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

film sheath: coloring Opadrai II (pink) 85G34736 5.0 mg (polyvinyl alcohol 44, 0%, titanium dioxide (E171) 19.3%, macrogol-4000 12.35%, talc 20.0%, lecithin soybean 3.5%, dye Azorubin (E122) 0.85%), coloring agent Opadrai II (white) 85F18378 5.0 mg (polyvinyl alcohol 40.0%, titanium dioxide (E171) 25.0%, macrogol-4000 20.2%, talc 14.8%).

Description:

Round, biconvex tablets, covered with a film coat, pink; a kind of tablets on a break: white or yellowish-white rough mass with a shell of pink color.

Pharmacotherapeutic group:Antiaggregant agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

Pharmacodynamics:

Pidogrel is a prodrug, one of the active metabolites of which is inhibitor of platelet aggregation.

The active metabolite of clopidogrel selectively inhibits binding adenosine diphosphate (ADP) with P2Y₁₂ receptors of platelets and subsequent ADP-mediated activation of glycoprotein GPIIb/IIIa complex, which leads to inhibition of platelets.

Suppression of platelet aggregation is irreversible and continues throughout the cell life cycle (about 7-10 days), so the rate of recovery of normal platelet function corresponds to the rate of their renewal. The platelet aggregation induced by other agonists, in addition to ADP,is also inhibited due to blockade of enhanced platelet activation by ADP. The active metabolite is formed by the action of isoenzymes CYP450, some of which may differ in polymorphism or may be inhibited by other drugs, therefore, adequate inhibition of platelet aggregation is not observed in all patients.

In the treatment of clopidogrel at a dose of 75 mg per day from the first day of therapy, there is a significant suppression of ADP-induced platelet aggregation, which gradually increases for 3-7 days and then reaches a constant level (when the equilibrium state is reached). In the equilibrium state, the degree of inhibition of platelet aggregation with clopidogrel at a dose of 75 mg per day, on average, was 40% to 60%. After stopping the use of clopidogrel, platelet aggregation and bleeding time gradually returned to baseline values, on average, for 5 days.

Clopidogrel prevents the development of atherothrombotic complications in patients with atherosclerotic lesions of vessels of any location, especially with damage to the cerebral, coronary or peripheral arteries.

Pharmacokinetics:

With a single and repeated oral administration at a dose of 75 mg per day clopidogrel quickly absorbed. The mean maximum concentration (C_m_Oh) 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 Using esterases, leads to the hydrolysis of clopidogrel with the formation of an inactive derivative of carboxylic acid (85% of the 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. The 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_m_Oh) 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_m_Ohis 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, the half-life (T1 / 2) of clopidogrel is approximately 6 hours.After a single administration and reception of repeated doses of clopidogrel T1 / 2 of its main circulating inactive inactive metabolite is 8 hours.

Pharmacogenetics

Using isoenzyme CYP2C19 formed as an active metabolite, and an intermediate metabolite - 2-oxo-clopidogrel. 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 completely functional metabolism, whereas the alleles of the genes CUR2C19 * 2 and CYP2C19*3 are non-functional. Alleles of genes СУР2С19 * 2 and CYP2C19*3 are the cause of a decrease in metabolism in the majority of representatives of the Caucasoid (85%) and Mongoloid races (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 genes CUR2C19 * 4, * 5, * 6, * 7 and * 8. Patients with low isoenzyme activity CYP2C19 should have the two alleles of the gene with loss of function indicated above. 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-study (40 volunteers) in which included persons 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 and inhibition of platelet aggregation (ADI) induced by ADP in volunteers with very high, high and intermediate isoenzyme activity CYP2C19 it was not revealed. In volunteers with low isoenzyme activity CYP2C19 Exposure of the active metabolite decreased by 63-71% compared to 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 IAT of 24% (after 24 hours) and 37% (on the 5th day of treatment) compared with 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 day 5 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 IAT was 32% (after 24 hours) and 61% (on the 5th day of treatment), which was more than that of individuals with low isoenzyme activity CYP2C19, who received the 300 mg / 75 mg treatment regimen and was similar to that in the higher intensity groups CYP2C19 - 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) 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 were in a state of reaching equilibrium concentration, showed that in comparison with volunteers with a high isoenzyme activity CYP2C19, volunteers with intermediate isoenzyme activity CYP2C19 Exposure of the active metabolite decreased by 28%, and in volunteers with low isoenzyme activity CYP2C19 - by 72%, while the IAB was reduced with differences in the IAT, which 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 CYP2C19.

