Zilt - instructions for use, reviews, analogs and formulations (75 mg tablets) of the drug for the treatment of thrombosis, embolism, blood thinning and the prevention of strokes and heart attacks in adults, children and pregnancy. Composition

In this article, you can read the instructions for using the drug Zilt. Presented are reviews of visitors to the site - consumers of this medication, as well as opinions of physicians specialists on the use of Zilt in their practice. A big request is to actively add their feedback on the drug: the medicine helped or did not help get rid of the disease, which were observed complications and side effects, possibly not declared by the manufacturer in the annotation. Analogues of Zilt in the presence of existing structural analogues. Use for treatment of thrombosis, embolism, blood thinning and prevention of strokes and heart attacks in adults, children, as well as during pregnancy and lactation.Composition of the drug based on clopidogrel.

Zilt antiaggregant. Clopidogrel (the active substance of the preparation Zilt) is a prodrug that selectively inhibits the binding of adenosine diphosphate (ADP) to P2Y12 receptor platelets and the subsequent ADP-mediated activation of the glycoprotein GP2b / 3a complex, which leads to inhibition of platelet aggregation.

Suppression of platelet aggregation is irreversible and continues throughout the cell life cycle (about 7-10 days), so the rate of recovery of normal platelet function corresponds to the rate of their renewal. Aggregation of platelets induced by other agonists other than ADP is also inhibited due to blockade of enhanced platelet activation by ADP.

The active metabolite is formed by the action of CYP450 isoenzymes, some of which may be polymorphic or may be inhibited by other drugs, so that adequate inhibition of platelet aggregation is not observed in all patients.

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

Zilt allows to prevent the development of atherothrombotic complications in patients with atherosclerotic lesions of vessels of any localization, especially with damage to the cerebral, coronary or peripheral arteries.

Composition

Clopidogrel hydrogensulfate + auxiliary substances.

Pharmacokinetics

After a single and repeated oral administration at a dose of 75 mg per day, Zilt is rapidly absorbed. Clopidogrel and the main circulating metabolite bind reversibly to plasma proteins under conditions (98% and 94%, respectively). This bond is unsaturated in a wide range of concentrations. Clopidogrel is actively metabolized in the liver. It is metabolized in two ways: the first is mediated by esterases and leads to hydrolysis with the formation of a pharmacologically inactive metabolite, a carboxylic acid derivative (85% of the circulating metabolites), and the other is catalyzed by various cytochrome P450 isoenzymes.Initially, clopidogrel is converted to an intermediate metabolite - 2-oxo-clopidogrel. Subsequent metabolism to 2-oxo-clopidogrel leads to the formation of an active metabolite of clopidogrel-thiol derivative. In in vitro conditions, this route is mediated by isoenzymes CYP3A4, CYP2S19, CYP1A2, CYP2B6. The active thiol metabolite, isolated under in vitro conditions, quickly and irreversibly interacts with the platelet receptors, blocking their aggregation. Within 120 hours after ingestion of labeled clopidogrel, approximately 50% is excreted by the kidneys and 46% by the intestine. The pharmacokinetics of the active metabolite in certain patient groups (elderly patients, children, patients with impaired renal and hepatic function) has not been studied.

Indications

Prevention of atherothrombotic complications in adult patients:

• with myocardial infarction (prescription from several days to 35 days), with ischemic stroke (prescription from 7 days to 6 months) or with diagnosed occlusive disease of peripheral arteries;
• with acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without Q wave formation), including patients who underwent stenting with percutaneous coronary intervention, in combination with acetylsalicylic acid;
• with acute coronary syndrome with ST segment elevation (acute myocardial infarction) with drug treatment and the possibility of performing thrombolytic therapy in combination with acetylsalicylic acid.

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

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

Forms of release

Tablets coated with 75 mg.

Instructions for use and dosing regimen

The drug is taken orally, regardless of food intake, once a day.

Adults and elderly patients with normal activity of the isoenzyme CYP2C19

With myocardial infarction, ischemic stroke or diagnosed occlusive disease of peripheral arteries, Zilt is recommended to take 1 tablet (75 mg) once a day.

In acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without Q wave), treatment with Zilt should be started with a single 300 mg loading dose,and then continued with a 75 mg dose once a day (in combination with Acetylsalicylic acid at a dose of 75-325 mg per day). Since the use of acetylsalicylic acid in high doses is associated with a high risk of bleeding, the recommended dose of acetylsalicylic acid should not exceed 100 mg. The maximum favorable effect is observed by the 3rd month of treatment. The optimal duration of treatment with this indication is not officially defined. The results of clinical studies confirm the advisability of using clopidogrel up to 12 months after the development of acute coronary syndrome without ST segment elevation.

