Pharmacological properties of the drug Zilt
By preventing the binding of ADP to receptors located on the surface of platelets and the activation of the GP IIb/IIIa complex, clopidogrel inhibits ADP-dependent platelet aggregation. Clopidogrel also inhibits platelet aggregation caused by other factors. The effect of clopidogrel persists throughout the life of platelets. With prolonged use of clopidogrel at a therapeutic dose (75 mg/day), a noticeable inhibition of platelet aggregation occurs already on the 1st day of treatment, then the antiplatelet effect gradually increases and reaches a maximum after 3–7 days of regular use of the drug. With prolonged use of clopidogrel at a therapeutic dose, the average level of inhibition of platelet aggregation is 40–60%. After cessation of treatment, the effect of clopidogrel on aggregation and bleeding duration disappears, usually after 5 days. After oral administration, clopidogrel is rapidly absorbed (the time to reach maximum plasma concentration is 0.7–0.8 hours). After 2 hours, the drug is no longer detectable in the blood plasma. Absorption is approximately 50% and does not depend on simultaneous food intake. The main part of clopidogrel and its main metabolite (98 and 94%, respectively) is reversibly bound to plasma proteins. Clopidogrel is a prodrug. Metabolized in the liver, the main metabolite is a pharmacologically inactive derivative of carboxylic acid. Its concentration in blood serum is 85% of the total amount of the drug. Maximum serum concentrations are achieved approximately 1 hour after administration. The active metabolite, a thiol derivative, is formed by the oxidation of clopidogrel to 2-oxoclopidogrel, followed by hydrolysis. This oxidation occurs with the participation of cytochrome P450. This active metabolite, which can be isolated in vitro , quickly and irreversibly binds to platelet receptors and inhibits their aggregation. It is not detected in blood serum. After a single or repeated dose, 50% of the administered dose of clopidogrel is excreted in the urine and 46% in the feces. The half-life of the main metabolite after a single or repeated dose of the drug is 8 hours.
Zilt, 28 pcs., 75 mg, film-coated tablets
Anticoagulants for oral administration:
simultaneous use of clopidogrel and oral anticoagulants may increase the intensity of bleeding, and therefore the use of this combination is not recommended.
The use of clopidogrel at a dose of 75 mg/day does not change the pharmacokinetics of warfarin (CYP2C9 isoenzyme substrate) or INR in patients receiving long-term warfarin. However, simultaneous use with warfarin increases the risk of bleeding due to its independent additional effect on blood clotting. Therefore, caution should be exercised when using warfarin and clopidogrel simultaneously.
Glycoprotein IIb/IIIa inhibitors:
simultaneous use of clopidogrel and glycoprotein IIb/IIIa inhibitors requires caution in patients with an increased risk of bleeding (in case of trauma, surgery or other pathological conditions) (see “Special Instructions”).
Acetylsalicylic acid:
Acetylsalicylic acid does not affect clopidogrel-induced inhibition of ADP-induced platelet aggregation, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, simultaneous administration of 500 mg of acetylsalicylic acid 2 times a day for one day does not significantly prolong the bleeding time caused by taking clopidogrel. The pharmacodynamic interaction between clopidogrel and acetylsalicylic acid may lead to an increased risk of bleeding. Given this, caution should be exercised when taking these drugs concomitantly, although in clinical studies, patients received combination therapy with clopidogrel and acetylsalicylic acid for one year.
Heparin:
According to a clinical study, in healthy individuals, when taking clopidogrel, no change in the dose of heparin was required, and the anticoagulant effect of heparin did not change. Concomitant use of heparin had no effect on the suppression of platelet aggregation by clopidogrel. There may be a pharmacodynamic interaction between clopidogrel and heparin, leading to an increased risk of bleeding. Therefore, the simultaneous use of these drugs requires caution.
Thrombolytics:
The safety of simultaneous use of clopidogrel, fibrin-specific or fibrin-specific thrombolytics and heparin was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was comparable to their frequency with the simultaneous use of thrombolytics, heparin with acetylsalicylic acid.
