Clopidogrel-SZ, pills 75mg, 60pcs

Composition

Film-coated tablets,75 mg.

Composition (1 table):

• Active ingredient:  clopidogrel hydrosulfate in terms of clopidogrel or clopidogrel bisulfate in terms of clopidogrel-75 mg;
• excipients (core):
• lactose monohydrate (milk sugar) – 38.4 mg, microcrystalline cellulose-129.48 mg, croscarmellose sodium (primellose) – 12.0 mg, colloidal silicon dioxide (aerosil) – 3.12 mg, sodium stearyl fumarate-2.0 mg;
• excipients (shell):
• Opadray II – 8 mg (polyvinyl alcohol, partially hydrolyzed – 3.52 mg, talc – 1.6 mg, titanium dioxide E 171 – 1.5336 mg, macrogol (polyethylene glycol 3350) – 0.988 mg, soy lecithin E 322 – 0.28 mg, aluminum paint based on the dye azorubin – 0.0408 mg, aluminum paint based on the dye crimson [Ponso 4R] – 0.0328 mg, aluminum paint based on the dye Indigo Carmine – 0.0048 mg).

Pharmacological action

Pharmacotherapeutic group:

antiplatelet agent.

ATX Code: [V 01 AC 04]

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 the binding of adenosine diphosphate (ADP) to the P2Y12 platelet receptor and subsequent ADP-mediated activation of the GPIIb/IIIa complex, leading to suppression of platelet aggregation. Due to irreversible binding, platelets remain immune to ADP stimulation for the rest of their life (approximately 7-10 days), and the restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal.

Platelet aggregation caused by agonists other than ADP is also inhibited by blocking enhanced platelet activation by released ADP. Since the formation of the active metabolite occurs with the help of isoenzymes of the P 450 system, some of which may differ in polymorphism or may be inhibited by other drugs, not all patients can adequately suppress platelets. Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular damage, in particular in lesions of the cerebral, coronary or peripheral arteries.

When taking clopidogrel daily at a dose of 75 mg from the first day of use, there is a significant suppression of ADP-induced platelet aggregation, which gradually increases over 3-7 days and then reaches a constant level (when an equilibrium state is reached). At steady state, platelet aggregation is suppressed by an average of 40-60%. After discontinuation of clopidogrel, platelet aggregation and bleeding time gradually return to baseline over an average of 5 days.

Pharmacokinetics

Suction

With a course of oral use at a dose of 75 mg per day, clopidogrel is rapidly absorbed. Average maximum plasma concentrations of unchanged clopidogrel (approximately 2.2-2.5 ng / ml after oral use of a single dose of 75 mg) are reached approximately 45 minutes after use. According to the renal excretion of clopidogrel metabolites, its absorption is approximately 50%.

In vitro distribution clopidogrel and its main circulating inactive metabolite reversibly bind to plasma proteins (by 98% and 94%, respectively) and this bond is unsaturated up to a concentration of 100 mg/l.

Metabolism

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, clopidogrel is metabolized in two ways: the first is via enzymes and subsequent hydrolysis to form an inactive carboxylic acid derivative (85% of the circulating metabolites), and the second is via the cytochrome P 450 system. Initially, clopidogrel is metabolized to 2-oxo-clopidogrel, an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of the active metabolite of clopidogrel, the thiol derivative of clopidogrel. In vitro, this pathway is metabolized by the isoenzymes CYP2CI9, CYP1A2, and CYP2B6. The active thiol metabolite of clopidogrel, which was isolated in vitro studies, binds rapidly and irreversibly to platelet receptors, thus blocking platelet aggregation.

Deduction

Within 120 hours of human ingestion of 14C-labeled clopidogrel, approximately 50% of the radioactivity is excreted by the kidneys and approximately 46% of the radioactivity is excreted through the intestines. After a single oral dose of 75 mg, the elimination half-life of clopidogrel is approximately 6 hours. After a single dose and repeated doses, the elimination half-life of the main inactive metabolite circulating in the blood is 8 hours.

