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

excipients: tablet core: mannitol 275.7 mg, Macrogol-6000 136.0 mg, cellulose microcrystalline (low water content, 90 μm) 124.0 mg, low-substituted giprolose 51.6 mg castor oil hydrogenated 13.2 mg;

film sheath: opedra® pink * 30.0 mg, carnauba wax-traces.

* Opadrai® pink contains lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, iron oxide, red oxide (E 172).

Description:

Oblong tablets covered with a pink film shell, engraved with 300 on one side and number 1332 on the other side.

Pharmacotherapeutic group:antiplatelet agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

Pharmacodynamics:

Clopidogrel is a prodrug, one of its metabolites is active and inhibits the aggregation of platelets. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to P2Y₁₂ a platelet receptor and subsequent ADP-mediated activation of a glycoprotein complex II/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 P450 system, some of which may differ in polymorphism or may be inhibited by other drugs, not all patients may adequately inhibit platelet aggregation (see "Pharmacokinetics, Pharmacogenetics").

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.

When comparing pharmacodynamic properties of clopidogrel in men and women, a smaller inhibition of ADP-induced platelet aggregation is observed in women, but no sex differences in lengthening of bleeding time are revealed.

In patients with recent myocardial infarction, stroke and diagnosed peripheral artery occlusive disease, taking Plavicc® 75 mg / day significantly reduces the risk of developing ischemic complications (combined myocardial infarction, stroke and cardiovascular death), and it has the greatest efficacy in patients with peripheral arterial occlusive disease, especially in combination with a history of myocardial infarction, and is also more effective in patients younger than 75 years;

In patients with acute coronary syndrome without segment elevation ST (unstable angina, myocardial infarction), taking Plavix® (loading dose 300 mg, then 75 mg / day) in combination with acetylsalicylic acid (ASA) (75-325 mg once a day) and other standard therapies, regardless of simultaneously conducted types of treatment (heparin therapy, glycoprotein blockers IIb/IIIa, lipid-lowering drugs, beta-adrenoblockers, angiotensin converting enzyme (ACE) inhibitors and dose of ASA, significantly reduces the overall risk of developing ischemic complications: acute myocardial infarction,stroke and cardiovascular death with a relative risk reduction in conservative treatment by 17%; after percutaneous transluminal coronary angioplasty (PTCA) with stenting or without stenting by 29% and after aortocoronary shunting by 10%.

In patients with acute myocardial infarction (MI) with segment elevation ST admission preparation of Plavikc® (during the first 12 hours, the IM loading dose is 300 mg, then 75 mg / day) in combination with ASA (loading dose of 150-325 mg, then by 75-162 mg once a day) and fibrinolytic and, according to indications, with heparin reduces the combined rate of angiography the moment of discharge from the hospital of occlusion of the coronary artery related to the zone heart attack, or fatalities, or the development of recurrent myocardial infarction; but for patients, who did not undergo angiography at discharge - the frequency of death or recurrence IM up to 8 days of MI or until discharge from the hospital, mainly due to decrease in the frequency of coronary artery occlusion related to the infarction zone.

In patients with acute myocardial infarction with segment elevation ST, a decrease in the segment ST or blockade of the left leg of the bundle.c® at 75 mg / day in combination with ASC at 162 mg once a day leads to a reduction in the incidence of fatalities for any of the causes and the total frequency of the first repeated myocardial infarction, stroke and death.

Pharmacokinetics:

Suction

Suction data were obtained with ingestion of 75 mg clopidogrel.

After a single dose and with oral administration at a dose of 75 mg per day clopidogrel quickly absorbed.

The mean maximum concentration of unchanged clopidogrel in the blood plasma (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 data on excretion of metabolites of clopidogrel through the kidneys, 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 / l.

Metabolism

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo Clopidogrel is metabolized in two ways: the first - through esterases and subsequent hydrolysis with the formation of an inactive derivative of carboxylic acid (85% of the circulating metabolites in the systemic bloodstream), and the second pathway through the cytochrome P450 system. Originally clopidogrel is metabolized to 2-oxoklopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxoclopidogrel leads to the formation of an active metabolite of clopidogrel-thiol clopidogrel derivative. In vitro this pathway of metabolism occurs by means of isoenzymes CYP2C19, CYP1A2 and CYP2B6. Active thiol metabolite of clopidogrel, which was isolated in studies in vitro, quickly and irreversibly binds to platelet receptors, thus inhibiting their aggregation.