NSAIDs:
According to a clinical study involving healthy volunteers, the simultaneous use of clopidogrel and naproxen increased occult gastrointestinal bleeding. However, due to the lack of interaction studies with other NSAIDs at this time, it is unknown whether the risk of gastrointestinal bleeding is increased when used together with other NSAIDs. Therefore, simultaneous therapy with NSAIDs, including COX-2 inhibitors, and clopidogrel should be carried out with caution (see "Special Instructions").
CYP2C19 isoenzyme inhibitors:
Clopidogrel is metabolized to the formation of its active metabolite, partly under the influence of the CYP2C19 isoenzyme. Therefore, drugs that inhibit this isoenzyme may cause a decrease in the concentration of the active metabolite of clopidogrel. The clinical significance of this interaction is unknown.
Concomitant use with strong or moderate inhibitors of the CYP2C19 isoenzyme should be avoided. Inhibitors of the CYP2C19 isoenzyme include: omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.
Proton pump inhibitors:
the use of omeprazole at a dose of 80 mg 1 time per day simultaneously with clopidogrel or with a 12-hour break between taking the two drugs reduced the systemic exposure (AUC) of the active metabolite of clopidogrel by 45% (after taking a loading dose of clopidogrel) and by 40% (after taking maintenance dose of clopidogrel). A decrease in the AUC of the active metabolite of clopidogrel is associated with a decrease in the degree of inhibition of platelet aggregation (39% after taking a loading dose of clopidogrel and 21% after taking a maintenance dose of clopidogrel). A similar interaction between clopidogrel and esomeprazole is expected.
Observational and clinical studies have reported conflicting data on clinical manifestations of the cardiovascular system regarding this pharmacokinetic/pharmacodynamic interaction. Concomitant use with omeprazole or esomeprazole should be avoided.
Proton pump inhibitors with minimal inhibitory effects on the CYP2C19 isoenzyme include pantoprazole and lansoprazole.
With simultaneous use of pantoprazole at a dose of 80 mg 1 time per day, a decrease in the concentration of the active metabolite of clopidogrel in the blood plasma was observed 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 the degree of inhibition of platelet aggregation by an average of 15 and 11%, respectively. Therefore, the simultaneous use of clopidogrel with pantoprazole is possible.
Other medicines
When studying the pharmacodynamic and pharmacokinetic interactions of clopidogrel and other drugs, the following was revealed:
- with simultaneous use of clopidogrel with atenolol and/or nifedipine, no clinically significant pharmacodynamic interaction was detected;
- the pharmacodynamic activity of clopidogrel did not change significantly when used simultaneously 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 can be safely used concomitantly with clopidogrel. It is unlikely that clopidogrel can affect the metabolism of other drugs, such as phenytoin and tolbutamide, as well as NSAIDs, which are metabolized by the CYP2C9 isoenzyme;
- diuretics, beta-blockers, ACE inhibitors, CCBs, lipid-lowering agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, drugs used in hormone replacement therapy: no clinically significant adverse interactions were identified in clinical studies.
Side effects of the drug Zilt
General reactions : chest pain, increased fatigue, asthenia. From the nervous system : headache, dizziness, paresthesia, leg cramps, hypoesthesia, neuralgia, loss of consciousness. From the cardiovascular system : peripheral edema, hypertension (arterial hypertension), heart failure, tachycardia. From the gastrointestinal tract : abdominal pain, dyspepsia, diarrhea, nausea, constipation, vomiting, flatulence, impaired taste, perforation of a stomach ulcer, hemorrhagic gastritis, gastrointestinal bleeding. From the liver and biliary tract : increased activity of liver transaminases, hyperbilirubinemia, hepatitis, liver steatosis. From the blood system : thrombocytopenia, anemia (aplastic or hypochromic), agranulocytosis, granulocytopenia, leukocytosis, leukopenia, neutropenia. From the blood coagulation system : nosebleeds, gastrointestinal bleeding, hemarthrosis, bleeding from the urinary tract, hemoptysis, intracranial hemorrhage, retroperitoneal bleeding, bleeding from a postoperative wound, hemorrhage in the eye, hemothorax, pulmonary hemorrhage, allergic purpura, thrombocytopenic purpura. From the musculoskeletal system: back pain, arthritis, arthrosis. From the central nervous system: depression. From the respiratory system : inflammation of the upper respiratory tract, shortness of breath, rhinitis, bronchitis, cough, pneumonia, sinusitis. Skin : rash, itching, eczema, skin ulcers, bullous dermatitis, erythematous rash, maculopapular rash, urticaria. From the senses : cataracts, conjunctivitis. From the genitourinary system : urinary tract infection, cystitis, hypermenorrhea, isolated cases of hemolytic uremic syndrome and membranous nephropathy. Allergic reactions: isolated cases of hypersensitivity reactions (angioedema, bronchospasm, anaphylaxis).