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 intensity CYP2C 19-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) when compared with young the volunteers did not receive any differences in the parameters of 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 impaired hepatic function

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, causing the intermediate and low activity of this isoenzyme, is different in 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 atherothrombotic complications:

- in adult patients with myocardial infarction (prescription from several days to 35 days), with ischemic stroke (from 7 days to 6 months old) or

diagnosed by occlusive disease of peripheral arteries;

- in adults with acute coronary syndrome:

· without segment elevation ST (unstable angina or myocardial infarction without a tooth Q), including patients who underwent stenting with percutaneous coronary intervention (in combination with acetylsalicylic acid);

· with segment lift ST (acute myocardial infarction) with drug treatment and the possibility of performing thrombolytic therapy in combination with acetylsalicylic acid.

Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation (atrial fibrillation):

- In adults 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).

Contraindications:

Hyper-raised sensitivity to clopidogrel and / or any of the auxiliary components of the drug; severe hepatic impairment; acute bleeding (eg bleeding from peptic ulcers or intracranial hemorrhage); pregnancy and the period of breastfeeding; children under 18 years of age (efficacy and safety of use not established); lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome.

Carefully:

In patients with moderate hepatic insufficiency, which may predispose to bleeding (clinical experience is limited), with renal failure (clinical experience is limited); in diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal or intraocular) and in patients taking medications that can cause damage to the mucosa gastrointestinal tract (such as acetylsalicylic acid and non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2)); in patients who have an increased risk of bleeding: due to trauma, surgical intervention or other pathological conditions, as well as in patients receiving, receiving therapy with acetylsalicylic acid, heparin, warfarin, inhibitors of glycoprotein Hb/IIIa, NSAIDs, including selective inhibitors of COX-2; in patients with low isoenzyme activity CYP2C19; with a history of allergic and hematologic reactions to other thienopyridine (such as ticlopidine, prasugrel) (risk of cross-allergic and hematological reactions); with recent transient impairment of cerebral circulation or ischemic stroke (with simultaneous use with acetylsalicylic acid); use clopidogrel concomitantly with peroral anticoagulants, selective serotonin reuptake inhibitors (SSRIs), and drugs that are substrates of the isoenzyme CYP2C8 (repaglinide, paclitaxel).

Pregnancy and lactation:

Because clinical data on the use of clopidogrel during pregnancy are not available, the drug Pidogrel is not recommended for use during pregnancy. Studies in animals have not revealed a direct or indirect adverse effect on pregnancy, embryo / fetus development, childbirth or postnatal development.

In animal studies, it has been shown that clopidogrel and / or its metabolites are excreted in breast milk. Therefore, if you need the drug Pidogrel during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Inside, regardless of food intake, once a day.

Adults and elderly patients with normal activity of the isoenzyme SUR2S19.

Myocardial infarction, ischemic stroke or diagnosed occlusive disease of peripheral arteries

The drug Pidogrel is taken in a dose of 75 mg (1 tablet) once a day.

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

Treatment with Pidogrel should be started with a single dose of loading dose (300 mg), 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 a greater risk of bleeding, the recommended dose of acetylsalicylic acid should not exceed 100 mg. The maximum favorable effect is observed by the 3rd month of therapy. The optimal duration of treatment with this indication is not officially defined. The results of clinical studies confirm the advisability of taking clopidogrel up to 12 months after the development of acute coronary syndrome without segment elevation ST.

Acute coronary syndrome with segment elevation ST (acute myocardial infarction) with drug treatment and the possibility of carrying out thrombolytic therapy, in combination with acetylsalicylic acid

The drug Pidogrel should be taken at a dose of 75 mg (1 tablet) once a day, starting with a loading dose, in combination with acetylsalicylic acid in combination or without thrombolytics. For patients older than 75 years, treatment with Pidogrel should be carried out without the use of a loading dose. Combination therapy is started as soon as possible after the onset of symptoms and continues for at least 4 weeks.

The effectiveness of combined therapy with clopidogrel and acetylsalicylic acid lasting more than 4 weeks in such patients has not been studied.