The maximum concentration of the active metabolite with a single dose of Plavicc® (300 mg) is twice that of Plavix® (75 mg) maintenance dose for 4 days. The maximum concentration of the active metabolite (C_max) is reached after 30-60 minutes after taking Plavic®.

Excretion

Within 120 hours after ingestion by a human ¹⁴C-labeled clopidogrel about 50% of radioactivity is released through the kidneys and approximately 46% of the radioactivity - through the intestine. After a single oral dose of 75 mg, the half-life of clopidogrel is approximately 6 hours.After a single reception and taking repeated doses, the half-life of the inactive metabolite circulating in the blood is 8 hours.

Pharmacogenetics

Using isoenzyme CYP2C19 are formed as an active metabolite, and an intermediate metabolite - 2-oxoklopidogrel. 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 races (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, which are weak metabolizers, should have the two alleles of the gene with loss of function indicated above. Published frequency of occurrence of phenotypes of weak metabolizers CYP2C19 are 2% in Caucasians, 4% in Negroid people and 14% in Chinese.

In a cross-sectional study of 40 volunteers, 10 patients in each group (ultrafast metabolizers, intensive metabolizers, intermediate metabolizers, weak metabolizers) evaluated the pharmacokinetics and antiplatelet effect when taking 300 mg of clopidogrel followed by 75 mg / day and with admission 600 mg of clopidogrel followed by 150 mg / day for 5 days (reaching the equilibrium state). There were no significant differences in the exposure of the active metabolite and the average inhibition of aggregation of tromocytes (IAT) (induced by ADP) in ultrafast, intensive and intermediate metabolizers. In weak metabolizers, the exposure of the active metabolite was reduced by 63-71% compared to intensive metabolizers. When the 300 mg / 75 mg treatment regimen was used in weak metabolizers, the antiplatelet effect was reduced with an average of 24% (24 hours) and 37% (5 days of treatment) as compared with the IB of 39% (24 hours) and 58% (on the 5th day of treatment) in intensive metabolizers and 37% (after 24 hours) and 60% (on the 5th day of treatment) in intermediate metabolizers.If the weak metabolizers received the 600 mg / 150 mg treatment regimen, the exposure of the active metabolite was higher than with the 300 mg / 75 mg treatment regimen. In addition, the IAT was 32% (24 hours) and 61% (at day 5 of treatment), which was greater than that of the weak metabolizers receiving the 300 mg / 75 mg treatment regimen and was similar to that in the higher-intensity CYP2C 19-metabolism, receiving a treatment regimen of 300 mg / 75 mg. However, in studies with clinical outcomes, the dosage regimen of clopidogrel for patients in this group has not yet been established.

According to the results of this study, a meta-analysis of six studies, which included data from 335 volunteers who received clopidogrel and were in the state of reaching the equilibrium concentration, showed that in the case of intermediate metabolizers, the exposure of the active metabolite decreased by 28% and in weak metabolizers by 72%, although the IAB was reduced in comparison with the intensive metabolizers with differences in the IB of 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-А, as well as in several published cohorts Isfromiceations.

In the study TRITON-TIMI 38 and 3 cohort studies (Collet, Sibbing, Giusti), the patients of the combined group with intermediate or weak metabolism had a higher incidence of cardiovascular complications (death, myocardial infarction and stroke) or stent thrombosis compared to those of intensive metabolizers.

In the study CHARISMA and one cohort study (Simon), an increase in the frequency of cardiovascular complications was observed only in weak metabolizers (when compared with intensive metabolizers).

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

Children of the age

No data available.

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), the inhibition of ADP-induced platelet aggregation was lower (25%) than in healthy volunteers, but the lengthening of time bleeding was similar to that of healthy volunteers who received clopidogrel in a dose of 75 mg per day.

Impaired liver function

After daily for 10 days of taking clopidogrel at a daily dose of 75 mg in patients with severe liver damage, 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, responsible for the intermediate and reduced metabolism, is different in representatives of different racial groups.There are very small literature data on their prevalence in the representatives of the Mongoloid race, which does not allow us to estimate the values of genotyping of the isoenzyme CYP2C19 for the development of ischemic complications.