Special instructions for the use of the drug Zilt
In patients with myocardial infarction, it is not recommended to begin treatment with clopidogrel in the first few days after the infarction. Clopidogrel increases the duration of bleeding. The drug should be used with caution in patients with an increased risk of bleeding due to injury, surgery or other pathological conditions, as well as in patients with a tendency to bleeding (gastrointestinal bleeding, hemorrhage in the eye). Treatment with clopidogrel must be discontinued at least 7 days before planned surgery (including dental procedures). Patients should be warned that during treatment with clopidogrel there is an increased risk of bleeding and that bleeding may continue longer than usual and then stop spontaneously. For minor cuts (during shaving) or other household injuries, special measures are usually not required to stop bleeding. If significant cuts or injuries occur, seek immediate medical attention. Due to insufficient experience with the use of clopidogrel in patients with impaired renal function, caution should be exercised when using the drug. If liver function is significantly impaired, the risk of bleeding increases, so clopidogrel should be used with caution in these patients. The safety and effectiveness of clopidogrel in children and adolescents under 18 years of age has not been established, therefore the drug is not prescribed to patients in this age group. Due to the lack of data, clopidogrel is not recommended for use during pregnancy and lactation. The drug can affect the psychophysical state, which is manifested by weakening of attention, slowing of psychomotor reactions and requires caution when driving vehicles and working with potentially dangerous mechanisms.
Zyllt®
Medicines that are associated with a risk of bleeding
There is an increased risk of bleeding due to the potential additive effect with clopidogrel. The concomitant use of clopidogrel with drugs that are associated with a risk of bleeding should be done with caution.
Thrombomytics
The safety of concomitant use of clopidogrel, fibrin-specific or fibrin-nonspecific thrombolytic agents and heparin has been studied in patients with acute myocardial infarction.
The incidence of clinically significant bleeding was similar to that observed with concomitant use of thrombotic agents and heparin.
IIb / IIIa receptor
blockers Due to the possibility of pharmacodynamic interaction between clopidogrel and IIb/IIIa receptor blockers, their simultaneous use requires caution, especially in patients with an increased risk of bleeding (in case of trauma and surgery or other pathological conditions) (see . section "Special instructions").
Injectable anticoagulants (eg, heparin)
According to a clinical study conducted in healthy volunteers, no change in heparin dose was required when taking clopidogrel. The anticoagulant effect of heparin did not change. Concomitant use of heparin did not change the antiplatelet effect of clopidogrel. There may be a pharmacodynamic interaction between clopidogrel and heparin, which may increase the risk of bleeding. When used simultaneously, caution should be exercised (see section "Special Instructions").
Oral anticoagulants (eg, warfarin)
Although taking clopidogrel 75 mg per day did not change the pharmacokinetics of warfarin (CYP2C9 isoenzyme substrate) or the INR in patients receiving long-term warfarin treatment, concomitant use of clopidogrel increases the risk of bleeding due to its independent additive effect on blood clotting. Therefore, caution should be exercised when taking warfarin and clopidogrel simultaneously.
ASK
ASA does not alter the ADP-induced platelet aggregation inhibitory effect of clopidogrel, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. However, simultaneous administration of ASA 500 mg 2 times a day with clopidogrel for one day did not cause a significant increase in the bleeding time caused by taking clopidogrel. There may be a pharmacodynamic interaction between clopidogrel and ASA, which leads to an increased risk of bleeding, so caution should be exercised when using them simultaneously. However, in clinical studies, patients received combination therapy with clopidogrel and ASA (75-325 mg once daily) for up to one year.
In a clinical study conducted in healthy volunteers, coadministration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies between clopidogrel and other NSAIDs, it is currently unknown whether there is an increased risk of gastrointestinal bleeding when clopidogrel is taken with other NSAIDs. Therefore, the use of NSAIDs, including COX-2 inhibitors, in combination with clopidogrel should be used with caution (see section "Special Instructions").
