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

auxiliary substances: core: mannitol 68.925 mg; cellulose microcrystalline 31,000 mg; macrogol 6000 34,000 mg; giprolose low-substituted 12,900 mg; castor oil hydrogenated 3,300 mg; film sheath: opadrai pink (lactose 40,000%, hypromellose 28,000%, titanium dioxide 23,460%, triacetin 8,000%, ferric iron oxide red 0.540%) 7.500 mg; wax carnauba - traces.

Description:

Round slightly biconvex tablets covered with a pink film membrane, 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 adenosine diphosphate (ADP) to P2Y₁₂ platelet receptor and subsequent ADP-mediated activation of the complex GPIIb/IIIa, leading to suppression of platelet aggregation. Due to irreversible binding, platelets remain immune to stimulation of ADP for the rest of their life (about 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the rate of platelet pool 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 means of a system of cytochrome P450 enzymes, some of which may be different or polymorphism can be inhibited by other drugs, not all patients may adequate platelet inhibition.

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.

With a daily intake of clopidogrel at a dose of 75 mg, a significant inhibition of ADP-induced platelet aggregation is noted from the first day of administration, which gradually increases for 3-7 days and then reaches a constant level (when the equilibrium state is reached). In the equilibrium state, platelet aggregation is suppressed on average by 40-60%. After stopping the use of clopidogrel, platelet aggregation and bleeding time gradually return to the baseline level on average for 5 days.

In a small study comparing the pharmacodynamic properties of clopidogrel in men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in bleeding time elongation. In a large controlled study CAPRIE (clopidogrel in comparison with acetylsalicylic acid in patients at risk of development of ischemic events), the frequency of clinical outcomes, other adverse reactions and abnormal clinical and laboratory parameters was the same for both men and women.

Pharmacokinetics:

Suction

When taking oral administration at a dose of 75 mg per day clopidogrel quickly absorbed. The mean peak concentrations of unchanged clopidogrel in the blood plasma (approximately 2.2-2.5 ng / ml after ingestion of a single dose of 75 mg) are reached approximately 45 minutes after administration. According to the deducing of metabolites of clopidogrel with 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 up 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), and the second pathway through the cytochrome P450 system. at first clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of an active metabolite of clopidogrel-thiol clopidogrel derivative.

In vitro this way of metabolism occurs with the help of cytochrome P450 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 blocking platelet aggregation.

Excretion

Within 120 hours after ingestion by a human ¹⁴C-labeled clopidogrel approximately 50% of the radioactive label is found in urine and approximately 46% in feces. After a single oral dose of 75 mg, the half-life of clopidogrel is approximately 6 hours. After a single dose and repeated doses, the half-life of the main non-active metabolite circulating in the blood is 8 hours.

Pharmacogenetics

Several polymorphic enzymes of the cytochrome P450 system are involved in the activation of clopidogrel. Isozyme CYP2C19 is involved in the formation of both an active metabolite and an intermediate metabolite, 2-oxoclopidogrel. Pharmacokinetics and antiplatelet effects of the active metabolite of clopidogrel, studied by platelet aggregation ex vivo, differ depending on the genotype of the isoenzyme CYP2C19. Gene allele CYP2C19 * 1 is responsible for the normally functioning metabolism, whereas the alleles of the isoenzyme gene CYP2C19 * 2 and isoenzyme CYP2C19 * 3 are responsible for reduced metabolism. These alleles are responsible for a decrease in metabolism in about 85% of the representatives of the Caucasoid race and 99% in the representatives of the Mongoloid race. Other alleles associated with reduced metabolism are represented by isoenzymes CYP2C19 * 4, * 5, * 6, * 7 and * 8, but they are rarely found in the general population. Patients with low isoenzyme activity CYP2C19, should have the two 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.Pharmacogenetic testing allows to determine genotype with variability of isoenzyme activity CYP2C19.

Genetic variants of other enzymes of the cytochrome P450 system with effects on the ability of formation of active metabolites of clopidogrel are also possible.

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 CYP2C19, the exposure of the active metabolite decreased compared to 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 certain groups of patients has 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 for 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), inhibition of ADP-induced platelet aggregation was lower (25%) than in healthy volunteers.However, the lengthening of bleeding time was similar to that of healthy volunteers who received clopidogrel in a dose of 75 mg per day.

Impaired liver 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.

Ethnicity

Prevalence of alleles of isoenzyme genes CYP2C19, responsible for the intermediate and reduced metabolism, is different in representatives of different ethnic groups. There are very small literary data among representatives of the Mongoloid race, which does not allow to assess the importance of genotyping isoenzyme CYP2C19 on the clinical outcome of the event.

