Zylt, 75 mg 84 pcs.

Prevention of thromboembolism, Prevention of thrombosis, Prevention of heart attacks and strokes, Prevention of heart attack

Secondary prevention of atherothrombotic complications:

• in adult patients after a recent myocardial infarction (several days to 35 days old), a recent ischemic stroke (seven days to six months old), or diagnosed peripheral arterial occlusive disease, clopidogrel administration reduced the frequency of the combined end point which included recurrent ischemic stroke (fatal or not), recurrent myocardial infarction (fatal or not), and other cardiovascular death;
• in adult patients with acute coronary syndrome:

acute coronary syndrome without ST-segment elevation (unstable angina/ myocardial infarction without Q-wave), including patients who should receive drug treatment, and patients who are shown percutaneous coronary intervention (with or without stenting) or coronary artery bypass surgery (CABG). Clopidogrel administration reduced the incidence of the combined end point including cardiovascular death, myocardial infarction, or stroke and the incidence of the combined end point including cardiovascular death, myocardial infarction, stroke, and refractory ischemia;

acute myocardial infarction with ST-segment elevation. Administration of clopidogrel reduced all-cause mortality as well as the incidence of the combined endpoint, which included death, recurrent myocardial infarction, or stroke.

Prevention of atherothrombotic and thromboembolic complications in adult patients with atrial fibrillation (atrial fibrillation)

In patients with atrial fibrillation with an increased risk of vascular complications, therapy with indirect anticoagulants that are vitamin K antagonists (VKAs) has been shown to be associated with greater clinical benefit compared to the use of ASA alone or the combination of clopidogrel with ASA in reducing the risk of stroke.

Patients with atrial fibrillation (atrial fibrillation) with at least one risk factor for vascular complications who cannot take AVC (e.g., if there is a particular risk for bleeding, inability, in the opinion of the treating physician, or if the patient does not tolerate AVC treatment), clopidogrel in combination with ASA is indicated to prevent atherothrombotic and thromboembolic complications, including stroke.

Clopidogrel in combination with ASA has been shown to reduce the incidence of the combined end point including stroke, myocardial infarction, systemic thromboembolism outside the CNS or cardiovascular death, primarily by reducing the incidence of stroke (see subsection “Pharmacodynamics”).

Active ingredient

Composition

for 1 tablet

nucleus:

Active substance:

Clopidogrel hydrosulfate 97.875 mg, equivalent to clopidogrel 75 mg

Associates: lactose, microcrystalline cellulose, pregelatinized starch, macrogol 6000, hydrogenated castor oil

Film coating:hypromellose, titanium dioxide (E171), talc, iron oxide red dye (E172), propylene glycol

How to take, the dosage

Clopidogrel should be taken orally, regardless of the time of meals.

Adults and elderly patients

Myocardial infarction, ischemic stroke, and diagnosed peripheral artery occlusive disease

The drug is taken 75 mg once daily.

In patients with myocardial infarction, treatment can be started from the first days to day 35 of MI, and in patients with ischemic stroke (IS), from 7 days to 6 months after IS.

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

Treatment with clopidogrel should be initiated with a single loading dose of 300 mg and then continued with a dose of 75 mg once daily (combined with ASA at doses of 75-325 mg daily). Since the use of higher doses of ASA is associated with an increased risk of bleeding, the recommended dose of ASA for this indication should not exceed 100 mg. The maximum favorable effect is observed by the third month of treatment. The course of treatment is up to 1 year.

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

Clopidogrel is administered once at a dose of 75 mg once daily with an initial once-daily loading dose in combination with ASA and thrombolytics (or without thrombolytics). Combination therapy is started as soon as possible after the onset of symptoms and continued for at least four weeks. In patients older than 75 years, treatment with clopidogrel should be started without its loading dose.

atrial fibrillation (atrial fibrillation)

The drug Zilt® is administered at a dose of 75 mg once daily. In combination with clopidogrel the therapy should be started and then acetylsalicylic acid should be continued in a dose of 75-100 mg daily.

Patients with genetically determined decreased CYP2C19 isoenzyme function

Decreased CYP2C19 isoenzyme activity may result in decreased effect of clopidogrel. The optimal dosing regimen for patients with decreased CYP2C19 isoenzyme activity has not yet been established.