In acute coronary syndrome segment elevation ST (acute myocardial infarction) with drug treatment and the possibility of thrombolytic therapy Zilt drug is administered in a dose of 75 mg 1 time per day, starting with a loading dose in combination with acetylsalicylic acid in combination with or without thrombolysis. For patients older than 75 years, treatment with Zilt should be performed without the use of a loading dose. Combination therapy starts as soon as possible after the onset of symptoms and lasts for at least 4 weeks.The effectiveness of combined therapy with clopidogrel and acetylsalicylic acid for more than 4 weeks in such patients has not been studied.

When atrial fibrillation (atrial fibrillation), Zilt is prescribed at a dose of 75 mg once a day. In combination with clopidogrel, you should start and then continue therapy with acetylsalicylic acid at a dose of 75-100 mg per day.

Skipping the next dose

If less than 12 hours have passed after missing the next dose, then immediately take the missed dose of Zilt and then take the next dose at the usual time.

If more than 12 hours have passed after missing the next dose, then the next dose should be taken at the usual time; Do not double the dose.

Adults and elderly patients with genetically determined reduced activity of the isoenzyme CYP2C19

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

Special patient groups

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

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

After using clopidogrel at a dose of 75 mg per day for 10 days in patients with severe impairment of liver function, the degree of inhibition of ADP-induced platelet aggregation and the mean elongation of bleeding time were comparable to those of healthy volunteers.

When comparing the pharmacodynamic properties of clopidogrel in men and women, a less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in lengthening the bleeding time. When comparing clopidogrel with acetylsalicylic acid in patients at risk of developing ischemic complications, the frequency of clinical outcomes, other side effects and deviations from the norm of clinical and laboratory indicators was the same for both men and women.

Side effect

• thrombocytopenia, leukopenia, eosinophilia, neutropenia, including cases of severe neutropenia, pancytopenia, agranulocytosis;
• thrombotic thrombocytopenic purpura (TTP);
• aplastic anemia;
• severe thrombocytopenia;
• granulocytopenia;
• anemia;
• intracranial hemorrhage (there are reports of several fatal cases);
• headache;
• paresthesia;
• dizziness;
• hallucinations;
• confusion of consciousness;
• hematoma;
• vasculitis;
• arterial hypotension;
• nose bleed;
• bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage);
• bronchospasm;
• interstitial pneumonitis;
• diarrhea, constipation;
• abdominal pain;
• dyspepsia;
• gastrointestinal bleeding;
• stomach ulcers and duodenal ulcers;
• gastritis;
• vomiting, nausea;
• flatulence;
• Gastrointestinal and retroperitoneal bleeding sometimes fatal;
• pancreatitis;
• colitis (including ulcerative colitis or lymphocytic colitis);
• stomatitis;
• hepatitis;
• acute liver failure;
• subcutaneous hematomas;
• rash;
• itching;
• cutaneous hemorrhage (purpura);
• bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme);
• erythematous rash;
• hives;
• eczema;
• flat lichen;
• hemorrhage in the muscles and joints (hemarthrosis);
• arthralgia;
• myalgia;
• hematuria;
• glomerulonephritis;
• intraocular hemorrhages (conjunctival, retinal);
• violation of taste perception;
• angioedema;
• eczema;
• serum sickness;
• anaphylactoid reactions;
• cross-reactive hypersensitivity to thienopyridine (eg, ticlopidine, prasugrel);
• drug rash with eosinophilia and systemic symptoms (DRESS-syndrome);
• prolonged bleeding time;
• bleeding from the point of vascular puncture;
• fever.

Contraindications

• increased sensitivity to clopidogrel and / or any of the components of the drug;
• severe liver dysfunction;
• acute bleeding (eg bleeding from peptic ulcers or intracranial hemorrhage);
• pregnancy;
• lactation period (breastfeeding);
• children and adolescents under 18 years of age (safety and efficacy not established);
• deficiency of lactase, lactose intolerance, glucose-galactose malabsorption syndrome.

Carefully

• moderate violations of liver function with a predisposition to bleeding (limited experience of use);
• impaired renal function (limited experience of use);
• pathological conditions that increase the risk of bleeding (including trauma, surgical interventions);
• diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal and intraocular);
• simultaneous use with non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors;
• simultaneous use of warfarin, heparin or glycoprotein 2b / 3a inhibitors;
• patients with low activity of the isoenzyme CYP2C19 (when using clopidogrel in the recommended dosesformed less active metabolite of clopidogrel and less expressed its antiplatelet effect; so when using clopidogrel at recommended doses for acute coronary syndrome or percutaneous intervention on the coronary arteries, the incidence of cardiovascular complications may be higher than in patients with normal activity of the isoenzyme CYP2C19);
• hypersensitivity to other thienopyridine (eg, ticlopidine, prasugrel).

Application in pregnancy and lactation

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

In animal studies, the penetration of clopidogrel into breast milk was proven. Therefore, if necessary, clopidogrel therapy is recommended to stop breastfeeding.

