Clopidogrel, 75 mg 30 pcs

Pharmacotherapeutic group: anti-aggregant drug

ATX code: B01AC04

Pharmacological properties

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 adenosine diphosphate (ADP) binding to the P2Y₁₂ receptor of platelets and subsequent ADP-mediated activation of the glycoprotein IIb/IIIa complex, leading to suppression of platelet aggregation. Through irreversible binding, platelets remain immune to ADP stimulation for the remainder of their lives (approximately 7-10 days), and recovery of normal platelet function occurs at a rate consistent with the rate of platelet renewal. Platelet aggregation caused by agonists other than ADP is also inhibited by blocking enhanced platelet activation by the released ADP.

Because formation of the active metabolite occurs via cytochrome P450 system isoenzymes, some of which may be polymorphic or may be inhibited by other drugs, not all patients may adequately inhibit platelet aggregation (see subsection “Pharmacogenetics” under “Pharmacological properties”).

Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular in cerebral, coronary or peripheral arteries.

When clopidogrel is taken daily at a dose of 75 mg a significant suppression of ADP-induced platelet aggregation is noted from the first day of administration, which gradually increases after 3-7 days and then reaches a constant level (when equilibrium state is reached). In the equilibrium state platelet aggregation is suppressed by an average of
40-60%. Platelet aggregation and bleeding time return to baseline on average within 5 days after discontinuation of clopidogrel.

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 prolongation of bleeding time. In the large controlled CAPRIE trial (clopidogrel versus acetylsalicylic acid (ASA) in patients at risk for ischemic events), the rates of clinical outcomes, other adverse events, and abnormal clinical and laboratory parameters were similar in both men and women.

Pharmacokinetics

Indications

Prevention of atherothrombotic complications:

– In patients with myocardial infarction (several days to 35 days old), ischemic stroke (7 days to 6 months old), or diagnosed peripheral artery occlusive disease.

– in patients with acute coronary syndrome:

– Without ST-segment elevation (unstable angina or myocardial infarction without a Q-wave), including patients who have had stenting for percutaneous coronary intervention (in combination with acetylsalicylic acid);

– with ST-segment elevation (acute myocardial infarction) with drug treatment and the possibility of thrombolysis (in combination with acetylsalicylic acid).

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

. In patients with atrial fibrillation (atrial fibrillation) who have at least one risk factor for vascular complications, cannot take indirect anticoagulants, and have a low risk of bleeding (in combination with ASA).

Active ingredient

Composition

1 film-coated tablet contains:

Composition of the tablet core:

Active ingredient: clopidogrel hydrosulfate –

97.87 mg (in terms of clopidogrel – 75.0 mg);

Excipients: Anhydrous lactose, 60.0 mg; microcrystalline cellulose, 69.93 mg; colloidal silicon dioxide,

6.0 mg; crosspovidone, 12.0 mg; hyprolose, 1.2 mg; glyceryl dibegenate, 3.0 mg.

Particle coating composition: opadray II pink (85F34610) – 8.00 mg (polyvinyl alcohol – 40%, titanium dioxide – 24.24%, macrogol 3350 – 20.2%, talc – 14.8%, iron oxide yellow – 0.37%, iron oxide red – 0.36%, iron oxide black – 0.03%).

How to take, the dosage

Ingestion, regardless of meals.

Patients with normal CYP2C19 isoenzyme activity

Myocardial infarction, ischemic stroke or diagnosed peripheral artery occlusive disease.

1 film-coated tablet (75 mg) once daily.

In patients with myocardial infarction (MI), 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)

The treatment with clopidogrel can be started in the first days before the 35th day of MI. Treatment with clopidogrel should be started with a single loading dose of 300 mg and then continued with a dose of
75 mg once daily (in combination 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 optimal duration of treatment for this indication has not been officially determined. The results of clinical studies confirm the appropriateness of the drug up to 12 months after the development of acute coronary syndrome without ST-segment elevation. Maximum favorable effect is observed by the third month of treatment.

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

Clopidogrel is indicated as a single dose of 75 mg once daily with an initial single loading dose of clopidogrel 300 mg in combination with ASA and thrombolytics (or without thrombolytics). In patients over 75 years old, treatment with clopidogrel should be started without its loading dose. Combination therapy should be started as soon as possible after the onset of symptoms and continued for at least four weeks. The effectiveness of combined use of clopidogrel and acetylsalicylic acid beyond 4 weeks in this indication has not been studied.

Atrial fibrillation (atrial fibrillation)

Clopidogrel should be taken once daily in a dose of 75 mg. In combination with clopidogrel, ASA should be started and then continued
(75-100 mg/day).