Pharmacogenetics

Both the active metabolite and the intermediate metabolite 2 – oxo-clopidogrel are formed by the isoenzyme SUR2-C19. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel in the study of platelet aggregation ex vivo vary depending on the genotype of the CYP2C19 isoenzyme. The CYP2C19*1 allele corresponds to fully functional metabolism, whereas the CYP2C19 alleles correspond to fully functional metabolism. *2 and CYP2C19*3 are non-functional.

Alleles of the CYP2C19 genes*2 and CYP2C19 * 3 are the cause of decreased metabolism in most representatives of the Caucasian (85%) and Mongoloid race (99%). Other alleles associated with an absence or decrease in metabolism are less common and include, but are not limited to, alleles of the CYP2C19 genes*4, *5, *6, *7 and *8. Patients with low activity of the CYP2C19 isoenzyme should have the two above-mentioned alleles of the gene with loss of function. The published frequencies of phenotypes of individuals with low activity of the CYP2C19 isoenzyme are 2% in Caucasians,4% in Negroes, and 14% in Chinese. Appropriate tests are available to determine the patient’s genotype of the CYP2C19 isoenzyme.

Based on a cross-sectional study (40 volunteers) and a meta-analysis of six studies (335 volunteers). The study group, which included individuals with very high, high, intermediate, and low CYP2C19 isoenzyme activity, did not show any significant differences in the exposure of the active metabolite and in the average values of platelet aggregation inhibition (IAT) (induced by ADP) in volunteers with very high, high, and intermediate CYP2C19 isoenzyme activity. In volunteers with low activity of the CYP2C19 isoenzyme, exposure to the active metabolite decreased compared to volunteers with high activity of the CYP2C19 isoenzyme.

When volunteers with low activity of the CYP2C19 isoenzyme received a 600 mg loading dose/150 mg maintenance dose regimen (600 mg/150 mg), exposure to the active metabolite was higher than when taking the 300 mg/75 mg treatment regimen. In addition, IAT was similar to that in the groups of patients with a higher rate of metabolism using the CYP2C19 isoenzyme, who received a 300 mg/75 mg treatment regimen. However, in studies based on clinical outcomes, the dosage regimen of clopidogrel for patients in this group (patients with low activity of the CYP2C19 isoenzyme) has not yet been established. The clinical studies conducted so far did not have a sufficient sample size to detect differences in the clinical outcome in patients with low activity of the CYP2C19 isoenzyme.

The

pharmacokinetics of the active metabolite of clopidogrel in elderly patients, children, and patients with kidney and liver diseases have not been studied.

Indications

• Prevention of atherothrombotic events in patients who have had a myocardial infarction (from a few days to 35 days ago), an ischemic stroke (from 7 days to 6 months ago), or who have been diagnosed with occlusive peripheral artery disease.
• Prevention of atherothrombotic events (in combination with acetylsalicylic acid) in patients with acute coronary syndrome:
  • non-ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), including patients who underwent stenting during percutaneous coronary intervention;
  • with ST-segment elevation (acute myocardial infarction) during drug treatment and the possibility of thrombolysis.

Contraindications

• Hypersensitivity to clopidogrel or any of the excipients of the drug.
• Severe liver failure.
• Acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage.
• Rare hereditary problems of lactose intolerance, lactase deficiency, and glucose-galactose malabsorption.
• Pregnancy and lactation (see “Pregnancy and lactation”).
• Children under 18 years of age (safety and efficacy have not been established).

