strong or moderate isozyme inhibitors of strong or moderate isoenzyme inhibitors CYP2C19 (e.g., omeprazole, esomeprazole). If proton pump inhibitors are to be taken concomitantly with clopidogrel, a proton pump inhibitor with the least inhibition of isoenzyme should be used CYP2C19, such as pantoprazole and lantoprazole.

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 both, concomitant drug interactions were not observed;

- simultaneous use of phenobarbital, cimetidine and estrogens did not have a significant effect on the pharmacokinetics of clopidogrel;

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

- antacids did not reduce the absorption of clopidogrel;

- phenytoin and tolbutamide can be safely used simultaneously with clopidogrel. It is unlikely that clopidogrel can affect the metabolism of other medicines, such as phenytoin and tolbutamide, as well as NSAIDs that are metabolized by isoenzyme CYP2C19 families of cytochrome P450;

- ACE inhibitors, diuretics, beta-blockers, blockers of "slow" calcium channels, lipid-lowering drugs, coronary vasodilators, hypoglycemic agents (incl.insulin), antiepileptic drugs, hormone replacement therapy and blockers IIb/IIIa receptors: clinical studies did not reveal clinically significant adverse interactions.

Special instructions:

In the case of surgical interventions, if antiaggregant effect is undesirable, the course of treatment should be discontinued 7 days before the operation. Patients should be warned that because the stoppage of bleeding that occurs during the use of the drug requires more time, they should inform the doctor of every case of unusual bleeding.

Patients should also inform the doctor about taking the drug if they are undergoing surgery (including dental surgery) or if the doctor prescribes a drug (drug) that is new to the patient.

Due to the risk of bleeding and adverse effects on the part of the blood in case of occurrence in the course of treatment of clinical symptoms, suspected of bleeding should urgently make a general clinical blood test to determine the APTT, platelet count, platelet functional activity indicators and conduct other necessary investigations.

Clopidogrel prolongs bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (especially gastrointestinal and intraocular). Drugs that can cause damage to the mucous membrane of the gastrointestinal tract (such as acetylsalicylic acid, NSAIDs) in patients taking clopidogrel, should be used with caution.

In case of severe violations of liver function, one should remember about the risk of hemorrhagic diathesis. During the course of treatment it is necessary to monitor the functional state of the liver.

It has been shown that in patients with recent transient impairment of cerebral circulation or stroke having a high risk of developing recurrent ischemic complications, the combination of ASA and clopidogrel increases the incidence of major bleeding. Therefore, such combination therapy should be conducted with caution and only in case of proven clinical benefit from its use.

It is not recommended to prescribe to patients with ischemic stroke less than 7 days old.

There was reported the presence of cross-allergic (rash, angioedema) and / or hematological (thrombocytopenia, neutropenia) reactions between thienopyridines. It is necessary to collect anamnesis in patients for the presence of previously allergic and / or allergic reactions to other thienopyridines (such as ticlopidine). Patients who have previously experienced allergic and / or hematologic reactions to one of the drugs of the thienopyridine group may have an increased risk of developing similar reactions to another drug of the thienopyridine group.

Simultaneous use with warfarin may increase the risk of bleeding, so caution should be exercised while using clopidogrel and warfarin.

There have been reports of cases of development of acquired hemophilia with clopidogrel. With confirmed isolated increase in activated partial thromboplastin time (APTT), accompanied or not accompanied by bleeding, consideration should be given to the possibility of developing acquired hemophilia. Patients with a confirmed diagnosis of acquired hemophilia should be observed and treated by specialists in this disease andstop taking clopidogrel.

In patients with low isoenzyme activity CYP2C19 when clopidogrel is used in recommended doses, less active metabolite of clopidogrel is formed and its antiplatelet effect is less pronounced, and therefore, when taking the usually recommended doses of clopidogrel in acute coronary syndrome or percutaneous coronary intervention, a higher incidence of cardiovascular complications is possible than in patients with normal isoenzyme activity CYP2C19. Available genotype testing CYP2C19 can be used in choosing a therapeutic strategy. In patients with low activity CYP2C19, the use of higher doses of clopidogrel is considered.

Since Targetec® tablets contain hydrogenated castor oil as an auxiliary, they can cause dyspepsia and diarrhea.

Very rarely, when taking clopidogrel, thrombotic thrombocytopenic purpura developed, sometimes after short-term use. The condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia, associated with neurologic disorders, kidney damage and fever.Thrombotic thrombocytopenic purpura is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

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

Targetek® does not significantly affect the abilities required for driving or working with machinery.

Form release / dosage:Tablets coated with a film coating, 75 mg.

Packaging:

7 tablets in a blister of aluminum foil, PVC film and polyamide, 2 or 4 blisters with instructions for use in a cardboard box.

10 tablets in a blister of aluminum foil, PVC film and polyamide.

1, 2 or 3 blisters with instructions for use in a cardboard box.

Storage conditions:

In a dry place, at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:PL-000777

Date of registration:29.09.2011 / 19.07.2016

Expiration Date:Unlimited

The owner of the registration certificate:San Pharmaceutical Industries Co., Ltd.San Pharmaceutical Industries Co., Ltd. India

Manufacturer: & nbsp

Sun Pharmaceutical Industries, Ltd. India

Representation: & nbspSAN PHARMACEUTICAL INDUSTRIES LTD. SAN PHARMACEUTICAL INDUSTRIES LTD. India

Information update date: & nbsp04.10.2016

Illustrated instructions

Instructions

Targetec® (Targetek® )