Missing the next dose

If less than 12 hours have passed since the next dose was missed, take the missed dose immediately and then take the next doses at the usual time.

If more than 12 hours have passed since the next dose was missed, the patient should take the next dose at the usual time (do not take a double dose).

Patients with genetically determined reduced CYP2C19 isoenzyme activity

Slow CYP2C19-metabolizer status is associated with decreased antiaggregant effect of clopidogrel. A higher dose regimen (600 mg – loading dose, then 150 mg once daily) in slow metabolizers increases the antiaggregant effect of clopidogrel (see section “Pharmacokinetics”). However, the optimal dosing regimen for patients with decreased activity of CYP2C19 isoenzyme has not yet been established in clinical trials.

Special patient groups

Elderly patients

Dose adjustment is not required.

Patients in pediatric patients

There is no experience with the drug in children.

Patients with impaired renal function

. After repeated administration of clopidogrel in dose 75 mg/day in patients with severe renal impairment (creatinine clearance from 5 to 15 ml/min) inhibition of ADP-induced platelet aggregation (25%) was less than in healthy volunteers, but prolongation of bleeding time was similar to that in healthy volunteers who received clopidogrel in dose 75 mg daily. In addition, all patients had good tolerability of the drug.

Patients with hepatic impairment

After 10 days of daily use of clopidogrel at a daily dose of
75 mg in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean bleeding time was also comparable in both groups.

Patients of different racial backgrounds

The prevalence of CYP2C19 isoenzyme gene alleles responsible for the intermediate and reduced metabolism of clopidogrel to its active metabolite varies among different ethnic groups (see section “Pharmacogenetics”). Only limited literature data are available for members of the Mongoloid race to assess the clinical relevance of CYP2C19 isoenzyme genotyping in predicting the development of ischemic complications.

Interaction

The administration of glycoprotein IIb/IIIa inhibitors together with clopidogrel requires caution in patients with increased risk of bleeding (in trauma and surgery or other pathological conditions) (see section “Special Precautions”).

Acetylsalicylic acid: ASA does not change the effect of clopidogrel inhibiting ADP-induced platelet aggregation, but clopidogrel increases the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of ASA twice daily for 1 day with clopidogrel did not significantly increase clopidogrel-induced bleeding time. Pharmacodynamic interaction is possible between clopidogrel and ASA, which leads to an increased risk of bleeding. Therefore, caution should be exercised when using them concomitantly, although in clinical trials patients received combined therapy with clopidogrel and ASA for up to one year.

Heparin: according to the data of a clinical study conducted with healthy volunteers, when taking clopidogrel no change in heparin dose was required and its anticoagulant effect was not changed. Co-administration of heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation. There is possible pharmacodynamic interaction between clopidogrel and heparin, which may increase the risk of bleeding, so the simultaneous use of this combination requires caution.

Trombolytics: 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 frequency of clinically significant bleeding was similar to that observed when thrombolytics and heparin were used together with ASA.

Non-steroidal anti-inflammatory drugs (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 taking clopidogrel with other NSAIDs. Therefore, the use of NSAIDs, including COX-2 inhibitors, in combination with clopidogrel should be used with caution.

Selective serotonin reuptake inhibitors (SSRIs): Because SSRIs disrupt platelet activation and increase the risk of bleeding, coadministration of SSRIs with clopidogrel should be used with caution.

CYP2C19 inhibitors

Because clopidogrel is metabolized to its active metabolite partially by the CYP2C19 isoenzyme, use of drugs that inhibit this isoenzyme may result in decreased levels of the active metabolite clopidogrel and decrease its clinical effectiveness. The clinical significance of this interaction has not been established. As a precautionary measure, it is recommended to avoid co-administration of clopidogrel with drugs that inhibit CYP2C19 isoenzyme (omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol).

Proton pump inhibitors

If it becomes necessary to prescribe proton pump inhibitors simultaneously with clopidogrel, the drug with the lowest CYP2C19 inhibition (pantoprazole or lanzoprazole) should be used.