With caution:

• Moderate hepatic insufficiency, with a possible predisposition to bleeding (limited clinical experience).
• Renal failure (limited clinical experience).
• Trauma, surgical procedures (see “Special instructions”).
• Diseases that have a predisposition to the development of bleeding (especially gastrointestinal or intraocular).
• Concomitant use of nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 (COX-2) inhibitors.
• Concomitant use of warfarin, heparin, and glycoprotein IIb/IIIa inhibitors.
• In patients with a genetically determined decrease in the function of the SUR2C19 isoenzyme at the recommended doses (there are literature data indicating that patients with a genetically determined decrease in the function of the SUR2C19 isoenzyme are exposed to less systemic exposure to the active metabolite of clopidogrel and have a less pronounced effect of the drug, in addition, they may have a higher frequency of cardiovascular complications after myocardial infarction compared to patients with normal function of the SUR2C19 isoenzyme).

Side effects

Classification of the frequency of side effects (WHO):

often – more than 1/100 and less than 1/10,

infrequently-more than 1/1000 and less than 1/100,

rarely-more than 1/10000 and less than 1/1000,

very rarely-less than 1/10000).

Central and peripheral nervous system disorders: 

infrequently – headache, dizziness and paresthesia: 

rarely-vertigo;

very rarely-violation of taste sensations.

From the digestive system: 

often – diarrhea, abdominal pain, dyspepsia;

infrequently-stomach and duodenal ulcers, gastritis, vomiting, nausea, constipation, flatulence;

very rarely – pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis.

Hemostatic disorders:

infrequently-prolongation of bleeding time.

Hematopoietic disorders: 

infrequently-thrombocytopenia, leukopenia, neutropenia and eosinophilia,

very rarely-thrombocytopenic thrombohemolytic purpura, severe thrombocytopenia (platelet count < 30 x 109/L), agranulocytosis, granulocytopenia, aplastic anemia (pancytopenia), anemia.

Skin and subcutaneous tissue disorders:

infrequently-skin rash and pruritus;

very rarely-angioedema, urticaria, erythematous rash (associated with clopidogrel or acetylsalicylic acid);

very rarely-bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), eczema and lichen planus.

Immune system disorders:

very rarely – anaphylactoid reactions, serum sickness.

Mental disorders:

very rarely – confusion, hallucinations.

Vascular system disorders: 

very rarely – vasculitis, marked decrease in blood pressure( BP), intracranial hemorrhage, ocular hemorrhages (conjunctival, in the tissues and retina of the eye), hematoma, nosebleeds, bleeding from the respiratory tract, gastrointestinal bleeding, retroperitoneal hemorrhage with fatal outcome, hemorrhages in muscles and joints, hematuria, etc.

Respiratory disorders:

very rarely – bronchospasm, interstitial pneumonitis.

Disorders of the hepatobiliary system: 

very rarely-acute liver failure, hepatitis.

Musculoskeletal disorders: 

very rarely – arthralgia, arthritis, myalgia.

Kidney and urinary tract disorders:

very rarely – glomerulonephritis.

General violations:

very rarely – fever.

Changes in laboratory parameters:

very rarely-changes in liver tests, an increase in the concentration of serum creatinine.

Interaction

Warfarin: concomitant use with clopidogrel may increase the intensity of bleeding, so the use of this combination is not recommended.

IIb/IIIa receptor blockers: the use of IIb/IIIa receptor blockers in combination with clopidogrel requires caution in patients who have an increased risk of bleeding (due to injuries and surgical interventions or other pathological conditions) (see the section “Special instructions”).

Acetylsalicylic Acid: acetylsalicylic acid does not alter the effect of clopidogrel, which inhibits ADP-induced platelet aggregation, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, concomitant use of acetylsalicylic acid as an antipyretic agent,500 mg twice daily for 1 day, with clopidogrel did not significantly increase the bleeding time caused by clopidogrel. There may be a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid, which leads to an increased risk of bleeding. Therefore, caution should be exercised when using them simultaneously, although in clinical studies patients received combination therapy with clopidogrel and acetylsalicylic acid for up to one year.

Heparin: according to a clinical study conducted in healthy volunteers, clopidogrel did not require a change in the dose of heparin and did not change its anticoagulant effect. Concomitant use of heparin did not alter the antiplatelet effect of clopidogrel. There may be a pharmacodynamic interaction between clopidogrel and heparin, which may increase the risk of bleeding, so the simultaneous use of these drugs requires caution.