Indications:

Prevention of atherothrombotic complications (in combination with acetylsalicylic acid) in patients with acute coronary syndrome:

- without segment elevation ST (unstable angina or myocardial infarction without a tooth Q), including patients who underwent stenting for percutaneous coronary intervention;

- with segment lift ST (acute myocardial infarction).

Contraindications:

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

severe hepatic impairment;

- Acute bleeding, for example, bleeding from a peptic ulcer or intracranial hemorrhage;

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

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

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

Carefully:

- With moderate hepatic insufficiency, which may predispose to bleeding (limited clinical experience of use);

- with renal failure (limited clinical experience of use);

- 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 mucous membrane of the gastrointestinal tract (such as acetylsalicylic acid [ASA] 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 ASA treatment, heparin, warfarin inhibitors of glycoprotein IIb / IIIa, NSAIDs, including selective inhibitors of COX-2, or selective serotonin reuptake inhibitors (SSRIs) (see section "Special instructions");

- in patients with low activity of the isoenzyme CYP2C19 (see Fig.section "Pharmacokinetics" subsection "Pharmacogenetics", sections "Method of administration and dose", "Special instructions");

- with history of allergic and hematologic reactions to other thienopyridine (such as ticlopidine, prasugrel) (possibility of cross allergic and hematological reactions, see section "Special instructions");

- with recent transient impairment of cerebral circulation or ischemic stroke (when combined with ASA, see section "Special instructions").

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 as a result of the absence of data from controlled clinical trials on the use of clopidogrel by pregnant women, clopidogrel is not recommended during pregnancy unless precautions are taken , its application 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 milk is unknown. Since many drugs can be excreted into breast milk and have an adverse effect on an infant, the attending physician, based on the importance of taking the drug Plavikc® for the mother, should recommend her or stop taking the drug, or take the drug, but give up breastfeeding.

Dosing and Administration:

Adults and Seniors

Plavikc® should be taken orally, regardless of food intake.

This tablet, containing 300 mg of clopidogrel, is intended for use as a loading dose for patients with acute coronary syndrome (see "Indications for Use").

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.

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 an initial single dose 300 mg loading dose in combination with acetylsalicylic acid and thrombolytic agents (or without thrombolytics). Combination therapy is started as soon as possible after the onset of symptoms and continues for at least four weeks. In patients older than 75 years, treatment with clopidogrel should begin without taking its loading dose.

As for the maintenance dose of clopidogrel, 75 mg, then Plavic® 75 mg is given for its administration.

Patients with a genetically determined decrease in the isoenzyme function CYP2C19

The weak CYP2C19 metabolizer is associated with a decrease in the antiplatelet effect of clopidogrel.The regime of high doses (600 mg - loading dose, then 150 mg once a day daily) in weak metabolizers increases the antiaggregant effect of clopidogrel (see "Pharmacokinetics", "Pharmacogenetics"). However, the optimal dosing regimen for patients with reduced metabolism by isoenzyme CYP2C19 in clinical studies on clinical outcomes has not yet been established (see "Pharmacokinetics", "Pharmacogenetics").

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 CAPRIE trial corresponded to the tolerability of acetylsalicylic acid 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 the CAPRIE clinical trial, the overall incidence of all bleeding in patients taking clopidogrel, and in patients taking clopidogrel, and in patients taking ASA, was 9.3%. The incidence of severe bleeding with clopidogrel and acetylsalicylic acid was comparable: 1.4% and 1.6%, respectively.

In general, the incidence of gastrointestinal bleeding in patients taking clopidogrel, and in patients taking ASA, were 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 combination therapy clopidogrel+ ASA and placebo + ASA

In a clinical study of 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 small 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 (0.1% 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 +acetylsalicylic acid (<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% (clopidogrel + ASA) and 6.3% (placebo + ASA).