Atrial fibrillation (atrial fibrillation)

The drug Pidogrel is prescribed in a dose of 75 mg once a day. In combination with clopidogrel, you should begin therapy and then continue taking acetylsalicylic acid at a dose of 75-100 mg per day.

Missing the next dose.

If less than 12 hours have elapsed after missing the next dose, you should immediately take the missed dose of Pidogrel and then take the next dose 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 double the dose).

Adults and elderly patients with genetically determined reduced isoenzyme activity CYP2C19

Low isoenzyme activity CYP2C19 is associated with a decrease in the antiplatelet effect of clopidogrel. The use of the drug Pidogrel at higher doses (loading dose of 600 mg, then 150 mg once a day) in patients with low isoenzyme activity CYP2C19 leads to an increase in the antiplatelet effect of clopidogrel (see the section Pharmacokinetics). However, clinical studies on clinical outcomes have not established an optimal dosing regimen for clopidogrel in patients with reduced metabolism due to genetically determined low isoenzyme activity CYP2C19.

Special patient groups

Elderly patients

In elderly volunteers (over 75 years old), when compared with young volunteers, no differences in platelet aggregation and bleeding time were found. Dose adjustments in elderly patients are not required.

Impaired renal function

After repeated use of clopidogrel at a dose of 75 mg per day in patients with severe renal dysfunction (SC 5-15 ml / min), the degree of inhibition of ADP-induced platelet aggregation is lower by 25%, than in healthy volunteers. However, the degree of lengthening of bleeding time was similar to that of healthy volunteers who received clopidogrel in a dose of 75 mg per day. The tolerability of the drug in all patients was good.

Impaired liver function

After using clopidogrel for 10 days in patients with severe impairment of liver function, the degree of inhibition of ADP-induced platelet aggregation and the mean elongation of bleeding time were comparable to healthy volunteers.

Ethnic Features

Prevalence of alleles of isoenzyme genes CYP2C19, associated with intermediate or reduced metabolism, is different in representatives of different racial / ethnic groups (see Pharmacokinetics section). There are only limited literature data that allow one to assess the importance of genotyping of the isoenzyme CYP2C19 on clinical outcomes for patients of the Mongoloid race.

Gender Effects

When comparing the pharmacodynamic properties of clopidogrel in men and women, a less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in lengthening the bleeding time. When comparing clopidogrel with acetylsalicylic acid in patients at 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 obtained in 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, independently from the age, sex and race of patients. The following are the clinically relevant adverse effects observed at 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, and in patients taking ASA, was (2.0% and 2.7%, respectively), including the incidence of gastrointestinal bleeding that required hospitalization was 0.7% and 1.1%, respectively.

The overall frequency of bleeding from another site with clopidogrel in comparison with ASA was higher (7.3% vs. 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, epistaxis. 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 combined therapy with clopidogrel + ASA and placebo + ASA In a clinical study CURE in patients taking clopidogrel + ASA, compared with patients taking placebo + ASA, there was an increase in the incidence of major bleeding (3.7% vs. 2.7%), and minor bleeding (5.1 % against 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 (0.1 % with both types of therapy).

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: 4.0%) .

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 type of fibrinolytic therapy or heparin therapy.

The frequency of fatal bleeding (0.8 % versus 10% 2%) and intracranial hemorrhages (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% vs. 4.3%, respectively). The large bleeding was mainly extracranial in both groups (5.3% vs. 3.5%), mainly from the gastrointestinal tract (3.5 % against 1.8%). In a group clopidogrel + ASA of intracranial hemorrhages was greater in comparison with the placebo + ASK group (1.4% vs. 0.8%, respectively). There were no statistically significant differences between these treatment groups in the frequency of fatal bleeding (1.1% vs. 0.7%) and hemorrhagic stroke (0.8% vs. 0.6 %).

Blood disorders

In Study CAPRIE, severe neutropenia (<0.45 10 ⁹/ 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, 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 (<80-10⁹/ l) was 0.2% in patients taking clopidogrel and 0.1% in patients taking ASA, very rare cases of a decrease in the number of platelets ≤ 30-10⁹/ l.

In studies CURE and CLARITY A comparable number of patients with thrombocytopenia or neutropenia in both treatment groups were observed.

