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

Excipients: mannitol 68,925 mg, macrogol-6000 34 mg, microcrystalline cellulose (low water content, 90 μm) 31.0 mg, low-substituted giprolose 12.9 mg, hydrogenated hydrogenated castor oil 3.3 mg;

film sheath: opadrai pink * 7.5 mg, carnauba wax - traces.

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

Description:

Round, slightly biconvex tablets, film-coated pink color, engraved "75" on one side and "1171" on the other side.

Pharmacotherapeutic group:antiplatelet agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

Pharmacodynamics:

Clopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of ADP to P2Yi₂ platelet receptor and subsequent ADP-mediated activation of the complex GPIIb/IIIa, leading to suppression of platelet aggregation. Due to irreversible binding, platelets remain immune to stimulation of ADP for the rest of their life (about 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal.

Aggregation of platelets caused by agonists other than ADP is also inhibited by blockade of enhanced platelet activation by the released ADP.

Since the formation of an active metabolite occurs by using enzymes from the P450 system, some of which may be polymorphic or may be inhibited by other drugs, not all patients can adequately inhibit platelet aggregation.

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, on average, for 5 days.

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

Clinical study ACTIVE-A, showed that patients with atrial fibrillation who had at least one risk factor for vascular complications but were unable to take indirect anticoagulants, clopidogrel in combination with acetylsalicylic acid (but compared with the use of only one acetylsalicylic acid) reduced the frequency of combined stroke, myocardial infarction, systemic thromboembolism outside the central nervous system (CNS), or vascular death, largely by reducing the risk of stroke. The efficacy of taking clopidogrel in combination with acetylsalicylic acid was detected early and persisted to 5 years. The decrease in the risk of major vascular complications in the group of patients taking clopidogrel in combination with acetylsalicylic acid, was mainly due to a greater reduction in the frequency of strokes. The risk of stroke of any severity with the use of clopidogrel in combination with acetylsalicylic acid was reduced, and there was a tendency to decrease the incidence of myocardial infarction in the group treated with clopidogrel in combination with acetylsalicylic acid, but there was no difference in the frequency of thromboembolism outside the CNS or vascular death. In addition, the use of clopidogrel in combination with acetylsalicylic acid reduced the total number of days of hospitalization for cardiovascular reasons.

Pharmacokinetics:

Suction

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 taking the drug. 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 (by 98% and 94%, respectively) and this bond is unsaturated in a wide range of concentrations.

Metabolism

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo Clopidogrel is metabolized in two ways: the first - through esterases and subsequent hydrolysis with the formation of an inactive derivative of carboxylic acid (85% of the circulating metabolites), and the second pathway through the cytochrome P450 system. at first clopidogrel is metabolized to 2-oxo-clonidogrel, 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 pathway of metabolism occurs by means of isoenzymes CYP3A4, CYP2C19, CYP1A2 and CYP2B6. Active thiol metabolite of clopidogrel, which was isolated in studies in vitro, quickly and irreversibly binds to platelet receptors, blocking the aggregation of platelets.

FROM_mOh active metabolite of clopidogrel after receiving its loading dose of 300 mg is 2 times higher than C_mOh after 4 days of taking a maintenance dose of clopidogrel 75 mg. In this case, when taking 300 mg clopidogrel C_max is achieved within approximately 30 to 60 minutes.

Excretion

Within 120 hours after ingestion by a human ¹⁴C-labeled clopidogrel about 50% of the radioactivity is released through the kidneys (into the urine) and approximately 46% of the radioactivity is excreted through the intestine with a fecal mass. After a single oral dose of 75 mg, the half-life period (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 inactive metabolite circulating in the blood is 8 hours.

Pharmacogenetics

Using isoenzyme CYP2C19 are formed as an active metabolite, as well as 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 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 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% in Caucasians, 4% in Negroid people and 14% in Chinese. To determine the patient's isoenzyme genotype CYP2C19 there are corresponding tests.

According to a cross-sectional study (40 volunteers) and according to a meta-analysis of six studies (335 volunteers), which included individuals with very high, high, intermediate and low isoenzyme activity CYP2C19, there were no significant differences in the exposure of the active metabolite and in the mean platelet aggregation inhibition (IAT) (induced by ADP) in volunteers with very high, high and intermediate isoenzyme activity CYP2C19 was not identified. In volunteers with low isoenzyme activity CYP2C19c Exposure of the active metabolite decreased in comparison with volunteers with high 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 similar to that in groups of patients with a higher metabolic rate by isoenzyme CYP2C19, who received 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.

