Clopidogrel-SZ - instructions for use, dose, side effects, contraindications

auxiliary substances (core): lactose monohydrate (sugar milk) 38.4 mg, microcrystalline cellulose 129.48 mg, croscarmellose sodium (impellose) 12.0 mg, silicon dioxide colloid (aerosil) 3.12 mg, sodium stearyl fumarate 2.0 mg.

auxiliary substances (shell): Opadrai 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 lacquer on based dye azorubin 0.0408 mg, aluminum lacquer based on the dye crimson [Ponso 4R] 0.0328 mg, aluminum lacquer based on indigo carmine dye 0.0048 mg).

Description:

Round, biconvex tablets, covered with a film coat from pink to dark pink.

Pharmacotherapeutic group:antiplatelet agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

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 P2Y12 receptor platelet and subsequent ADP-mediated activation of the complex GPIIb/IIIa, leading to suppression of platelet aggregation.Due to irreversible binding, platelets remain immune to stimulation of ADP for the rest of their life (about 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal. Aggregation of platelets caused by agonists other than ADP is also inhibited by blockade of enhanced platelet activation by the released ADP. Since the formation of an active metabolite occurs with the isoenzymes of the P450 system, some of which may be polymorphic or may be inhibited by other drugs, adequate platelet suppression is not possible in all patients.

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

With a daily intake of clopidogrel at a dose of 75 mg, a significant inhibition of ADP-induced platelet aggregation is noted from the first day of administration, which gradually increases for 3-7 days and then reaches a constant level (when the equilibrium state is reached).In the equilibrium state, platelet aggregation is suppressed on average by 40-60%. After stopping the use of clopidogrel, platelet aggregation and bleeding time gradually return to the baseline level on average for 5 days.

Pharmacokinetics:

Suction

When taking oral administration at a dose of 75 mg per day clopidogrel quickly absorbed.

The mean maximum concentration of unchanged clopidogrel in the blood plasma (approximately 2.2-2.5 ng / ml after ingestion of a single dose of 75 mg) is reached approximately 45 minutes after administration. According to excretion of metabolites of clopidogrel with kidneys, its absorption is approximately 50%.

Distribution

In vitro Clopidogrel and its main circulating non-active metabolite in the blood 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 through enzymes and subsequent hydrolysis with the formation of an inactive carboxylic acid derivative (85% of the circulating metabolites), and the second pathway through the cytochrome P450 system. at first clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of an active metabolite of clopidogrel-thiol clopidogrel derivative. In vitro this pathway of metabolism occurs with the help of isoenzymes CYP2CI9, CYP1A2 and CYP2B6. The active thiol clopidogrel metabolite, which was isolated in in vitro studies, quickly and irreversibly binds to platelet receptors, thus blocking the platelet aggregation.

Excretion

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

Pharmacogenetics

Using isoenzyme CYP2C19 are formed as an active metabolite, as well as an intermediate metabolite - 2-oxo-clopidogrel. Pharmacokinetics and antiplatelet effect of the active metabolite clopidogrel, in the study of platelet aggregation ex vivo, vary depending on the genotype of the isoenzyme CYP2C19.The allele of the gene СUR2С19 * 1 corresponds completely to the functional metabolism, whereas the alleles of the genes CYP2C19 * 2 and CYP2C19 * 3 are non-functional. Alleles of the genes СУР2С19 * 2 and СУР2С19 * 3 are the reason for the decrease in metabolism in the majority of representatives of the Caucasoid (85%) and Mongoloid race (99%). Other alleles that are associated with a lack or decrease in metabolism are less common and include, but are not limited to, gene alleles CYP2C19M, * 5, * 6, * 7 and * 8. Patients with low isoenzyme activity CYP2C19, should have the two alleles of the gene with loss of function. Published frequency of occurrence of phenotypes of persons with low isozyme activity CYP2C19 are 2% in Caucasians, 4% in Negroid people and 14% in Chinese. To determine the patient's isoenzyme genotype CYP2C19 there are corresponding tests.