Interaction

Drugs the use of which is associated with the risk of bleeding

There is an increased risk of bleeding due to their potential additive effect with clopidogrel. Concomitant use of drugs with clopidogrel, the use of which is associated with the risk of bleeding, should be performed with caution.

Varfarin

Although administration of clopidogrel 75 mg/day did not alter the pharmacokinetics of warfarin (a substrate of the CYP2C9 isoenzyme) or INR in patients treated with long-term warfarin, concomitant administration of clopidogrel increases bleeding risk due to its independent additional effect on blood clotting. Therefore, caution should be exercised when concomitant use of warfarin and clopidogrel.

Blockers IIb/IIIa-receptors

Due to the possibility of pharmacodynamic interaction between clopidogrel and IIb/IIIa-receptor blockers, their combined use requires caution, especially in patients with an increased risk of bleeding (in trauma and surgery or other pathological conditions) (see See sect. “Special Precautions”).

ASK

ASK does not alter the ADP-induced platelet aggregation inhibitory effect of clopidogrel, but clopidogrel potentiates the effect of ASK on collagen-induced platelet aggregation. Nevertheless, concomitant administration of ASA at 500 mg twice daily for one day with clopidogrel did not cause a significant increase in bleeding time caused by clopidogrel administration. Since pharmacodynamic interaction is possible between clopidogrel and ASA, which leads to an increased risk of bleeding, so caution should be exercised when using them simultaneously. Nevertheless, in clinical trials patients received combined therapy with clopidogrel and ASA (75-325 mg once daily) up to one year.

Heparin

According to a clinical trial conducted with healthy subjects, no change in heparin dose was required while taking clopidogrel and its anticoagulant effect was not altered. Concomitant use of heparin did not change the antiaggregant effect of clopidogrel. There is a possible pharmacodynamic interaction between clopidogrel and heparin, which may increase the risk of bleeding, therefore, concomitant use of clopidogrel and heparin requires caution.

Trombolytics

The safety of coadministration of clopidogrel, fibrin-specific or fibrin-unspecific thrombolytics, and heparin has been studied in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytics and heparin were used together with ASA.

NSAIDs

In a clinical study involving healthy volunteers, coadministration of clopidogrel and naproxen increased latent blood loss through the GI tract. However, due to the lack of studies on the interaction of clopidogrel with other NSAIDs, it is currently unknown whether there is an increased risk of gastrointestinal bleeding when clopidogrel is taken 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 indications”).

SIOPS

Since SSRIs disrupt platelet activation and increase the risk of bleeding, concomitant use of SSRIs with clopidogrel should be performed with caution.

strong and moderate CYP2C9 isoenzyme inhibitors

Since clopidogrel is metabolized to form its active metabolite in part by the CYP2C19 isoenzyme, use of drugs that inhibit this isoenzyme may reduce the formation of the active metabolite clopidogrel.

The clinical significance of this interaction has not been established. As a precautionary measure, concomitant use of clopidogrel and strong or moderate inhibitors of CYP2C9 isoenzyme should be avoided. Strong and moderate inhibitors of CYP2C9 isoenzyme are omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol, efavirenz.

Current use of proton pump inhibitors that are strong to moderate inhibitors of CYP2C19 isoenzyme (e.g., omeprazole, esomeprazole) should be avoided with clopidogrel (see section Pharmacokinetics, subsection, “Pharmacogenetics”, section “Cautionary Note”). If proton pump inhibitors are to be taken concomitantly with clopidogrel, the proton pump inhibitor with the least CYP2C19 isoenzyme inhibition, such as pantoprazole and lansoprazole, should be taken.

There is no evidence that other drugs that reduce gastric acidity, such as H2 receptor blockers or antacids, affect the antiaggregant effect of clopidogrel.

In HIV-infected patients receiving antiretroviral therapy (ART) enhanced with ritonavir or cobicistat, a significant decrease in plasma concentration of the active metabolite clopidogrel and a decrease in platelet aggregation suppression were demonstrated.

Although the clinical significance of the findings has not been conclusively confirmed, spontaneous reports received described HIV-infected patients receiving enhanced ART who experienced recurrent occlusion after debulking or thrombotic events when using a loading dose of clopidogrel. The effect of clopidogrel and the average rate of platelet aggregation inhibition may be reduced when concomitantly used with ritonavir. Therefore, concomitant use of clopidogrel with boosted ART is not recommended.