Indications:

Prevention of atherothrombotic events in 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.

Prevention of atherothrombotic events (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) with drug treatment and the possibility of carrying out thrombolysis.

Preventing atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation in adults with atrial fibrillation who 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, eg bleeding from peptic ulcers or intracranial hemorrhage;

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

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

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

Carefully:

- With moderate hepatic insufficiency (7-9 points on the Child-Pugh scale), which can predispose to bleeding (limited clinical experience of use);

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

- with injuries and surgical interventions (see "Special instructions");

- with simultaneous reception of selective serotonin reuptake inhibitors (SSRIs);

- if there is an anamnesis of allergic and hematological reactions to other thienopyridine (such as ticlopidine, prasugrel) in connection with the possibility of cross-allergic and hematological reactions;

- at diseases at which there is a predisposition to development of bleedings (especially gastrointestinal or intraocular);

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

- with the simultaneous administration of warfarin, heparin, a glycoprotein IIb / IIIa inhibitor;

- in patients with a genetically determined decrease in the function of the isoenzyme CYP2C19 (there is literature data suggesting that patients with a genetically determined decrease in the isoenzyme function CYP2C19 are exposed to less systemic exposure to the active metabolite of clopidogrel and have a less pronounced antiaggregant effect of the drug, in addition they may have a greater incidence of cardiovascular complications after myocardial infarction compared to patients with normal isoenzyme function CYP2C19).

Pregnancy and lactation:

As a precautionary measure, the use of clopidogrel is contraindicated during pregnancy due to the lack of clinical data on its intake by pregnant women, although animal studies have revealed neither direct nor indirect adverse effects on the course of pregnancy, embryonic development, childbirth and postnatal development.

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

Dosing and Administration:

Adults

A drug CLOSED HAMMER should be taken orally, regardless of food intake.

Myocardial infarction (MI), ischemic stroke (AI), and diagnosed peripheral arterial occlusive disease

The drug is taken 75 mg once a day.

In patients with MI, treatment can be started from the first days to 35 days after MI, and in patients with AI - from 7 days to 6 months after the AI.

Acute coronary syndrome without ST segment elevation (unstable angina, myocardial infarction without Q-wave)

Treatment with drug CLOSED HAMMER should be started with a single intake of a loading 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. The results of clinical studies confirm the advisability of taking the drug up to 12 months after the development of acute coronary syndrome without segment elevation ST.

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

A drug CLOSED HAMMER is given once in a dose of 75 mg once a day with the initial single dose loading in combination with acetylsalicylic acid and thrombolytic agents (or without thrombolytics).Combination therapy starts as soon as possible after the onset of symptoms and lasts for at least 4 weeks. The effectiveness of combined use of clopidogrel and acetylsalicylic acid for more than 4 weeks at this indication has not been studied.

Atrial fibrillation

FROM prevention of thrombotic and thromboembolic complications CLOSED HAMMER should be taken at 75 mg once a day in combination with taking acetylsalicylic acid in a daily dose of 75-100 mg.

Skipping the next dose

If less than 12 hours have elapsed since the next dose was missed, the missed dose of the drug should be taken immediately, the patient should take the subsequent doses at the usual time.

If more than 12 hours have elapsed since the next dose was missed, the patient should take the next dose at the usual time.

Patients with a genetically determined decrease in the isoenzyme function CYP2C19

Weakening of metabolism with the help of isoenzyme CYP2C19 can lead to a decrease in the effect of clopidogrel. Optimum dosage regimen for patients with metabolic isozyme reduction CYP2C19 has not yet been installed.

Special patient groups

Elderly patients

In patients older than 75 years, treatment with the drug CLOSED HAMMER should begin without taking a loading dose.

Children

The experience of using the drug in children is absent.

Side effects:

When clopidogrel is used, the following side effects can occur, which are divided according to the system-organ classes in accordance with the classification of the Medical Dictionary for Regulatory Activities (MedDRA). The frequency of adverse reactions was determined according to the following classification of the WHO (World Health Organization): very frequent - more than 1/10, frequent - more than 1/100 to less than 1/10, infrequent - more than 1/1000 to less than 1/100, from more than 1/10000 to less than 1/1000, very rare - from less than 1/10000, including individual messages, the frequency is unknown - it is not possible to determine the incidence of side effects from available data.

Violations from the blood and lymphatic system: infrequent - prolongation of bleeding time, thrombocytopenia, leukopenia and eosinophilia; rare - neutropenia, including acute neutropenia; very rare - aplastic anemia,pancytopenia, agranulocytosis, severe thrombocytopenia, thrombotic thrombocytopenic purpura, granulocytopenia, anemia; frequency unknown - acquired hemophilia. Immune system disorders: frequency unknown - anaphylactoid reactions, serum sickness, cross-allergic hematologic reactions with other thienopyridines (such as ticlopidine, prasugrel).