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

The frequency of unwanted reactions,which were observed during the above clinical trials are presented in accordance with the WHO classification: very often ≥ 10%; often ≥ 1% and <10%; infrequently ≥0,1 % and <1%; rarely ≥ 0.01% and <0.1%; very rarely <0.01%; the frequency is unknown - it is not possible to determine the frequency of occurrence of an undesired reaction according to available data.

Disturbances from the nervous system

Infrequently: 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

Infrequently: a rash, itchy skin.

Violations of the blood and lymphatic system

Infrequently: increased bleeding time, a decrease in the number of platelets in the 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 unknown: cases of serious bleeding, mainly subcutaneous, musculoskeletal, ocular hemorrhage (conjunctival, in the tissue and retina of the eye), bleeding and respiratory tract (hemoptysis, pulmonary hemorrhage), nasal bleeding, hematuria and bleeding from postoperative wounds and cases of bleeding with a lethal outcome (especially intracranial hemorrhages, gastrointestinal bleeding and retroperitoneal hemorrhages); agranulocytosis, granulocytopenia, aplastic anemia / pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A.

Immune system disorders

Frequency 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

Frequency unknown: confusion, hallucinations.

Disturbances from the nervous system

Frequency unknown: violation of taste perception.

Vascular disorders

Frequency unknown: vasculitis, lowering blood pressure.

Disturbances from the respiratory system, chest and mediastinal organs

Frequency unknown: bronchospasm, interstitial pneumonia, eosinophilic pneumonia.

Disorders from the gastrointestinal tract

Frequency unknown: colitis (including ulcerative colitis or lymphocytic colitis), pancreatitis, stomatitis.

Disturbances from the liver and bile ducts

Frequency unknown: hepatitis (non-infectious), acute hepatic failure.

Disturbances from the skin and subcutaneous tissues

Frequency unknown: Makulezno-erythematous papular or Exfoliative rash, hives, itchy skin, angioneurotic edema, 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), eczema, flat lichen.

Disturbances from musculoskeletal and connective tissue

Frequency unknown: arthralgia (joint pain), arthritis, myalgia.

Disorders from the nochek and urinary tract

Frequency unknown: glomerulonephritis.

Violations of the genitals and mammary gland

Frequency unknown: gynecomastia.

General disorders and disorders at the site of administration

Frequency unknown: fever.

Laboratory and instrumental data

Frequency unknown: deviation from the norm of laboratory indicators the functional state of the liver, increasing the concentration of creatinine in the blood.

Overdose:

Symptoms: prolonged bleeding time, hemorrhagic complications.

Treatment: when bleeding occurs, a appropriate therapy. If rapid correction of prolonged bleeding time is necessary, transfusion of platelet mass is recommended. There is no specific antidote.

Interaction:

Anticoagulants for oral administration: simultaneous use of clopidogrel and anticoagulants for oral administration may increase the intensity of bleeding, and therefore, the use of this combination is not recommended. Taking clopidogrel 75 mg / day does not affect the pharmacokinetics of warfarin (substrate isoenzyme CYP2C9) or international normalized ratio (INR) in patients who have been taking long-term warfarin. The simultaneous administration of warfarin with clopidogrel may increase the development of bleeding due to its independent additional effect on blood coagulability.Therefore, care should be taken when using warfarin and clopidogrel simultaneously.

Inhibitors of glycoprotein IIb/IIIa: simultaneous use of inhibitors of glycoprotein Hb / Sha requires caution in patients with an increased risk of bleeding (with trauma, surgery or other pathological conditions) (see section "Special instructions").

Acetylsalicylic acid (ASA): does not affect clopidogrel-induced platelet aggregation-induced platelet-induced inhibition of ADP, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. Nevertheless, the simultaneous administration of 500 mg ASA 2 times a day for one day does not substantially prolong the bleeding time caused by the use of clopidogrel. The pharmacodynamic interaction between clopidogrel and ASA probably leads to an increased risk of bleeding. Given this, caution should be exercised while using these drugs simultaneously, although in clinical trials patients took combination therapy with clopidogrel and ASA for one year.

Heparin: according to a clinical study conducted on healthy volunteers with the use of clopidogrel did not require a change in the dose of heparin, and also did not change the anticoagulant effect of heparin. The simultaneous use of heparin did not affect the suppression of platelet aggregation with clopidogrel. Possible pharmacodynamic interaction between clopidogrel and heparin, leading to an increased risk of bleeding. The simultaneous use of these drugs requires caution.

