Zilt

Zilt is an antithrombotic drug, belongs to the group of antiplatelet agents.

Indications Zilta

It is used to prevent the occurrence of atherothrombotic symptoms in individuals:

• those who have had a myocardial infarction (therapy must be started within a period of several days to 35 days after its development);
• those who have suffered an ischemic stroke (the course must be started within 7 days, but no later than six months after its development);
• who were diagnosed with pathology in the area of peripheral arteries (arterial lesion, as well as vascular atherothrombosis in the legs).

For prevention also for people with ACS:

• without ST segment elevation (in the development of unstable angina or myocardial infarction without the presence of a Q wave). This category also includes persons who have had a stent inserted during percutaneous coronary angioplasty; together with aspirin;
• in acute myocardial infarction, when there is an increase in the ST segment level - together with aspirin; people who are receiving therapy with standard drugs and who require thrombolytic treatment.

The drug is also used for the prevention of thromboembolic and atherothrombotic manifestations during atrial fibrillation.

For the above purpose, clopidogrel in combination with aspirin is prescribed to individuals with atrial fibrillation who have at least 1 risk factor for vascular disorders. In addition, such individuals have contraindications to the use of phylloquinone antagonists, and at the same time, they have a low risk of bleeding.

Release form

Released in tablets, 7 pieces inside a blister cell. Inside a separate pack - 4 such blisters.

Pharmacodynamics

The substance clopidogrel selectively inhibits the process of ADP synthesis with a receptor located on the platelet, as well as the subsequent activation of the GP IIb/IIIa complex (as a result of the effect of ADP), thereby inhibiting the possibility of platelet aggregation.

To obtain an active inhibitor of the platelet aggregation process, biotransformation of the substance clopidogrel is required. This component also inhibits platelet aggregation caused by other agonists - by blocking the increase in platelet activity under the influence of the released ADP element. Irreversible binding of the active component of the drug to platelet ADP receptors is carried out. As a result, those platelets that have been exposed to clopidogrel are damaged before the end of their life cycle. At the same time, the restoration of normal platelet function occurs at a rate similar to the rate at which platelets are renewed.

From the first day of using the drug in repeated daily doses (75 mg), there is a noticeable inhibition of ADP-induced platelet aggregation. This effect progressively increases and then stabilizes in the period of 3-7 days. At equilibrium, the average rate of suppression of the aggregation process under the influence of a daily dose of 75 mg is within 40-60%. Bleeding times, as well as platelet aggregation, return to their initial values 5 days (on average) after the end of therapy.

Pharmacokinetics

Following repeated oral administration of Zilt at a daily dose of 75 mg, clopidogrel is rapidly absorbed. Peak plasma levels of unchanged drug (approximately 2.2-2.5 ng/mL after a single oral dose of 75 mg) are reached approximately 45 minutes after administration. The absorption rate is at least 50%, based on the level of drug breakdown products excreted in the urine.

Clopidogrel together with the inactive main breakdown product circulate in the bloodstream. They are reversibly synthesized (in vitro) with plasma protein - respectively by 98% and 94%. This relationship remains unsaturable during action in vitro within a wide range of different concentrations.

Clopidogrel undergoes extensive hepatic metabolism. In vitro and in vivo, there are 2 main metabolic pathways of the substance: one is mediated by esterases and causes hydrolysis, resulting in the formation of an inactive carboxylic acid derivative (it accounts for 85% of all circulating plasma degradation products). The second pathway is action with the participation of enzymes of the hemoprotein P450 system. Initially, clopidogrel is converted to an intermediate degradation product: 2-oxo-clopidogrel. As it continues to undergo metabolism, this element is converted to a thiol derivative, which is an active degradation product. In vitro, this metabolic pathway is mediated by the enzymes CYP3A4 with CYP2C19, and CYP1A2 with CYP2B6. The thiol derivative isolated in vitro is irreversibly and fairly quickly synthesized with receptors located on platelets, preventing aggregation with them.

After oral administration of a single dose of Zilt (75 mg), the half-life of the active component is approximately 6 hours. The main circulating breakdown product has an 8-hour half-life (when taken once or repeatedly).

When a dose of a drug with a 14C index is taken orally, approximately 50% of the substance is excreted in the urine, and another 46% in the feces within 120 hours after administration.

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Dosing and administration

Clopidogrel is taken once a day at a dosage of 75 mg, regardless of food intake.