A number of clinical studies have been performed with clopidogrel and other concomitantly used drugs to examine possible pharmacodynamic and pharmacokinetic interactions, which showed that:

– no clinically significant pharmacodynamic interaction was observed when using clopidogrel together with atenololol, nifedipine or both these drugs taken simultaneously;

– simultaneous use of phenobarbital and estrogen had no significant effect on the pharmacodynamics of clopidogrel;

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

– antacids did not reduce absorption of clopidogrel;

-Phenytoin and tolbutamide can safely be used concomitantly with clopidogrel (CAPRIE study). It is unlikely that clopidogrel can affect the metabolism of other drugs such as phenytoin and tolbutamide, as well as NSAIDs that are metabolized by the cytochrome P450 system CYP2C9 isoenzyme;

– ACE inhibitors, diuretics, beta-adrenoblockers, slow calcium channel blockers, hypolipidemic agents, coronary vasodilators, hypoglycemic agents (incl. including insulin, antiepileptic agents, hormone replacement therapy and GPIIb/IIIa-receptor blockers: no clinically significant adverse interactions have been observed in the clinical trials.

Drugs that are substrates of CYP2C8 isoenzyme

Clopidogrel was shown to increase systemic exposure to repaglinide in healthy volunteers. in vitro studies have shown that increased systemic exposure of repaglinide is a consequence of inhibition of the CYP2C8 isoenzyme by the glucuronide metabolite clopidogrel. Caution should be exercised when concomitant use of clopidogrel and drugs predominantly excreted by metabolism by CYP2C8 isoenzyme (e.g., repaglinide, paclitaxel) due to the risk of increasing their plasma concentrations.

Special Instructions

– Moderate liver function impairment with predisposition to bleeding (limited clinical experience).

– Renal dysfunction (limited clinical experience of use).

– Diseases with a predisposition to bleeding (particularly gastrointestinal and intraocular) and especially when concomitant use of drugs that can cause gastrointestinal mucosal damage (such as ASA and nonsteroidal anti-inflammatory drugs [NSAIDs]).

– In patients who have an increased risk of bleeding Because of trauma, surgery, or other pathological conditions, and in patients treated with ASA, heparin, warfarin, glycoprotein IIb/IIIa inhibitors, NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, and other medications whose use is associated with the risk of bleeding, selective serotonin reuptake inhibitors (SSRIs) (see Interaction with other medicinal products” and “Cautions”).

– Concurrent use with medicinal products which are substrates of CYP2C8 isoenzyme (repaglinide, paclitaxel) (see section “Interaction with other medicinal products”).

– In patients with low activity of CYP2C19 isoenzyme (see section “Pharmacokinetics” subsection “Pharmacogenetics”, sections “Administration and doses”, “Special indications”).

– If there is a history of allergic and hematologic reactions to other thienopyridines (such as ticlopidine, prasugrel) (possible cross-allergic and hematologic reactions, see “Special Indications”).

– In recent transient cerebral circulation disorder or ischemic stroke (when combined with ASA, see “Special Indications”).

It is contraindicated in persons under 18 years of age (safety and efficacy of use have not been established).

Elderly patients

Myocardial infarction, ischemic stroke, and diagnosed peripheral artery occlusive disease

The drug is taken at 75 mg once daily.

In patients with myocardial infarction, treatment can be started from the first days to day 35 of MI, and in patients with ischemic stroke (IS), from 7 days to 6 months after IS.

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

Treatment with clopidogrel should be initiated with a single loading dose of 300 mg and then continued with a dose of 75 mg once daily (combined with ASA at doses of 75-325 mg daily). Since the use of higher doses of ASA is associated with an increased risk of bleeding, the recommended dose of ASA for this indication should not exceed 100 mg. The maximum favorable effect is observed by the third month of treatment. The course of treatment is up to 1 year.