Since SSRIs impair platelet activation and increase the risk of bleeding, concomitant use of SSRIs with clopidogrel should be done with caution.
Inducers of isoenzyme C Y Р2С19
Since clopidogrel is metabolized to its active metabolite in part by the CYP2C19 isoenzyme, it is expected that the use of drugs that induce the activity of this isoenzyme may lead to an increase in the concentration of the active metabolite of clopidogrel in the blood plasma.
Rifampicin, being a powerful inducer of the CYP2C19 isoenzyme, when used simultaneously with clopidogrel, leads to both an increase in the concentration of the active metabolite of clopidogrel in the blood plasma and platelet inhibition, which may increase the risk of bleeding. As a precautionary measure, it is not recommended to use simultaneously powerful inducers of the CYP2C19 isoenzyme and clopidogrel (see section “Special instructions”).
Inhibitors of isoenzyme C Y Р2С9
Since clopidogrel is metabolized to the formation of its active metabolite in part by the CYP2C19 isoenzyme, the use of drugs that inhibit this isoenzyme may lead to a decrease in the formation of the active metabolite of clopidogrel.
The clinical significance of this interaction has not been established. As a precaution, the simultaneous use of clopidogrel and strong or moderate inhibitors of the CYP2C9 isoenzyme should be avoided. Potent and moderate inhibitors of the CYP2C9 isoenzyme are omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol and efavirenz.
Avoid simultaneous use with clopidogrel of proton pump inhibitors that are strong or moderate inhibitors of the CYP2C19 isoenzyme (for example, omeprazole, esomeprazole) (see sections “Pharmacological properties. Pharmacogenetics”, “Special instructions”). If proton pump inhibitors are to be taken concomitantly with clopidogrel, the proton pump inhibitor with the least CYP2C19 inhibition, such as pantoprazole and lansoprazole, should be taken.
There is no evidence of the effect of other drugs that reduce gastric acidity, such as H2 blockers or antacids, on the antiplatelet effect of clopidogrel.
Other medicines
A number of clinical studies have been conducted with clopidogrel and other concomitantly administered drugs to study possible pharmacodynamic and pharmacokinetic interactions, which showed that:
When clopidogrel was used in combination with atenolol, nifedipine, or with both of these drugs taken simultaneously, no clinically significant pharmacodynamic interaction was observed;
simultaneous use of phenobarbital and estrogens did not have a significant effect on the pharmacodynamics of clopidogrel;
the pharmacokinetic parameters of digoxin and theophylline did not change when they were used together with clopidogrel;
antacids did not reduce the absorption of clopidogrel;
Phenytoin and tolbutamide can be safely 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, which are metabolized by the CYP2C9 isoenzyme of the cytochrome P450 system;
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 (IIb/IIIa receptors: in clinical studies no clinically significant adverse interactions were identified.
Medicines that are substrates of the C Y P2C8
Clopidogrel was shown to increase the systemic exposure of repaglinide in healthy volunteers. In
vitro
studies have shown that the increase in systemic exposure of repaglinide is a consequence of inhibition of the CYP2C8 isoenzyme by the glucuronide metabolite of clopidogrel. Caution should be exercised during the simultaneous use of clopidogrel and drugs that are predominantly excreted from the body by metabolism via the CYP2C8 isoenzyme (for example, repaglinide, paclitaxel) due to the risk of increasing their plasma concentrations (see section "Special Instructions").
Opioid agonists _
As with other oral P2Y12 inhibitors, concomitant use of opioid agonists may delay and reduce the absorption of clopidogrel, possibly by reducing the rate of gastric emptying. The clinical significance of this interaction is unknown. Consider the use of a parenteral antiplatelet agent in patients with acute coronary syndrome who require concomitant use of morphine or other opiate agonists.
Intensified antiretroviral therapy (ART)
HIV-infected patients receiving intensified ART are at high risk of developing vascular events. Significant reductions in platelet aggregation suppression have been demonstrated in HIV-infected patients receiving ART boosted with ritonavir or cobicistat.