Thrombolytics: The safety of concomitant use of clopidogrel, fibrin-specific or fibrin-specific thrombolytic drugs, and heparin has been studied in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the case of simultaneous use of thrombolytics and heparin with acetylsalicylic acid.

Nonsteroidal anti-inflammatory drugs (NSAIDs):in a clinical study conducted in healthy volunteers, concomitant use of clopidogrel and naproxen increased hidden blood loss through the gastrointestinal tract. However, due to the lack of studies on the interaction of clopidogrel with other NSAIDs, it is not currently known whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel together with other NSAIDs. Therefore, the use of NSAIDs, including selective COX-2 inhibitors, in combination with clopidogrel should be carried out with caution (see the section “Special instructions”).

Other combination therapies

Since clopidogrel is metabolized to form its active metabolite partly by the CYP2C19 isoenzyme, the use of drugs that inhibit this system may lead to a decrease in the level of the active metabolite of clopidogrel and a decrease in its clinical effectiveness. Concomitant use of drugs that inhibit the CYP2C19 isoenzyme (for example, omeprazole) is not recommended.

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

• no clinically significant pharmacodynamic interaction was observed when clopidogrel was co-administered with atenolol, nifedipine, or both drugs simultaneously;
• the concomitant use of phenobarbital, cimetidine, and estrogens did not significantly affect the pharmacodynamics of clopidogrel;
• the pharmacokinetic parameters of digoxin and theophylline did not change when they were co-administered with clopidogrel.
• antacids did not reduce the absorption of clopidogrel.
• phenytoin and tolbutamide can be safely used in conjunction with clopidogrel, despite the fact that the data obtained in studies with human liver microsomes indicate that carboxyl metabolite of clopidogrel may inhibit the activity of isozyme CYP2C9, which may lead to increased plasma concentrations of certain drugs (phenytoin, tolbutamide, and some NSAIDs) that are metabolized via CYP2C9 isoenzyme.
• the angiotensin-converting enzyme (ACE), diuretics, beta-blockers, blockers of “slow” calcium channels, hypoglycaemic agents (including insulin), hypolipidemic means antiepileptic remedies, hormone replacement therapy and blockers of GPIIb/IIIa receptors: clinical studies have not revealed clinically significant undesirable interactions.

How to take, course of use and dosage

Adults and elderly patients with normal activity of the SUR 2 isoenzyme C 19

Clopidogrel-SZ should be taken orally, regardless of food intake.

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

The drug is taken at 75 mg once a day.

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

Non-ST-segment elevation acute coronary syndrome (unstable angina, non-Q-wave myocardial infarction)

Treatment with Clopidogrel-SZ should be started with a single loading dose of 300 mg, and then continued with a dose of 75 mg once a day (in combination with acetylsalicylic acid as an antiplatelet agent in doses of 75-325 mg per day). Since the use of higher doses of acetylsalicylic acid is associated with an increased risk of bleeding, the recommended dose of acetylsalicylic acid for this indication should not exceed 100 mg. The maximum therapeutic effect is observed by the third month of treatment. The course of treatment is up to 1 year.

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

Clopidogrel-SZ is prescribed once at a dose of 75 mg once a day with an initial single loading dose in combination with acetylsalicylic acid as an antiplatelet agent and thrombolytics (or without thrombolytics). Combination therapy should be initiated as early as possible after the onset of symptoms and continued for at least four weeks. In patients over 75 years of age, treatment with Clopidogrel-SZ should begin without taking its loading dose.

Patients with a genetically determined decrease in the function of the SUR 2 isoenzyme P 19

Attenuation of metabolism by the CYP2C19 isoenzyme may lead to a decrease in the antiplatelet effect of clopidogrel. The optimal dosage regimen for patients with impaired metabolism with the help of the SUR 2 C19 isoenzyme has not yet been established.