In the CLARITY clinical trial, the frequency of major bleeding (defined as intracranial hemorrhage or hemorrhage bleeding with> 5 g / dL) in both groups (clopidogrel + ASA and placebo + ASA) was comparable in both treatment groups (1.3% vs. 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 the COMMIT clinical trial, the overall incidence of non-cerebral large bleeding or cerebral bleeding was low and the same in both treatment groups (0.6% in the group clopidogrel+ ASA and 0.5% in the placebo + ASA group).

In the clinical study ACTIVE-A, the incidence of major bleeding in the group clopidogrel+ ASA was higher than in the placebo + ASA group (6.7% vs. 4.3%, respectively). Large bleeding was mainly extracranial in both groups (5.3% vs. 3.5%), mainly gastrointestinal bleeding (3.5% vs. 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 the CAPRIE study, severe neutropenia (<0.45x10⁹/ 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 (<80x10⁹/ 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 ≤ 30x10⁹/ l.

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

Other clinically relevant adverse reactions observed with clinical trials of CAPRIE, CURE, CLARITY COMMIT, and ACTIVE-A

The incidence of adverse reactions that were observed during the above clinical trials is 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%; unknown frequency - it is not possible to determine the incidence of side effects from available data.

Disturbances from the nervous system

Infrequently: headache, dizziness, paresthesia.

Rarely: vertigo.

Disorders from the gastrointestinal tract

Often: dyspepsia, abdominal pain, diarrhea.

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

Disturbances from the skin and subcutaneous tissue

Infrequent: rash, itching.

Violations of the blood and lymphatic system

Infrequently: increase time bleeding, decline number of platelets in peripheral blood; leukopenia, decrease number of neutrophils in peripheral blood, eosinophilia.

Postmarketing experience with the drug

Violations of the blood and lymphatic system

Frequency unknown: cases serious bleeding, mainly subcutaneous, musculoskeletal, ocular hemorrhages (conjunctival, in fabric and retina of the eye), bleeding from respiratory ways (hemoptysis, pulmonary bleeding), nasal bleeding, hematuria and bleeding of postoperative wounds; cases of bleeding with a lethal outcome (in particular intracranial hemorrhages, gastrointestinal bleeding and retroperitoneal hemorrhage), agranulocytosis, granulocytopenia, aplastic anemia / pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A.

Immune system disorders

Frequency unknown: anaphylactoid reactions, serum sickness; cross-allergy with other thienopyridines (such as ticlopidine, prasugrel) (see section "Special instructions").

Disorders of the psyche

Frequency 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, chest and mediastinal organs

Frequency 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

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

Disturbances from the skin and subcutaneous tissues

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

Disturbances from musculoskeletal and connective tissue

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

Disorders from the kidneys and urinary tract

Frequency unknown: glomerulopathy (including glomerulonephritis).

General disorders and disorders at the site of administration

Frequency unknown: fever.

Laboratory and instrumental data

The frequency is unknown: a deviation from the norm of laboratory indicators of the functional state of the liver, an increase in the concentration of creatinine in the blood.

Overdose:

Symptoms

An overdose of clopidogrel may lead to an increase in bleeding time with subsequent complications in the form of bleeding.

Treatment

When bleeding occurs, appropriate treatment is required. The antidote of clopidogrel is not established. If a rapid recovery of prolonged bleeding time is required, then platelet transfusion is recommended.

Interaction:

Warfarin: although administration of clopidogrel 75 mg / day did not alter the pharmacokinetics of warfarin (substrate of the isoenzyme CYP2C9) or INR (international normalized ratio) in patients receiving long-term treatment with warfarin, concurrent administration of clopidogrel increases the risk of bleeding due to its independent additional effect on blood clotting. Therefore, care should be taken while taking warfarin and clopidogrel.

Blockers IIb / IIIa receptors: use of blockers IIb / IIIa receptors in conjunction with clopidogrel requires caution in patients who have an increased risk of bleeding (with trauma and surgical interventions or other pathological conditions).section "Special instructions").

ASA: ASA does not alter the effect of clopidogrel, an inhibitor of ADP-induced platelet aggregation, but clopidogrel potentiates the effect of ASA on collagen-induced aggregation of platelets. Nevertheless, simultaneous with clopidogrel administration of ASA 500 mg twice a day for 1 day did not cause a significant increase in bleeding time caused by the use of clopidogrel. Between clopidogrel and ASA, 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 ASA for up to one 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 the preparation of Plavikc® and heparin, pharmacodynamic interaction is possible, which may increase the risk of bleeding, therefore simultaneous use of clopidogrel and heparin requires caution.