According to a cross-sectional study (40 volunteers) and according to a meta-analysis of six studies (335 volunteers). These included persons with very high, high, intermediate and low isoenzyme activity CYP2C19, there were no significant differences in the exposure of the active metabolite and in the mean platelet aggregation inhibition (IAT) (induced by ADP) involunteers with very high, high and intermediate isoenzyme activity CYP2C19 was not identified. In volunteers with low isoenzyme activity CYP2C19, the exposure of the active metabolite decreased compared to volunteers with high isoenzyme activity CYP2C19.

When volunteers with low isoenzyme activity CYP2C19 received a treatment regimen of 600 mg loading dose / 150 mg maintenance dose (600 mg / 150 mg), the exposure of the active metabolite was higher than when taking the 300 mg / 75 mg treatment regimen. In addition, the IAT was similar to that in groups of patients with a higher metabolic rate by isoenzyme CYP2C19, who received a treatment regimen of 300 mg / 75 mg. However, in studies with clinical outcomes, the dosing regimen of clopidogrel for patients in this group (patients with low isoenzyme activity CYP2C19) is not yet installed.

Clinical studies conducted to date have not had a sufficient sample size to detect differences in clinical outcome in patients with low isoenzyme activity CYP2C19.

Individual patient groups

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

Indications:

Prevention of atherothrombotic events in patients who underwent myocardial infarction (with a duration of several days to 35 days), ischemic stroke (with a duration of 7 days to 6 months) or having peripheral arteries diagnosed with occlusive disease.

Prevention of atherothrombotic events (in combination with acetylsalicylic acid) in patients with acute coronary syndrome:

- without segment elevation ST (unstable angina or myocardial infarction without a tooth Q), including patients who underwent stenting for percutaneous coronary intervention;

- with segment lift ST (acute myocardial infarction) with drug treatment and the possibility of carrying out thrombolysis.

Contraindications:

- Hypersensitivity to clopidogrel or any of the excipients of the drug;

severe hepatic impairment;

- Acute bleeding, for example, bleeding from a peptic ulcer or intracranial hemorrhage;

- rare hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption;

- pregnancy and lactation (see "Pregnancy and the period of breastfeeding");

- Children under 18 years of age (safety and efficacy not established).

Carefully:

- Moderate hepatic insufficiency, in which a predisposition to bleeding is possible (limited clinical experience of use);

- renal failure (limited clinical experience);

- trauma, surgery (see "Special instructions");

- diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal or intraocular);

- simultaneous administration of non-steroidal anti-inflammatory drugs, including selective inhibitors of cyclooxygenase-2 (COX-2);

- simultaneous administration of warfarin, heparin, glycoprotein inhibitors IIb/IIIa;

- in patients with a genetically determined decrease in the isoenzyme function CYP2C19 at recommended doses (there are literature data indicating that patients with a genetically determined decrease in the isoenzyme function CYP2C19 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 greater incidence of cardiovascular complications after myocardial infarction compared to patients with normal isoenzyme function CYP2C19).

Pregnancy and lactation:

As a precautionary measure, the use of clopidogrel during pregnancy is not recommended due to the lack of clinical data on its intake by pregnant women, although animal studies have revealed neither direct nor indirect adverse effects on pregnancy, fetal development, childbirth and postnatal development.

Breastfeeding with clopidogrel should be discontinued, as studies in rats have shown that clopidogrel and / or its metabolites are excreted into breast milk. Does it penetrate clopidogrel in human breast milk is unknown.

Dosing and Administration:

Adults and elderly patients with normal isoenzyme activity CYP2C19

Clopidogrel should be taken orally, regardless of food intake.

Myocardial infarction, ischemic stroke and diagnosed peripheral arterial occlusive disease

The drug is taken 75 mg once a day.

In patients with myocardial infarction (MI) treatment can start from the first days to 35 days of MI, and in patients with ischemic stroke (AI) - in the period from 7 days to 6 months after the AI.