Another combination therapy

A number of clinical studies have been conducted with clopidogrel and other concomitant medications to examine possible pharmacodynamic and pharmacokinetic interactions, which showed that:

– no clinically significant pharmacodynamic interactions were observed when clopidogrel was used together with atenololol, nifedipine, or both drugs concurrently;

– concurrent use of phenobarbital, cimetidine, and estrogen had no significant effect on the pharmacodynamics of clopidogrel;

– the pharmacokinetic parameters of digoxin and theophylline were not altered by their concomitant use with clopidogrel;

– antacids did not decrease absorption of clopidogrel;

– According to the CAPRIE study, phenytoin and tobutamide can be safely used with clopidogrel. It is unlikely that clopidogrel can affect the metabolism of other drugs, such as phenytoin and tobutamide, as well as NSAIDs that are metabolized by CYP2C19 isoenzyme;

– In clinical studies no clinically significant adverse interactions of clopidogrel with angiotensin-converting enzyme inhibitors, diuretics, beta-adrenoblockers, “slow” calcium channel blockers, hypolipidemic agents, coronary vasodilators, hypoglycemic agents (including insulin) have been revealed.including with insulin), antiepileptic drugs, preparations for hormone replacement therapy.

Special Instructions

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.

Because of the risk of bleeding and hematologic adverse effects (see section “Side effects”), if clinical symptoms indicating possible bleeding occur during treatment, clinical blood counts, activated partial thromboplastin time (APTB), platelet counts, platelet functional activity parameters and other necessary tests should be performed urgently.

. Clopidogrel, as well as other antiplatelet agents, should be used with caution in patients who are at increased risk of bleeding due to trauma, surgery or other pathological conditions, as well as in patients receiving ASA, NSAIDs including COX-2 inhibitors, heparin or glycoprotein IIb/IIIa inhibitors, SSRIs and thrombolytics.

The co-administration of clopidogrel with warfarin may increase the intensity of bleeding (see section “Interaction with other medicinal products”), so caution should be exercised when co-administering clopidogrel and warfarin.

If the patient is to have elective surgery and there is no need for antiplatelet effects, clopidogrel should be discontinued 7 days prior to surgery.

Clopidogrel prolongs bleeding time and should be used with caution in patients with conditions 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 clopidogrel is taken (alone or in combination with ASA) and that they should inform their physician if they have unusual bleeding (in location or duration). Patients should tell their doctor (including their dentist) about clopidogrel before any upcoming surgery and before starting any new medication.

Very rare cases of thrombotic thrombocytopenic purpura, characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever, have been reported after clopidogrel use (sometimes even short-term) and are a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

Hypatic function should be monitored during treatment. In severe liver lesions, be aware of the risk of hemorrhagic diathesis.

The drug should be used with caution in patients with impaired renal function.

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

In patients with recent transient cerebral haemorrhage or stroke who have a high risk of recurrent ischemic complications, the combination of ASA and clopidogrel increases the incidence of major bleeding. Therefore, such combination therapy should be used with caution and only if there is proven clinical benefit from its use.

Cases of acquired hemophilia have been reported when taking clopidogrel. If an isolated increase in ACTV is confirmed, 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, the use of clopidogrel at recommended doses produces less of the active metabolite clopidogrel and its antiaggregant effect is less pronounced; therefore, a higher incidence of cardiovascular complications may occur with the commonly recommended doses of clopidogrel in acute coronary syndrome or percutaneous coronary intervention than in patients with normal CYP2C19 isoenzyme activity. Tests are available to determine the CYP2C19 genotype. These tests 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 subsection “Pharmacogenetics” of section “Pharmacological properties”, sections “Caution”, “Dosage and administration”).

The patients’ history of allergic and/or hematological reactions to other thienopyridine derivatives (ticlopidine, prasugrel) should be specified since there have been described cases of cross-allergic and/or hematological reactions between thienopyridines (see section “Adverse effects”). Patients who have previously had allergic and/or hematological reactions to other thienopyridine derivatives require close monitoring during the entire period of therapy to detect signs of hypersensitivity to clopidogrel.

Clopidogrel should not be taken in patients with rare hereditary galactose intolerance, lactose deficiency and glucose-galactose malabsorption syndrome.

The effect of the drug on performance of potentially hazardous activities requiring increased concentration and rapid psychomotor reactions

Clopidogrel has no significant effect on the ability to drive or engage in potentially hazardous activities.

Synopsis

The tablets are round, biconvex, film-coated, pink, with a groove on one side.

Contraindications

– Hypersensitivity to clopidogrel and/or any other component of the drug;

– Severe hepatic impairment;

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

– Rare hereditary galactose intolerance, lactase deficiency, and glucose-galactose malabsorption;

– Pregnancy and breastfeeding (see Pregnancy and breastfeeding (see section “Pregnancy and breastfeeding”);

– Childhood under 18 years of age (safety and effectiveness of use have not been established).

With caution

– In moderate hepatic impairment with possible predisposition to bleeding (limited clinical experience of use).