Use in children

Contraindicated use of the drug in children and adolescents under the age of 18 years.

Application in elderly patients

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

For patients older than 75 years, Zild's treatment should be performed without the use of a loading dose.

special instructions

During treatment with clopidogrel, especially in the first weeks and / or after invasive cardiac procedures / surgical interventions, careful monitoring of patients should be performed to exclude signs of bleeding (including latent). Given the risk of bleeding and hematological adverse events, when clinical symptoms of possible bleeding occur during treatment, it is necessary to immediately perform a clinical blood test with the definition of APTT, platelet function indicators, counting the number of platelets and conduct other necessary studies.

Clopidogrel prolongs bleeding time. Therefore, with caution should prescribe the drug to patients with an increased risk of bleeding after injury, surgery or as a result of other pathological conditions,patients with a tendency to bleeding (especially gastrointestinal and intraocular hemorrhages), as well as patients receiving acetylsalicylic acid, NSAIDs (including COX-2 inhibitors), Heparin and glycoprotein 2b / 3a inhibitors.

The simultaneous use of clopidogrel with Warfarin may increase the risk of bleeding. Therefore, care should be taken when using warfarin and clopidogrel simultaneously.

When conducting a planned surgical intervention, when the antiplatelet effect is undesirable, clopidogrel should be discontinued 5-7 days before the operation.

The patient should be informed that when using clopidogrel (as monotherapy or in combination with acetylsalicylic acid), it may take longer to stop bleeding. Patients should inform the attending physician about each case of unusual (for localization or duration) bleeding. It is also necessary to inform the doctor about taking clopidogrel if the patient is to have surgery (including dental surgery) or before starting a new medication.

Very rarely, with the use of clopidogrel (sometimes even a short one), there have been cases of thrombotic thrombocytopenic purpura. The condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia, associated with neurologic disorders, impaired renal function and fever. Thrombotic thrombocytopenic purpura is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

During the treatment it is necessary to monitor the function of the liver. In severe violations of the liver should be remembered about the risk of hemorrhagic diathesis.

The use of clopidogrel is not recommended for patients with acute ischemic stroke less than 7 days old (no data on use in this state).

Patients should be examined for hypersensitivity to other thienopyridine (eg, ticlopidine, prasugrel) because It is known about cross-reactive hypersensitivity between thienopyridines. Patients with a hypersensitivity to other thienopyridine in a history should be carefully monitored to identify signs of hypersensitivity to clopidogrel during therapy.

Zilt should not be taken to patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome, because the preparation contains lactose.

The drug Zilt contains castor oil hydrogenated, which can cause in patients indigestion and diarrhea.

Impact on the ability to drive vehicles and manage mechanisms

Zilt has no significant effect on the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

The simultaneous use of clopidogrel and oral anticoagulants is not recommended (possibly intensifying bleeding).

The use of clopidogrel at a dose of 75 mg per day does not change the pharmacokinetics of warfarin (the substrate of the isoenzyme CYP2C9) or MHO in patients who are long-treated with warfarin. However, simultaneous use with warfarin increases the risk of bleeding due to its independent additional effect on blood coagulability.Therefore, care should be taken when using warfarin and clopidogrel simultaneously.

The simultaneous use of clopidogrel and glycoprotein 2b / 3a inhibitors requires caution in patients with an increased risk of bleeding (with trauma, surgical interventions or other pathological conditions).

Acetylsalicylic acid does not affect the clopidogrel-induced platelet aggregation inhibition induced by ADP, but clopidogrel potentiates the action of acetylsalicylic acid on collagen-induced platelet aggregation. Nevertheless, simultaneous intake of acetylsalicylic acid in a dose of 500 mg twice a day for one day does not substantially prolong the bleeding time caused by the use of clopidogrel. The pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, and leads to an increased risk of bleeding. Given this, caution should be exercised while taking these medications simultaneously, although in clinical trials patients received combination therapy with clopidogrel and acetylsalicylic acid for one year.

According to the clinical study in healthy individuals with the use of clopidogrel did not require a change in the dose of heparin, and also did not change the anticoagulant effect of heparin. Simultaneous use of heparin had no effect on suppression of platelet aggregation with clopidogrel. Possible pharmacodynamic interaction between clopidogrel and heparin, leading to an increased risk of bleeding. Therefore, the simultaneous use of these drugs requires caution.

The safety of simultaneous use of clopidogrel, fibrin-specific or nonspecific thrombolytics and heparin was evaluated in patients with acute myocardial infarction. The frequency of development of clinically significant bleeding was comparable to that of the simultaneous use of thrombolytics, heparin with acetylsalicylic acid.