Thrombolytics: security fibrin-specific or joint use of clopidogrel, fibrinesispecific thrombolytic drugs and heparin was investigated in patients with acute myocardial infarction myocardium. The frequency of clinically significant bleeding was similar to that of which was observed in the case of joint use of thrombolytic means and heparin with ASA.

Non-steroidal anti-inflammatory drugs (NSAIDs): according to a clinical study involving healthy volunteers, the simultaneous use of clopidogrel and naproxen increased latent gastrointestinal bleeding.However, due to the lack of studies on interactions with other NSAIDs at present, it is not known whether the risk of developing gastrointestinal bleeding increases when used concomitantly with other NSAIDs. Therefore, concomitant therapy with NSAIDs, including cyclooxygenase-2 (COX-2) inhibitors and clopidogrel should be used with caution (see section "Special instructions").

Inhibitor inhibitors CYP2C19: metabolism of clopidogrel with the formation of an active metabolite is partially accomplished by means of an isoenzyme CYP2C19. The use of isozyme inhibitory drugs CYP2C19, can lead to a decrease in the concentration of the active metabolite clopidogrel. The clinical significance of this interaction is unknown. Simultaneous application with potent or moderate isoenzyme inhibitors should be avoided CYP2C19. To inhibitors of isoenzyme CYP2C19 relate: omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.

Proton Pump Inhibitors: the use of omeprazole at a dose of 80 mg once a day concomitantly with clopidogrel or with a 12-hour break between taking two drugs, reduced the value of systemic exposure (AUC) of the active metabolite of clopidogrel by 45% (after taking a loading dose of clopidogrel) and 40% (after taking a maintenance dose of clopidogrel). Decrease AUC of the active metabolite of clopidogrel is associated with a decrease in the degree of platelet inhibition (39% after taking a loading dose Clopidogrel and 21% - after taking a maintenance dose of clopidogrel).

An analogous interaction of clopidogrel with esomeprazole is suggested.

In observational and clinical studies, conflicting data on the clinical manifestations of the cardiovascular system with respect to this pharmacokinetic / pharmacodynamic interaction were recorded. You should avoid simultaneous use with omeprazole or esomeprazole. To inhibitors of the proton pump with minimal inhibiting effect on the isoenzyme CYP2C19 relate: pantoprazole and lansoprazole. At simultaneous The use of pantoprazole at a dose of 80 mg per day showed a decrease in the concentration of the active metabolite of clopidogrel in the blood plasma by 20% (after taking a loading dose of clopidogrel) and by 14% (after taking a maintenance dose of clopidogrel).Ego was accompanied by a decrease in the degree of inhibition of platelet aggregation, on average, by 15% and 11%, respectively. Therefore, the simultaneous use of clopidogrel with pantoprazole is possible.

Selective serotonin reuptake inhibitors (SSRIs): since SSRIs disrupt the activation of platelets and increase the risk of bleeding, simultaneous use of SSRI with clopidogrel should be conducted with caution.

FROM medicines that are substrates of isoenzyme CYP2C8: it was shown that clopidogrel increased the systemic exposure of repaglinide in healthy volunteers. Research in vitro showed that an increase in the systemic exposure of repaglinide is a consequence of inhibition of the isoenzyme CYP2C8 glucuronide metabolite of clopidogrel. Caution should be exercised with the simultaneous use of clopidogrel and drugs, mainly excreted from the body by metabolism with the help of isoenzyme CYP2C8 (eg, repaglinide, paclitaxel) due to the risk of increasing their plasma concentrations.

Other medicines: when studying the pharmacodynamic and pharmacokinetic interaction of clopidogrel and other drugs the following is revealed:

· with simultaneous use of clopidogrel with atenolol and / or nifedipine, there is no clinically significant interaction;

· the pharmacodynamic activity of clopidogrel did not change significantly with simultaneous use with phenobarbital, cimetidine or estrogens;

· the pharmacokinetics of digoxin or theophylline did not change;

· antacids do not affect the degree of absorption of clopidogrel;

· phenytoin and tolbutamide can safely be used concomitantly with clopidogrel. It is unlikely that clopidogrel can influence the metabolism of other medicines, such as phenytoin and tolbutamide, as well as NSAIDs, which are metabolized by isoenzyme CYP2C9;

· diuretics, beta-blockers, angiotensin-converting inhibitors enzyme (ACE), blockers of "slow" calcium channels, lipid-lowering drugs, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, hormone replacement therapy: in clinical studies it was not clinically detectedsignificant undesirable interactions.