For people with ACS:

• in the absence of ST segment elevation, therapy begins with a single dose of 300 mg loading dose, followed by 75 mg once daily (in combination with aspirin at a dose of 75-325 mg daily). Since the use of aspirin in stronger doses increases the likelihood of bleeding, do not exceed 100 mg when dosing it. There is no information on the optimal duration of therapy. The results of clinical tests suggest that the most suitable regimen is one with a course lasting no longer than 1 year. The maximum effect of the drug is observed after 3 months of treatment;
• Persons with an acute attack of myocardial infarction, in which an increase in the ST segment is observed: it is necessary to take the drug 75 mg once a day, starting with a loading dose of 300 mg, in combination with aspirin and thrombolytics or without them. At the same time, persons over 75 years of age should begin treatment without using a loading dose. Complex treatment should be started as soon as possible after the onset of signs of the disorder, and continued for at least 1 month. In this category of patients, the benefits of using Zilt in combination with aspirin for a period longer than 4 weeks have not been studied.

People with atrial fibrillation need to take the medicine in the amount of 75 mg once a day. Aspirin is also used together with the medicine (in a daily dosage of 75-100 mg).

If a dose is missed:

• if less than 12 hours have passed since the time at which the medication is usually taken, the missed dose must be taken immediately and the next dose taken at the standard time;
• If an interval of more than 12 hours has passed, the patient must take the next tablet in order at the standard time. Doubling the dose to compensate for the missed one is prohibited.

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Use Zilta during pregnancy

Since there is no information about the effects of clopidogrel on pregnant women, the drug is contraindicated during this period of time.

There is also no information on the passage of clopidogrel into breast milk, therefore, breastfeeding should be discontinued while using the drug.

No negative impact of Zilt on the fertility level of laboratory animals was detected.

Contraindications

Among the contraindications:

• hypersensitivity to the active component of the drug or its other auxiliary elements;
• severe liver dysfunction;
• acute form of bleeding (for example, intracranial hemorrhage or ulcer);
• There is no information on the use of the drug in childhood or adolescence.

Side effects Zilta

The use of the drug may provoke the appearance of certain side effects:

• disorders of lymph and systemic blood flow: development of leukopenia, neutro- (including severe forms), granulocyto-, pancyto- or thrombocytopenia (also severe), as well as eosinophilia. In addition, TTP, anemia (both normal and aplastic), agranulocytosis, and acquired hemophilia may be observed;
• immune manifestations: development of serum sickness, as well as anaphylactoid symptoms. Cross-intolerance between thienopyridines (eg, prasugrel or ticlopidine) may also develop;
• mental disorders: feeling of confusion, as well as the appearance of hallucinations;
• reactions of the nervous system: bleeding inside the skull (sometimes leading to death), paresthesia, dizziness, taste bud disorders and headaches;
• problems with the visual organs: hemorrhage in the eyes (in the conjunctiva, as well as retinal or ocular hemorrhage);
• manifestations in the vascular system: severe hemorrhage, the appearance of vasculitis, hematoma, bleeding from a surgical wound, as well as a decrease in blood pressure;
• disorders of the respiratory system, sternum organs, and mediastinum: nosebleeds, as well as bleeding in the respiratory duct area (bleeding in the lungs, as well as hemoptysis), bronchial spasms, fibrosing alveolitis, and eosinophilic pneumonia;
• manifestations in the gastrointestinal tract: bleeding in this area, abdominal pain, diarrhea, dyspeptic manifestations, gastritis, bloating, as well as vomiting and ulcerative pathology in the stomach or duodenum. In addition, nausea, retroperitoneal hemorrhages, gastrointestinal and retroperitoneal bleeding (fatal), as well as stomatitis and pancreatitis with colitis (this includes its lymphocytic or ulcerative form) develop;
• manifestations from the biliary tract and liver: acute liver dysfunction, hepatitis, as well as abnormal levels of functional liver parameters;
• manifestations in the subcutaneous layer and skin: rashes, subcutaneous hemorrhage, itching, purpura, and bullous dermatitis (TEN, erythema multiforme, and Stevens-Johnson syndrome). In addition, Quincke's edema, erythematous rash, urticaria, drug intolerance syndrome, drug-type rash accompanied by eosinophilia, as well as general symptoms (the so-called DRESS syndrome), and lichen planus or eczema develop;
• connective tissues and bone structure with muscles: development of myalgia, hemarthrosis, arthralgia or arthritis;
• disorders of the urinary system and kidneys: development of glomerulonephritis or hematuria, as well as an increase in creatinine levels;
• systemic disorders: feverish state;
• changes in the results of instrumental and laboratory tests: a decrease in the number of platelets with neutrophils, as well as prolongation of bleeding time.