According to a clinical study involving healthy volunteers, the simultaneous use of clopidogrel and Naproxen increased latent gastrointestinal bleeding. However, due to a lack of studies on interactions with other NSAIDs, it is currently unknown whether the risk of gastrointestinal bleeding increases for all NSAIDs.Therefore, concurrent therapy with NSAIDs, including COX-2 inhibitors, and clopidogrel should be performed with caution.

Inhibitors of the isoenzyme CYP2C19: clopidogrel is metabolized prior to the formation of its active metabolite partly under the action of the CYP2C19 isoenzyme. Therefore, drugs that inhibit this isoenzyme can cause a decrease in the concentration of the active metabolite clopidogrel. The clinical significance of this interaction is unknown. Simultaneous application with potent or moderate inhibitors of the CYP2C19 isoenzyme should be avoided. CYP2C19 inhibitors include: omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.

The use of Omeprazole at a dose of 80 mg once daily with clopidogrel or with a 12-hour interval between taking two drugs reduced the systemic exposure (AUC) of the active metabolite of clopidogrel by 45% (after taking a loading dose of clopidogrel) and 40% (after receiving a maintenance dose of clopidogrel). Reduction of the AUC of the active metabolite of clopidogrel is associated with a decrease in the degree of inhibition of aggregationthrombocytes (39% after taking a loading dose of clopidogrel and 21% after taking a maintenance dose of clopidogrel). An analogous interaction of clopidogrel with esomeprazole is suggested. In observational and clinical studies, conflicting data on the clinical manifestations of the cardiovascular system with respect to this pharmacokinetic / pharmacodynamic interaction were recorded. You should avoid simultaneous use with omeprazole or esomeprazole.

The inhibitors of the proton pump with minimal inhibiting effect on the isoenzyme CYP2C19 include Pantoprazole and lansoprazole. With the simultaneous use of pantoprazole at a dose of 80 mg once a day, the concentration of the active metabolite of clopidogrel in the blood plasma was reduced by 20% (after taking a loading dose of clopidogrel) and by 14% (after taking a maintenance dose of clopidogrel). This was accompanied by a decrease in inhibition of platelet aggregation, on average, by 15% and 11%, respectively. Therefore, the simultaneous use of clopidogrel with pantoprazole is possible.

Other combination therapy

In studying the pharmacodynamic and pharmacokinetic interaction of clopidogrel and other drugs, the following is revealed:

• with simultaneous use of clopidogrel with atenolol and / or nifedipine, there was no clinically significant pharmacodynamic interaction;
• the pharmacodynamic activity of clopidogrel did not change significantly with simultaneous use with phenobarbital, cimetidine or estrogens;
• the pharmacokinetics of digoxin or theophylline did not change;
• antacids do not affect the degree of absorption of clopidogrel;
• Phenytoin and tolbutamide safely combine with clopidogrel. It is unlikely that clopidogrel may affect the metabolism of other drugs, such as phenytoin and tolbutamide, as well as NSAIDs that are metabolized by the enzyme CYP2C9;
• in clinical studies, there was no clinically significant adverse interaction with diuretics, beta-adrenoblockers, ACE inhibitors, slow calcium channel blockers, lipid-lowering agents, coronary vasodilators, hypoglycemic agents (incl.insulin), antiepileptic drugs, drugs for hormone replacement therapy.

Analogues of the drug Zilt

Structural analogs for the active substance:

• Agregal;
• Payplat 75;
• Detromb;
• Kardogrel;
• Cardutol;
• Klapitaks;
• Clopigrant;
• Clopidex;
• Clopidogrel;
• Clopidogrel hydrogen sulfate;
• Clopidogrel bisulfate;
• Clopilet;
• Lirta;
• Listab 75;
• Lopyrel;
• Plavix;
• Plagril;
• Plyglare;
• Target;
• Troken;
• Thrombex;
• Thromboreal;
• Egitromb.

Analogues for the pharmacological group (antiaggregants):

• Agapurin;
• Agregal;
• Agrilin;
• Aclotine;
• Alprostan;
• ASA cardio;
• Aspen;
• Aspirin Cardio;
• Acetylsalicylic acid;
• Ventavis;
• Godasal;
• Dipyridamole;
• Doxylek;
• Ibustrin;
• Cardiocipine;
• Cardiomagnet;
• Collorite;
• Complymine;
• Coplawix;
• Xantinol nicotinate;
• Courantil;
• Lapal;
• Methyl ethylpyridinol;
• Myristin;
• Monophram;
• Parsedil;
• Pentylin;
• Pentoxifylline;
• Pentomer;
• Persantin;
• Plolidol 100;
• Radomine;
• Ralofect;
• Tagren;
• Tyclid;
• Ticlo;
• Trenpental;
• Trental;
• Trombo ACC;
• Thrombogard 100;
• Thromboreductin;
• Flexitale;
• Cilostazol;
• Eikonol;
• Emoxipine;
• Effective.

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