Disorders of the psyche: very rare - hallucinations, confusion.

Disturbances from the nervous system: infrequent - intracranial hemorrhage (including fatal), headache, dizziness and paresthesia; very rare - changes in taste.

Disorders from the gastrointestinal tract: frequent - gastrointestinal bleeding, diarrhea, abdominal pain, dyspepsia; infrequent - ulcer of the stomach and duodenum, gastritis, vomiting, nausea, constipation, flatulence; rare - retroperitoneal bleeding; very rare - gastrointestinal and retroperitoneal bleeding with fatal outcome, pancreatitis, colitis (including ulcer and lymphocytic colitis), stomatitis.

Disturbances on the part of the organ of sight: infrequent - retinal hemorrhage, conjunctival hemorrhage, hemophthalmus.

Hearing disorders and labyrinthine disorders: rare - vertigo.

Vascular disorders: frequent - hematomas; very rare - heavy bleeding, bleeding from the operating wound, vasculitis, lowering blood pressure.

Disturbances from the respiratory system, chest and mediastinal organs: frequent - nosebleeds; very rare - hemoptysis, pulmonary hemorrhage, bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.

Disturbances from the skin and subcutaneous tissues: frequent - "bruises" (local subcutaneous hemorrhage); infrequent - rash, thrombocytopenic purpura; very rare - eczema, flat lichen; frequency unknown - maculopapular or erythematous rash, hives, itching, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations (DRESS syndrome).

Disorders from the liver and bile ducts: very rare - acute liver failure, hepatitis (non-infectious), an increase in the activity of "liver" transaminases.

Disturbances from musculoskeletal and connective tissue: very rare - hemarthrosis, arthralgia, arthritis, myalgia.

Disorders from the kidneys and urinary tract: infrequent - hematuria, very rare - glomerulonephritis, an increase in creatinine in the blood plasma.

General disorders and disorders at the site of administration: often bleeding at the injection site; very rare - fever.

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 rapid correction of prolonged time of bleeding is necessary, then transfusion of platelet mass is recommended.

Interaction:

Oral anticoagulants: simultaneous reception together with clopidogrel may increase the intensity of bleeding, so the use of this combination is not recommended.

Blockers IIb/IIIa-receptors: the appointment 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 "Special instructions").

Acetylsalicylic acid: acetylsalicylic acid does not alter the effect of clopidogrel, which inhibits ADP-induced platelet aggregation, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. Nevertheless, simultaneous with clopidogrel, the intake of acetylsalicylic acid 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 acetylsalicylic acid, pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, when they are used simultaneously, care should be taken, although in clinical trials patients received combined therapy with clopidogrel and acetylsalicylic acid for up to one year.

Heparin: according to a clinical trial conducted with the participation of healthy individuals, when taking clopidogrel did not require a change in the dose of heparin and did not change its anticoagulant effect. The simultaneous use of heparin did not alter the antiplatelet effect of clopidogrel. Between clopidogrel and heparin, pharmacodynamic interaction is possible, which may increase the risk of bleeding, so the simultaneous use of these drugs requires caution.

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

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

Non-steroidal anti-inflammatory drugs (NSAIDs): 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 along with other NSAIDs. Therefore, the appointment of NSAIDs, including COX-2 inhibitors, in combination with clopidogrel should be carried out with caution (see "Special instructions").

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

Proton Pump Inhibitors: simultaneous administration of clopidogrel and proton pump inhibitors (such as omeprazole and esomeprazole) Not recommended. If proton pump inhibitors are to be taken with clopidogrel, the drug with the least effect on isoenzyme should be selected CYP2C19, for example, pantoprazole and lansoprazole.

Other combination therapy

As clopidogrel metabolized to the formation of its active metabolite partially by means of the system CYP2C19, the use of drugs that inhibit this system can lead to a decrease in the level of the active metabolite of clopidogrel and a decrease in its clinical efficacy.

A number of clinical studies with clopidogrel and other concomitantly prescribed drugs were conducted to study possible pharmacodynamic and pharmacokinetic interactions that showed that:

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

- simultaneous use of phenobarbital, cimetidine and estrogens had no significant effect on the pharmacodynamics of clopidogrel;

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

- antacids did not reduce the absorption of clopidogrel;

- phenytoin and tolbutamide can be safely used simultaneously with clopidogrel (study CAPRIE), despite the fact that the data obtained in studies with human liver microsomes indicate that the carboxylic metabolite clopidogrel can inhibit the activity of the isoenzyme CYP2C9, which may lead to increased plasma concentrations of certain drugs (phenytoin, tolbutamide and some NSAIDs) that are metabolized with this isoenzyme, ACE inhibitors, diuretics, beta-blockers, slow calcium channel blockers, lipid-lowering agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, hormone replacement therapy and blockers GPIIb/IIIa-receptors: Clinical studies did not reveal clinically significant adverse interactions.