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

Clopidogrel is administered once at a dose of 75 mg once daily with an initial once-daily loading dose in combination with ASA and thrombolytics (or without thrombolytics). Combination therapy is started as soon as possible after the onset of symptoms and continued for at least four weeks. In patients older than 75 years, treatment with clopidogrel should be started without its loading dose.

atrial fibrillation (atrial fibrillation)

The drug Zilt® is administered at a dose of 75 mg once daily. In combination with clopidogrel the therapy should be started and then acetylsalicylic acid should be continued in a dose of 75-100 mg daily.

Patients with genetically determined decreased CYP2C19 isoenzyme function

Decreased CYP2C19 isoenzyme activity may result in decreased effect of clopidogrel. The optimal dosing regimen for patients with decreased CYP2C19 isoenzyme activity has not been established yet.

When treating with clopidogrel, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients should be closely monitored for signs of bleeding, including hidden bleeding.

Due to the risk of bleeding and adverse blood effects (see

In case of clinical symptoms suspicious of bleeding occurring during treatment, a complete clinical blood count, activated partial thromboplastin time (APT), platelet count, platelet function tests, and other necessary tests should be performed urgently.

Clopidogrel, as well as other antiplatelet agents, should be used with caution in patients who have an increased risk of bleeding associated with trauma, surgery or other pathological conditions, as well as in patients taking ASA, NSAIDs including COX-2 inhibitors, heparin or glycoprotein IIb/IIIa inhibitors, SSRIs or other medications whose use is associated with the risk of bleeding, such as pentoxifylline.

Concomitant use of clopidogrel with warfarin may increase the risk of bleeding (see section “Interaction with other medicinal products”), therefore caution should be exercised when using clopidogrel and warfarin concomitantly.

If the patient will have elective surgery and there is no need for antiplatelet effect, clopidogrel should be discontinued 5-7 days before surgery.

Clopidogrel prolongs bleeding time and should be used with caution in patients with diseases that predispose to bleeding (especially gastrointestinal and intraocular). Drugs that may cause gastrointestinal mucosal damage (such as ASA, NSAIDs) in patients taking clopidogrel should be used with caution.

Patients should be warned that it may take longer to stop bleeding when taking clopidogrel (alone or in combination with ASA) and that if they experience unusual (in location or duration) bleeding, they should inform their physician. Before any upcoming surgery and before starting any new medication, patients should tell their doctor (including their dentist) about taking clopidogrel.

Very rare cases of TTP, characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, renal dysfunction and fever, have been reported after clopidogrel use (sometimes even briefly). TTP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

The combination of ASA and clopidogrel has been shown to increase the incidence of major bleeding in patients with a recent transient cerebrovascular event or stroke who are at high risk for recurrent ischemic complications. Therefore, such combination therapy should be used with caution and only in case of proven clinical benefit from its use.

Cases of acquired hemophilia have been reported while taking clopidogrel. With a confirmed isolated increase in the ACEF with or without bleeding, the possibility of acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated by specialists in this disease and discontinue clopidogrel.

In patients with low CYP2C19 isoenzyme activity, when using clopidogrel in recommended doses, less active clopidogrel metabolite is formed and its antiaggregant effect is weaker; therefore, when using normally recommended doses of clopidogrel for acute coronary syndrome or percutaneous coronary intervention, a higher rate of cardiovascular complications is possible than in patients with normal CYP2C19 isoenzyme activity. Tests are available to determine the CYP2C19 genotype, which can be used to assist in the choice of therapeutic strategy. The use of higher doses of clopidogrel in patients with low CYP2C19 isoenzyme activity is being considered (see section “Pharmacokinetics”, subsection “Pharmacogenetics”, sections “Caution”, “Dosage and administration”).

Since clopidogrel is metabolized to the active metabolite partially by CYP2C19 isoenzyme, the use of drugs that inhibit this isoenzyme may decrease the concentration of the active metabolite of clopidogrel. The clinical significance of this interaction has not been established. As a precautionary measure, concomitant use of clopidogrel and potent or moderate inhibitors of CYP2C19 isoenzyme is not recommended.

Caution should be exercised when using clopidogrel concomitantly with drugs that are substrates of CYP2C8 isoenzyme.