– In mild to moderate chronic renal failure (limited clinical experience of use).

. – In diseases with predisposition to bleeding (especially gastrointestinal and intraocular), and in patients simultaneously taking medications that can cause gastrointestinal mucosal damage (such as ASA and nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors).

– In patients who have an increased risk of bleeding: Due to trauma, surgery, or other pathological conditions, and in patients treated with ASA, heparin, oral anticoagulants, glycoprotein IIb/IIIa inhibitors, NSAIDs, including selective COX-2 inhibitors, or selective serotonin reuptake inhibitors (SSRIs) (see See section “Special Indications”).

– If there is a history of allergic and hematological reactions to other thienopyridines (such as ticlopidine, prasugrel) due to the possibility of cross-reactions (see section “Special Precautions”).

– In recent transient cerebral circulation disorder or ischemic stroke (when used concomitantly with ASA, see section “Special Precautions”).

Side effects

The following WHO classification is used to estimate the incidence of adverse events:

Very common (≥ 1/10)

Frequent (≥ 1/100 and < 1/10)

Infrequent (≥ 1/1000 and < 1/100)

Rarely (≥ 1/10,000 and < 1/1000)

Very rare (≥ 1/10,000)

The frequency is unknown (it is not possible to determine the incidence of the adverse event from the available data).

Blood and lymphatic system disorders:

infrequent – thrombocytopenia, leukopenia, eosinophilia;

rare – neutropenia, including severe neutropenia;

very rare – thrombotic thrombocytopenic purpura, aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anemia;

frequency unknown – acquired hemophilia A.

The immune system:

very rare – anaphylactic reactions, serum sickness;

frequency unknown – cross-sensitivity to other thienopyridines (e.g., ticlopidine, prasugrel);

Nervous system disorders:

infrequent – intracranial hemorrhage (several cases with fatal outcome), headache, paresthesias, dizziness;

very rare – disorders of taste perception.

Mental disorders:

very rarely – confusion, hallucinations.

Visually impaired:

infrequent – retinal hemorrhage, conjunctival hemorrhage, hemophthalmus.

Hearing organ and labyrinth disorders:

rarely – vertigo.

Skin and subcutaneous tissue disorders:

often – “bruising” (localized subcutaneous hemorrhages);

infrequently – skin rash and itching, thrombocytopenic purpura;

very rare – angioedema, erythematous rash, urticaria, bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), eczema, lichen planus, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations (DRESS syndrome), exfoliative rash.

Renal and urinary tract disorders:

infrequent – hematuria;

very rare – glomerulopathy (including glomerulonephritis), hypercreatininemia.

Musculoskeletal and connective tissue disorders:

very rarely – muscle and joint hemorrhages, arthritis, arthralgia, myalgia.

In the gastrointestinal tract:

very often – gastrointestinal bleeding, diarrhea, abdominal pain, dyspepsia;

infrequently – gastric and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence;

rare – retroperitoneal hemorrhage;

very rare – gastrointestinal bleeding and retroperitoneal hemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative colitis or lymphocytic colitis), stomatitis.

Hepatic and biliary tract disorders:

very rarely – acute liver failure, hepatitis (non-infectious).

Respiratory system, chest and mediastinum:

often – nasal bleeding;

very rare – respiratory bleeding (hemoptysis, pulmonary bleeding), interstitial pneumonitis, bronchospasm, eosinophilic pneumonia.

The cardiovascular system:

often – hematoma;

very rarely – severe bleeding, bleeding from the operating wound, vasculitis, decreased blood pressure.

Laboratory and instrumental findings:

infrequent – prolongation of bleeding time, decreased number of neutrophils and/or platelets in peripheral blood, abnormalities of liver functional tests, increased plasma creatinine concentration.

General disorders and disorders at the site of administration:

often – bleeding from the site of puncture of vessels;

very rarely – increase in body temperature.

Overdose

Symptoms: increased bleeding time with subsequent complications in the form of bleeding development.

Treatment: at the appearance of bleeding requires appropriate treatment measures, platelet transfusion. There is no specific antidote.

Pregnancy use

Animal studies have shown no direct or indirect adverse effects on pregnancy, fetal development, labor, and postnatal development. Because it is not always possible to predict response in humans from animal studies, and because there are no data from controlled clinical trials 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.

In studies in rats, clopidogrel and/or its metabolites have been shown to be excreted into breast milk. There are no data on the excretion of clopidogrel into breast milk in humans. Breastfeeding should be discontinued if clopidogrel is treated.

Similarities