Although the clinical significance of these findings has not been definitively confirmed, spontaneous reports have described HIV-infected patients receiving ritonavir-boosted ART who experienced reocclusion after disobstruction or thrombotic events while receiving a loading dose of clopidogrel. The mean IAT may be reduced when clopidogrel is used concomitantly with ritonavir. Therefore, concomitant use of clopidogrel with intensified ART is not recommended.
Drug interactions Zilt
Due to the increased risk of bleeding, simultaneous use of clopidogrel and warfarin is not recommended. When clopidogrel is used concomitantly with heparin or other thrombolytic agents, the risk of bleeding may increase, so the combined use of these drugs requires caution. The simultaneous use of clopidogrel and NSAIDs increases the risk of ulcerogenic effects and the development of bleeding from ulcers, so the use of clopidogrel with NSAIDs requires caution. With simultaneous use of clopidogrel with atenolol, nifedipine, digoxin, phenobarbital, cimetidine, estrogens or theophylline, no clinically significant interaction was observed. There is data on the safety of simultaneous use of clopidogrel with phenytoin and tolbutamide. Antacids do not affect the absorption of clopidogrel.
Zyllt®
The simultaneous use of clopidogrel and oral anticoagulants is not recommended (the intensity of bleeding may increase).
The simultaneous use of clopidogrel and IIb/IIIa receptor blockers requires caution in patients with an increased risk of bleeding (in case of trauma, surgery or other pathological conditions requiring simultaneous use of glycoprotein IIb/IIIa inhibitors).
Acetylsalicylic acid (ASA) does not affect the clopidogrel-induced suppression of ADP-induced platelet aggregation, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. However, simultaneous administration of ASA at a dose of 500 mg 2 times a day for one day does not significantly prolong the bleeding time caused by taking clopidogrel. Pharmacodynamic interaction between clopidogrel and ASA is possible and leads to an increased risk of bleeding. Given this, caution should be exercised when taking these drugs concomitantly, although in clinical studies, patients received combination therapy with clopidogrel and ASA for one year.
According to a clinical study in healthy individuals, when taking clopidogrel, no change in the dose of heparin was required, and the anticoagulant effect of heparin did not change. Co-administration of heparin had no effect on the suppression of platelet aggregation by clopidogrel. There may be a 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 non-specific thrombolytics and heparin was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was comparable to that with the simultaneous use of thrombolytics, heparin and ASA.
In a clinical study in healthy volunteers, concomitant use of clopidogrel and naproxen increased occult gastrointestinal bleeding. However, due to a lack of interaction studies with other NSAIDs, it is currently unknown whether the risk of gastrointestinal bleeding is increased for all NSAIDs. Therefore, simultaneous therapy with NSAIDs, including COX-2 inhibitors, and clopidogrel should be carried out with caution.
Other combination therapy: Several clinical studies have been conducted with clopidogrel and other concomitantly administered medicinal products to examine possible pharmacodynamic and pharmacokinetic interactions.
— with simultaneous use of clopidogrel with atenolol and/or nifedipine, no clinically significant pharmacodynamic interaction was detected;
- the pharmacodynamic activity of clopidogrel did not change significantly when combined 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 can be safely combined with clopidogrel. However, it is possible to inhibit the activity of cytochrome P450 using the 2C9 isoenzyme with the carboxyl metabolite of clopidogrel. This could potentially lead to increased plasma concentrations of drugs such as phenytoin and tolbutamide, as well as NSAIDs that are metabolized by cytochrome P450 2C9;
- Apart from the specific drug interactions described above, no other studies have been conducted. However, in patients participating in clinical studies with clopidogrel and concomitantly taking diuretics, beta-blockers, ACE inhibitors, calcium antagonists, lipid-lowering agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs and antagonists glycoprotein IIb/IIIa, no clinically significant interactions were identified.
Overdose of the drug Zilt, symptoms and treatment
One case of an intentional overdose of clopidogrel has been described, when a 34-year-old woman with suicidal intent took 1050 mg (14 tablets) of clopidogrel. There were no symptoms of overdose or complications noted, no special treatment was performed. After healthy volunteers took 600 mg of clopidogrel, no side effects (except for a 1.7-fold increase in bleeding time) were noted. There is no specific antidote. The effects of clopidogrel can be reversed by platelet transfusion.