Acute coronary syndrome without segment elevation ST (unstable angina, myocardial infarction without a tooth Q)

Treatment with drug Clopidogrel should be started with a single dose of a loading dose of 300 mg, and then continued with a 75 mg dose once a day (in combination with acetylsalicylic acid as an antiaggregant 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 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 coronary syndrome with segment elevation ST (acute myocardial infarction with segment elevation ST)

Clopidogrel is given once in a dose of 75 mg once a day with the initial single dose loading in combination with acetylsalicylic acid as an antiaggregant and thrombolytic agents (or without thrombolytic agents). Combination therapy is started as soon as possible after the onset of symptoms and continues for at least four weeks.In patients older than 75 years, treatment with the drug Clopidogrel should begin without taking its loading dose.

Patients with a genetically determined decrease in the isoenzyme function CYP2C19

Weakening of metabolism with the help of isoenzyme CYP2C19 can lead to a decrease in the antiplatelet effect of clopidogrel. Optimum dosage regimen for patients with metabolic isozyme reduction CYP2C19 is not yet installed.

Patients with impaired renal function

After repeated administration of the drug Clopidogrel at a dose of 75 mg / day in patients with severe renal disease (creatinine clearance from 5 to 15 ml / min) inhibition of ADP-induced platelet aggregation (25%) was lower than that of healthy volunteers, however, the lengthening of bleeding time was similar that of healthy volunteers who received Clopidogrel in a dose of 75 mg per day. In addition, all patients had good tolerability of the drug.

Patients with impaired hepatic function

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

Patients of different ethnicity

Prevalence of alleles of isoenzyme genes CYP2C19, responsible for the intermediate and decreased metabolism of clopidogrel to its active metabolite, is different in representatives of different ethnic groups (see section "Pharmacogenetics"). There are only limited data for representatives of the Mongoloid race on the impact of the genotype of the isoenzyme CYP2C19 on clinical outcome events.

Side effects:

Classification of the incidence of adverse events (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).

From the central and peripheral nervous system: infrequently - headache, dizziness and paresthesia: rarely - vertigo; very rarely - a violation of taste.

From the digestive system: often - diarrhea, abdominal pain, indigestion; infrequently - ulcers of the stomach and duodenum, gastritis, vomiting, nausea, constipation, flatulence; very rarely - pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis.

Hemostasis disorders: infrequent - prolongation of bleeding time.

Disorders from the hematopoiesis: infrequently - thrombocytopenia, leukopenia, neutropenia and eosinophilia, very rarely thrombocytopenic thrombohemolytic purpura, severe thrombocytopenia (platelet count <30x10⁹/ l), agranulocytosis, granulocytopenia, aplastic anemia (pancytopenia), anemia.

Disturbances from the skin and subcutaneous tissues: infrequently - skin rash and itching; 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 flat lichen.

Impaired immune system disorders: very rarely - anaphylactoid reactions, serum sickness.

Mental disorders: very rarely - confusion, hallucinations.

Disorders from the vascular system: very rarely - vasculitis, marked decrease in blood pressure (BP), intracranial hemorrhage, eye hemorrhage (conjunctival, in the tissue and retina of the eye), hematoma, epistaxis, bleeding from the respiratory tract, gastrointestinal bleeding, retroperitoneal hemorrhage, hemorrhages in the muscles and joints, hematuria, etc.

Disturbances from the respiratory organs: very rarely - bronchospasm, interstitial pneumonitis.

Disorders from the hepato-binary system: very rarely - acute liver failure, hepatitis.

Disorders from the musculoskeletal system: very rarely - arthralgia, arthritis, myalgia.

Disorders from the kidneys and urinary tract: very rarely glomerulonephritis.

Common violations: very rarely - fever.

Changes in laboratory indicators: very rarely - a change in liver samples, an increase in the concentration of serum creatinine.

Overdose:

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

Treatment: stop bleeding, transfusion of platelet mass. The antidote is unknown.