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Overdose

As a result of an overdose, the bleeding period may be prolonged with further development of complications.

Treatment is aimed at eliminating the manifestations of the disorder. The drug has no antidote. If immediate correction of prolonged bleeding is required, the effects of the drug can be eliminated by transfusing platelet mass.

Interactions with other drugs

Oral anticoagulants.

Combination with these drugs is not recommended because such a combination may provoke an increase in the intensity of bleeding. Although the use of clopidogrel at a daily dose of 75 mg does not affect the pharmacokinetics of S-warfarin or the INR in people who are treated with warfarin for a long time, the combined use of these drugs increases the likelihood of bleeding due to the presence of independent effects on the hemostasis process.

Drugs that inhibit the activity of glycoprotein IIb/IIIa.

Clopidogrel should be used with caution in patients at increased risk of bleeding due to surgery, trauma, or other disorders, together with agents that inhibit glycoprotein IIb/IIIa.

Aspirin.

Aspirin does not affect ADP-induced platelet aggregation due to clopidogrel, but clopidogrel potentiates the effect of aspirin on collagen-induced platelet aggregation. Although the combined use of 500 mg aspirin twice daily during the first day did not cause a significant increase in bleeding time, which is increased by the use of clopidogrel. Since aspirin and clopidogrel can interact, increasing the likelihood of bleeding, the combined use of these drugs should be done with caution. But there are data on the parallel use of Zilt with aspirin for up to 12 months.

Heparin.

Since the drug interaction with heparin increases the likelihood of bleeding, these medications must be combined with caution.

Thrombolytic drugs.

The safety of the combined use of clopidogrel, as well as heparin and fibrin-specific or non-fibrin-specific thrombolytics, was assessed in people with acute myocardial infarction. The incidence of drug-related bleeding was similar to that observed with the combined use of thrombolytic drugs and aspirin with heparin.

NSAIDs.

Combination of the drug with naproxen increases the incidence of hidden bleeding within the gastrointestinal tract. However, it has not yet been possible to determine whether the likelihood of gastrointestinal bleeding increases with the use of any NSAID. For this reason, caution is required when combining the drug with NSAIDs (this also includes COX-2 inhibitors).

Combination with other medications.

Since clopidogrel is transformed into its active degradation product, and this occurs partly through the action of the CYP2C19 element, therefore the use of drugs that reduce the activity of this enzyme will probably also reduce the plasma values of the metabolite. To prevent such an effect, it is necessary to avoid combined use of the drug with strong or moderate inhibitors of the CYP2C19 element.

Drugs that reduce the effectiveness of CYP2C19 include esomeprazole, voriconazole with omeprazole, fluoxetine, fluconazole with fluvoxamine, as well as ticlopidine with moclobemide, cimetidine with chloramphenicol, ciprofloxacin, and oxcarbazepine with carbamazepine.

PPI drugs.

A single daily dose of omeprazole 80 mg, in combination with clopidogrel or when these drugs are taken within 12 hours, the level of the active decay product decreased by 45% (with a loading dose) and 40% (with a maintenance dose). Against the background of such a decrease, the inhibition of platelet aggregation also decreased - by 39% (with a loading dose) and by 21% (with a maintenance dose). It can be expected that the drug will have a similar interaction with esomeprazole. Therefore, taking the above drugs in combination is not recommended.

A less noticeable decrease in the level of the metabolite in the blood was noted in the case of a combination with lansoprazole or pantoprazole. It is quite possible to use Zilt and pantoprazole in combination.

Combination therapy with other medications.

Antacids do not affect the degree of absorption of clopidogrel. Carboxyl degradation products of the substance are capable of inhibiting the activity of hemoprotein P450 2C9. As a result, the plasma value of the following drugs may increase - tolbutamide, phenytoin, as well as NSAIDs metabolized with the participation of hemoprotein P450 2C9. Tolbutamide with phenytoin is allowed to be combined with clopidogrel.

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Storage conditions

Zilt must be kept in a place protected from moisture and sunlight, and inaccessible to small children.

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Special instructions

Reviews

Zilt is considered a very effective medication. Its advantage is also considered to be a fairly low price (in comparison with other analogues). Reviews show that the drug is highly effective in case of use after stent installation, as well as after a heart attack. Improvement in health, disappearance of angina attacks and thrombosis in the veins with arteries are noted.

Among the disadvantages - individual patients report the development of side effects (such as severe dyspnea and urticaria). But with continued therapy, these negative manifestations disappear on their own after a short period of time.

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Shelf life

Zilt can be used for a period of 3 years from the date of manufacture of the medicinal product.