Clinical studies conducted to date have not had a sufficient sample size to detect differences in clinical outcome in patients with low isoenzyme activity CYP2C19.

Individual patient groups

The pharmacokinetics of the active metabolite of clopidogrel in elderly patients, children, patients with kidney and liver diseases have not been studied.

Indications:

Prevention of atherothrombotic complications:

- the adult patients with myocardial infarction (with a duration of several days to 35 days), ischemic stroke (with a duration of 7 days to 6 months) or with diagnosed occlusive disease of peripheral arteries;

- the adult patients with acute coronary syndrome: no ST segment elevation (unstable angina or Q-free myocardial infarction), including patients who underwent stenting with percutaneous coronary intervention (in combination with acetylsalicylic acid); with the rise of the ST segment (acute myocardial infarction) with drug treatment and the possibility of carrying out thrombolysis (in combination with acetylsalicylic acid).

Prevention of atherothrombotic and thromboembolic complications, including stroke, with atrial fibrillation (atrial fibrillation).

In patients with atrial fibrillation (atrial fibrillation), which have at least one risk factor for vascular complications,can not take indirect anticoagulants and have a low risk of bleeding (in combination with acetylsalicylic acid).

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, surgery or other pathological conditions, as well as in patients receiving ASA treatment, heparin, warfarin inhibitors of glycoprotein IIb / IIIa, NSAIDs, including selective inhibitors COX-2, or selective serotonin reuptake inhibitors (SSRIs) (see section "Specific guidance");

- in patients with low activity of the isoenzyme CYP2C19 (see the section "Pharmacokinetics" subsection "Pharmacogenetics", sections "Dosing and Administration", "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 the infant, the treating doctor, based on the importance of taking Plavicc® for the mother, should recommend that she stop taking the drug, or take the drug, but stop 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 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 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 taken at the usual time in the following doses;

- if more than 12 hours pass after missed 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 moment 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 a 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,the prolongation of 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, responsible for the intermediate and decreased metabolism of clopidogrel to its active metabolite, is different in representatives of different ethnic groups (see section "Pharmacogenetics"). There are only limited data for representatives of the Mongoloid race on the impact of the genotype of the isoenzyme CYP2C19 on clinical outcome events.

Female and male patients

In a small study comparing the pharmacodynamic properties of clopidogrel in men and women,in women, there was less inhibition of ADP-induced platelet aggregation, but there was no difference in bleeding time elongation. In a large controlled study CAPRIE (clopidogrel in comparison with acetylsalicylic acid in patients with the 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 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 as compared with patients treated with placebo + ASA (1.6% and 1%, respectively), but the incidence of intracranial hemorrhage was similar (0.1% for 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 the incidence of major bleeding in the placebo group +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 receiving 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 inperipheral 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-inducedhypersensitivity, 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:

Overdose Symptoms

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

Measures to help with overdose

When bleeding occurs, appropriate treatment is required. The antidote of clopidogrel is not established. If rapid correction of prolonged time of bleeding is necessary, then transfusion of platelet mass 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: the use of IIb / IIIa receptor blockers in conjunction with clopidogrel requires caution in patients who have an increased risk of bleeding (with trauma and surgical interventions or other pathological conditions) (see 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 Plavic® and heparin, pharmacodynamic interaction is possible, which may 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-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 is metabolized to the formation of its active metabolite in part by means of the CYP2C19 isoenzyme, the use of drugs inhibiting 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:

- the application of clopidogrel together with atenolol, nifedipine or both of these drugs taken simultaneously, clinically znachimogofarmakodinamicheskogo interaction was not 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-blockers, blockers "slow" calcium channel blockers, lipid-lowering drugs,coronary vasodilators, hypoglycemic agents (including insulin), antiepileptics, 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 COX-2 inhibitors, heparin or glycoprotein IIb / IIIa inhibitors.

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:

Tablets coated with a film coating, 75 mg.

Packaging:

By 7, 10 or 14 tablets in a blister of PVC / PVDC and aluminum foil or PA / Al / PVC and aluminum foil.

For 1, 2 or 3 blisters for 7 or 14 tablets; 1, 2, 3 or 10 blisters of 10 tablets 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 expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015542 / 01

Date of registration:05.03.2009

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®)