Patients should have a history of previous allergic and/or hematological reactions to other thienopyridines (such as ticlopidine, prasugrel), since cross-allergic and/or hematological reactions between thienopyridines have been reported (see section “Adverse effects”). Thienopyridines may cause moderate to severe allergic reactions (such as skin rash, angioedema) or hematological reactions (such as thrombocytopenia and neutropenia). Patients who have previously had allergic and/or hematological reactions to one of the drugs of thienopyridine group may have an increased risk of similar reactions to another drug of thienopyridine group. Monitoring of cross-allergic and/or hematologic reactions is recommended.

During the treatment it is necessary to monitor the liver functional state. In case of severe liver lesions one should remember about the risk of hemorrhagic diathesis.

Taking clopidogrel is not recommended in acute stroke less than 7 days old (because there are no data on its use in this condition).

Special information on excipients

The drug Zilt® should not be taken by patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome because it contains lactose.

Zylt® contains hydrogenated castor oil, which may cause stomach upset and diarrhea in patients.

The drug Zylt® has no significant effect on the ability to drive a vehicle or engage in other potentially dangerous activities.

Synopsis

Round, slightly biconvex tablets with a pink film coating.

Breakage appearance: white to almost white rough mass with a pink film coating.

Contraindications

Hypersensitivity to clopidogrel or any of the excipients of the drug.

Severe liver function disorder.

Acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage.

Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

Pregnancy and breast-feeding (see “Administration during pregnancy and breast-feeding”).

Childhood under 18 years (safety and effectiveness of use not established).

Side effects

Data from clinical trials

Safety of clopidogrel was studied in more than 44,000 patients, including more than 12,000 patients treated for a year or more. Overall, the tolerability of clopidogrel at a dose of 75 mg/day in the CAPRIE study was similar to that of ASA at a dose of 325 mg/day, regardless of patient age, sex, or race. Listed below are the clinically significant adverse effects observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE A.

bleeding and hemorrhage

Comparison of clopidogrel and ASA monotherapy

In the CAPRIE clinical trial, the overall rate of all bleeding in patients taking clopidogrel and those taking ASA was 9.3%. The incidence of major bleeding with clopidogrel and ASA was comparable: 1.4% and 1.6%, respectively.

Overall, the incidence of gastrointestinal bleeding in patients taking clopidogrel and patients taking ASA was 2.0% and 2.7%, respectively, including the incidence of gastrointestinal bleeding that required hospitalization was 0.7% and 1.1%, respectively.

The overall incidence of other localized bleeding was higher with clopidogrel compared with ASA administration (7.3% versus 6.5%, respectively). However, the incidence of major bleeding with clopidogrel and ASA was comparable (0.6% or 0.4%, respectively). The most frequently reported bleeding events were: purpura/bleeding, nasal bleeding. Less commonly reported were hematoma, hematuria, and ocular hemorrhages (mainly conjunctival).

The frequency of intracranial hemorrhages with clopidogrel and ASA was comparable (0.4% or 0.5%, respectively).

Comparison of clopidogrel + ASA and placebo + ASA combination therapy

In the CURE clinical trial, patients taking clopidogrel + ASA compared with patients taking placebo + ASA had an increased incidence of major bleeding (3.7% vs. 2.7%) and minor bleeding (5.1% vs. 2.4%). The gastrointestinal tract (GIT) and arterial puncture sites were the main sources of major bleeding.

Overdose

Symptoms

Clopidogrel overdose may prolong bleeding time with subsequent complications of bleeding development.

Treatment

If bleeding occurs, appropriate treatment measures are required. An antidote for clopidogrel has not been established. If rapid correction of prolonged bleeding time is necessary, platelet transfusion is recommended.

Pregnancy use

Pregnancy

Animal studies have found no direct or indirect adverse effects on pregnancy, embryonic development, birth and postnatal development. Because it is not always possible to predict response in humans based on animal studies, and because there are no controlled clinical trial data on clopidogrel administration in pregnant women, clopidogrel administration during pregnancy is not recommended as a precaution unless, in the opinion of the physician, its use is imperative.

Breastfeeding period

Clopidogrel and/or its metabolites have been shown to be excreted into breast milk in rat studies. Whether clopidogrel passes into human breast milk is unknown. Because many medications can be excreted into breast milk and have adverse effects on the infant, the treating physician, based on the importance of taking ZiltÒ to the mother, should recommend that she either stop taking the drug or take the drug but stop breastfeeding.

Similarities