Thrombolytics: the safety of the combined use of clopidogrel, fibrin-specific or fibrin-specific 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 not currently known 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 (see section "Special instructions").

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 the CYP2C9 isoenzyme

As clopidogrel metabolized to the formation of its active metabolite partly by means of the CYP2C19 isoenzyme, 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 inhibitors of the CYP2C9 isoenzyme should be avoided. Strong and moderate inhibitors of the isoenzyme CYP2C9 are omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol

The simultaneous use of proton pump inhibitors with potent or moderate inhibitors of the CYP2C19 isoenzyme (eg, omeprazole, esomeprazole) should be avoided with clopidogrel (see "Pharmacokinetics, subsection, Pharmacogenetics", section "Specific guidance"). If proton pump inhibitors are to be taken concomitantly with clopidogrel,Use a proton pump inhibitor with the least inhibition of the CYP2C19 isoenzyme, such as pantoprazole or lansoprazole.

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 is used in conjunction with atenolol, nifedipine, or both of these drugs taken concomitantly, clinically significant no pharmacodynamic interaction was observed;

- simultaneous use of phenobarbital, cimetidine and estrogens did not significantly affect the pharmacodynamics of clopidogrel;

- pharmacokinetic indices of digoxin and theophylline did not change when they were used together with clopidogrel;

- antacids did not reduce the absorption of clopidogrel;

- phenytoin and tolbutamide, as well as NSAIDs that are metabolized by the CYP2C9 isoenzyme of the cytochrome P450 family;

- ACE inhibitors, diuretics, beta-adrenoblockers, "slow" calcium channel blockers, lipid-lowering agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, hormone replacement therapy and blockers of GPIIb / IIIa receptors: clinical studies have not revealed clinically significant adverse interactions.

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.

In connection with the risk of bleeding and undesirable effects from the blood (see the section "Side effect"), if clinical symptoms appearing during treatment, suspicious for bleeding, it is urgent to make a general clinical blood test, determine APTT, the number of platelets, indicators functional activity of thrombocytes and conduct other necessary studies.

Clopidogrel, as well as other antiplatelet agents, should be used with caution in patients who have an increased risk of bleeding associated with trauma,surgical interventions or other pathological conditions, as well as in patients taking acetylsalicylic acid, non-steroidal anti-inflammatory drugs, including inhibitors of COX-2, heparin or inhibitors of glycoprotein 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 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 warned,that when taking clopidogrel (alone or in combination with acetylsalicylic acid) it may take more time to stop bleeding, and that if they have an unusual (for localization or duration) bleeding, they should inform their own doctor . 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 cerebral infringement or stroke having a high risk of developing recurrent ischemic complications, the combination of ASA and clopidogrel increases the risk of developing large bleeding.Therefore, such combination therapy should be conducted with caution and only in the case of clinical evidence of the benefits of its use.

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 a low activity of the isoenzyme CYP2C19, when clopidogrel is used, at recommended doses, less active clopidogrel metabolite 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, vascular complications than in patients with normal activity of the isoenzyme CYP2C19. There are tests to determine the genotype of CYP2C19.These tests can be used to help in choosing a therapeutic strategy. The question of the use of higher doses of clopidogrel in patients with low activity of CYP2C19 is considered (see the section "Pharmacokinetics" in the 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 Plavikc® does not significantly affect the abilities necessary to drive a car or to engage in other potentially hazardous activities.

Form release / dosage:

Film-coated tablets, 300 mg.

Packaging:

10 tablets in a blister of aluminum foil / aluminum foil.

For 1 or 3 blisters together with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-009024/10

Date of registration:31.08.2010

The owner of the registration certificate:Sanofi Pharma Bristol-Myers Squibb EsenSiSanofi Pharma Bristol-Myers Squibb EsenSi France

Manufacturer: & nbsp

SANOFI WINTHROP INDUSTRIE France

Representation: & nbspSanofi Aventis GroupSanofi Aventis Group

Information update date: & nbsp07.08.2015

Illustrated instructions

Instructions

Plavix® (Plavix®)