Patients with impaired renal function

After repeated use of Clopidogrel-SZ at a dose of 75 mg / day in patients with severe renal impairment (creatinine clearance from 5 to 15 ml / min), the inhibition of ADP-induced platelet aggregation (25%) was lower compared to that in healthy volunteers, however, the prolongation of bleeding time was similar to that in healthy volunteers receiving Clopidogrel-SZ at a dose of 75 mg / day. In addition, all patients had good drug tolerance.

Patients with impaired liver function

After taking Clopidogrel-SZ 75 mg daily for 10 days in patients with severe liver damage, the 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 ethnic backgrounds

The prevalence of alleles of the CYP2C19 isoenzyme genes responsible for the intermediate and reduced metabolism of clopidogrel to its active metabolite varies among representatives of different ethnic groups (see the section “Pharmacogenetics”). There are only limited data available for the Mongoloid race to assess the effect of the CYP2C19 isoenzyme genotype on clinical outcome events.

Overdose

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

Treatment: stopping bleeding, platelet transfusion. The antidote is unknown.

Special instructions

During treatment with Clopidogrel-SZ, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients should be carefully monitored for signs of bleeding, including latent bleeding.

Due to the risk of bleeding and hematological undesirable effects (see the section “Side effects”), if clinical symptoms appear during treatment that are suspicious of the occurrence of bleeding, a clinical blood test should be urgently performed, activated partial thromboplastin time (APTT), platelet count, platelet functional activity indicators should be determined, and other necessary studies should be performed.

Clopidogrel-Sz, as well as other antiplatelet drugs should be used with caution in patients having an increased risk of bleeding associated with trauma, surgery or other pathological conditions and in patients receiving acetylsalicylic acid, nonsteroidal anti-inflammatory drugs, including COX-2 inhibitors, heparin, or inhibitors of glycoprotein IIb/IIIa.

The combined use of clopidogrel with warfarin may increase the intensity of bleeding (see “Interaction with other medications”), therefore, with the exception of special rare clinical situations (such as the presence of a floating blood clot in the left ventricle, stenting in patients with atrial fibrillation), the combined use of clopidogrel and warfarin is not recommended.

If the patient is going to have a planned surgical intervention, and there is no need for an antiplatelet effect, then 7 days before the operation, Clopidogrel-SZ should be discontinued.

Clopidogrel prolongs the bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (especially gastrointestinal and intraocular).

Patients should be warned that when taking Clopidogrel-SZ (alone or in combination with acetylsalicylic acid), it may take longer to stop bleeding, and that if they experience unusual (by location or duration) bleeding, they should inform their doctor about this. Patients should inform their doctor (including their dentist) about the use of Clopidogrel-SZ before any upcoming surgery and before starting any new medication.

Very rarely, after the use of Clopidogrel-SZ (sometimes even for a short time), there were cases of thrombocytopenic thrombohemolytic purpura (THP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever. DVT is a potentially life-threatening condition that requires immediate treatment, including plasmapheresis.

During the treatment period, it is necessary to monitor the functional activity of the liver. In severe hepatic impairment, the risk of hemorrhagic diathesis should be considered. Taking Clopidogrel-SZ is not recommended for acute stroke with a duration of less than 7 days (since there are no data on its use in this condition). Clopidogrel-SZ should not be taken in patients with rare hereditary problems of galactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome (see “Composition”).

INFLUENCE ON THE ABILITY TO DRIVE MOTOR VEHICLES AND MANAGE MECHANISMS

Clopidogrel-SZ does not significantly affect the ability required for driving vehicles or working with mechanisms.

Form of production

Round, biconvex tablets, covered with a film-coated pink to dark pink color.

Storage conditions

The drug should be stored out of the reach of children, dry, protected from light at a temperature not exceeding 25°C.

Shelf

life is 3 years. Do not use after the expiration date indicated on the package.

Active ingredient

Clopidogrel

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Indications

Angina, Stroke prevention, Thrombosis prevention, Thromboembolism prevention, Acute Myocardial infarction prevention