The active metabolite of clopidogrel inhibits isoenzyme activity CYP2C9, as a result of which concentrations of phenytoin, tolbutamide and NSAIDs metabolized by the isoenzyme may increase CYP2C9, in the blood plasma.

Special instructions:

In the treatment of clopidogrel, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgical intervention, it is necessary to carefully monitor patients for the exclusion of signs of bleeding, including concealed ones.

Due to the risk of bleeding and undesirable effects from the blood (see section "Side effect") in case of appearance during treatment clinical symptoms, suspicious for bleeding, it is urgent to make a general clinical analysis of blood, determine APTT, the number of platelets, the indicators of the functional activity of platelets and conduct other necessary studies.

Clopidogrel, as well as other antiplatelet agents, should use with caution in patients with an increased risk of bleeding associated with trauma, surgical interventions or other pathological conditions, as well as in patients taking ASA, NSAIDs, including COX-2 inhibitors, heparin or glycoprotein inhibitors IIb/IIIa.

Joint use of clopidogrel with warfarin may increase the risk of bleeding (see section "Interaction with other drugs"), so caution should be exercised when using clopidogrel and warfarin together.

If the patient is scheduled surgery, and there is no need for an antiplatelet effect, then for 5-7 days before the operation, the use of clopidogrel should be discontinued.

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 gastrointestinal mucosa (such as ASA, NSAIDs) in patients taking clopidogrel, should be used with caution.

Patients should be cautioned that when taking Clopidogrel (alone or in combination with ASA) to stop bleeding may take longer,and also that, in case of occurrence at them unusual (on localization or duration) bleedings, they should inform on it to the attending physician. Before any future operation and before starting any new drug, patients should inform the doctor (including the dentist) about taking clopidogrel.

Very rarely, after the use of clopidogrel (sometimes even a short one), 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 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 the case of proven clinical benefit from itapplication.

The cases of development of acquired hemophilia with the use of clopidogrel were reported. With confirmed isolated increase in activated partial thromboplastin time (aCTT), accompanied or not accompanied by the development of 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 and stop taking clopidogrel.

In patients with low isoenzyme activity CYP2C19 when clopidogrel is used in recommended doses, less active clopidogrel metabolite is formed and its antiplatelet effect is less pronounced, and therefore a higher incidence of cardiovascular complications is possible when taking the usually recommended doses of clopidogrel in acute coronary syndrome or percutaneous coronary intervention than in patients with clopidogrel normal activity of isoenzyme CYP2C19. There are tests to determine the genotype CYP2C19, these tests can be used to help choose a therapeutic strategy.

The question of the use of higher doses of clopidogrel in patients with low activity CYP2C19 (see section D "Pharmacokinetics" subsection "Pharmacogenetics", sections "With caution", "Method of administration and dose").

Patients should collect anamnesis for any previously allergic and / or hematologic reactions to other thienopyridine (such as ticlopidine, prasugrel), since there was reported the presence of cross-allergic and / or hematological reactions between thienopyridines (see section "Side effect").

Tienopyridines can cause mild to severe allergic reactions (such as rash, angioedema) or hematologic reactions (such as thrombocytopenia and neutropenia).

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.

It is recommended to monitor cross-allergic and / or hematological reactions.

During the treatment it is necessary to monitor the functional state 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).

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

The drug Pidogrel does not significantly affect the ability to drive vehicles and work with technical devices that require an increased concentration of attention and speed of psychomotor reactions.

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

Packaging:For 10 tablets in aluminum (aluminum / aluminum) blister; 3 blisters per pack of cardboard along with instructions for use.

Storage conditions:At a temperature of no higher than 30 ° 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:LP-004125

Date of registration:08.02.2017

Expiration Date:08.02.2022

The owner of the registration certificate:Laboratories Medis, TunisiaLaboratories Medis, Tunisia Tunisia

Manufacturer: & nbsp

Les Laboratoires MediS, S.A. Tunisia

Representation: & nbspLaboratories MedisLaboratories MedisTunisia

Information update date: & nbsp09.03.2017

Illustrated instructions

Instructions

Pidogrel (Pidogrel)