Special instructions:

When treating the drug CLOSED HAMMER, 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 latent. In connection with the risk of bleeding and hematological adverse effects (see "Side Effects"), if clinical symptoms that are suspect for bleeding occur during treatment, it is urgent to do a clinical blood test, determine activated partial thromboplastin time (APTT), platelet count , indicators of the functional activity of platelets and conduct other necessary studies.

Acquired hemophilia. It is reported that cases of development of acquired hemophilia with the use of clopidogrel. With confirmed isolated increase in AChVT, accompanied or not accompanied by the development of bleeding, it is necessary to suspect the possibility of developing acquired hemophilia.Patients with a confirmed diagnosis of acquired hemophilia should be observed and treated by specialists in this disease. The use of clopidogrel must be discontinued. A drug CLOSED HAMMER, as well as other antiplatelet drugs, should be used with caution in patients with an increased risk of bleeding associated with trauma, surgery or other pathological conditions, as well as in patients receiving acetylsalicylic acid, non-steroidal anti-inflammatory drugs, including COX inhibitors -2, heparin or glycoprotein inhibitors IIb/IIIa, SSRIs or thrombolytic drugs.

Joint use of clopidogrel with warfarin may increase the intensity of bleeding (see "Interaction with other drugs"), therefore, with the exception of special rare clinical situations (such as the presence of a floating thrombus in the left ventricle, stenting in patients with atrial fibrillation) CLOSED HAMMER and warfarin is not recommended.

If the patient is scheduled surgical operation,and thus there is no need for an antiplatelet effect, then 7 days before the operation, taking the drug CLOSED HAMMER should be discontinued,

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

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

Very rarely, after the use of clopidogrel (sometimes even briefly), there have been cases of the development of idiopathic thrombocytopenic purpura (ITP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever.ITP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

During the treatment it is necessary to monitor the functional activity of the liver. With severe liver damage should be remembered about the risk of hemorrhagic diathesis. Reception of the drug CLOSED HAMMER It is not recommended for acute stroke less than 7 days old (as there is no data on its use in this condition). Cross-allergic and / or hematologic reactions between thienopyridines. It should be clarified the presence in the patient's history of allergic and / or hematological reactions to other thienopyridine derivatives (such as ticlopidine and prasugrel), t. cases of cross-allergic and / or hematological reactions between thienopyridines are described. Tienopyridines can cause mild and severe allergic reactions (rash, angioedema) or hematologic reactions (thrombocytopenia, neutropenia). Patients who have previously experienced allergic and / or hematologic reactions to one of the drugs - thienopyridine derivatives, may cause an increased risk of such reactions when taking another drug from the group of thienopyridines.Such patients require careful observation during the entire period of therapy to detect signs of hypersensitivity to clopidogrel.

In patients who have recently undergone AI or transient ischemic attack with a high risk of recurrent atherothrombotic events, combination therapy with clopidogrel and acetylsalicylic acid has not demonstrated greater efficacy in comparison with clopidogrel monotherapy, but may increase the risk of major bleeding.

A drug CLOSED HAMMER should not be taken to patients with a rare hereditary intolerance to galactose, a deficiency of lactase and a glucose-galactose malabsorption syndrome (see the "Composition" section)

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

A drug CLOSED HAMMER in rare cases, can cause side effects from the nervous system (headache, dizziness, system dizziness, confusion, hallucinations) that can potentially affect the ability to drive vehicles and engage in other potentially hazardous activities requiring increased concentration and speed psychomotor reactions. Nevertheless, in most cases clopidogrel does not have a significant impact on the ability to drive vehicles and mechanisms.

Form release / dosage:

Tablets coated with a film coating, 75 mg.

Packaging:

For 28, 30 or 90 tablets in dark glass bottles with a screwed HDPE lid with a dehumidifier and first opening control.

Each bottle is placed in a cardboard box along with the instructions for use.

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-002260

Date of registration:01.10.2013

Date of cancellation:2017-11-14

The owner of the registration certificate:Zentiva c.s.Zentiva c.s. Czech Republic

Manufacturer: & nbsp

ZENTIVA, k.s. Czech Republic

Representation: & nbspZENTIVA ZENTIVA Czech Republic

Information update date: & nbsp14.11.2017

Illustrated instructions

Instructions

Clopidogrel (Clopidogrel)