Interaction:

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

Blockers IIb/IIIa-receptors: the appointment of IIb / IIIa receptor blockers in conjunction with clopidogrel requires caution in patients who have an increased risk of bleeding (with trauma and surgical interventions or other pathological conditions) (see 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, concurrent with clopidogrel, acetylsalicylic acid, as an antipyretic agent, 500 mg twice a day for 1 day did not cause a significant increase in bleeding time caused by the use of clopidogrel. Between clopidogrel and acetylsalicylic acid, pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, when they are used simultaneously, care should be taken, although in clinical trials patients received combined therapy with clopidogrel and acetylsalicylic acid for up to one year.

Heparin: according to a clinical study conducted with the participation of healthy volunteers, when taking clopidogrel did not require a change in the dose of heparin and did not change its anticoagulant effect. The simultaneous use of heparin did not alter the antiplatelet effect of clopidogrel.Between clopidogrel and heparin, pharmacodynamic interaction is possible, which can increase the risk of bleeding, so the simultaneous use of these drugs requires caution.

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

Non-steroidal anti-inflammatory drugs (NSAIDs): in a clinical study conducted with the participation of healthy volunteers, the simultaneous use of clopidogrel and naproxen increased hidden blood loss through the gastrointestinal tract. However, due to the lack of research 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 appointment of NSAIDs, including selective inhibitors of COX-2,in combination with clopidogrel should be carried out with caution (see section "Special instructions").

Other combination therapy

As clopidogrel metabolized to the formation of its active metabolite in part by means of isoenzyme CYP2C19, the use of drugs that inhibit this system can lead to a decrease in the level of the active metabolite of clopidogrel and a decrease in its clinical efficacy. Simultaneous reception of preparations inhibiting isoenzyme CYP2C19 (e.g., omeprazole) Not recommended.

A number of clinical studies with clopidogrel and other concomitantly prescribed drugs were conducted to study possible pharmacodynamic and pharmacokinetic interactions that showed that:

- when clopidogrel was used together with atenolol, nifedipine, or with both drugs, clinically significant pharmacodynamic interaction was not observed;

- simultaneous use of phenobarbital, cimetidine and estrogens had no significant effect on the pharmacodynamics of clopidogrel;

- pharmacokinetic indices of digoxin and theophylline did not change with their simultaneous use with clopidogrel.

- antacids did not reduce the absorption of clopidogrel.

- phenytoin, tolbutamide and safety can be used simultaneously with clopidogrel, despite the fact that the data obtained in studies with human liver microsomes, suggest that carboxylic metabolite of clopidogrel can inhibit isozyme activity CYP2C9, which can lead to increased plasma concentrations of certain drugs (phenytoin, tolbutamide and certain NSAIDs) that are metabolized via isoenzyme CYP2C9.

- angiotensin-converting enzyme (ACE) inhibitors, diuretics, beta-blockers, blockers "slow" calcium channel hypoglycemic agents (including insulin), lipid lowering agents, antiepileptic agents, hormone replacement therapy and blockers GPIIb/IIIa-receptors: Clinical studies did not reveal clinically significant adverse interactions.

Special instructions:

When treating the drug Clopidogrel, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgical intervention, careful monitoring of patients for the exclusion of signsbleeding, including hidden.

In connection with the risk of bleeding and hematologic adverse effects (see the section "Side effect"), if clinical symptoms appearing during treatment, suspicious for bleeding, it is urgent to do a clinical blood test, determine activated partial thromboplastin time (APTT), quantity platelets, indicators of the functional activity of platelets and conduct other necessary studies.

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

Joint use of clopidogrel with warfarin may increase the intensity of bleeding (see "Interaction with other medicinal products"), therefore,with the exception of special rare clinical situations (such as the presence of a floating thrombus in the left ventricle, stenting in patients with atrial fibrillation), the combined use of clopidogrel and warfarin is not recommended.

If the patient is scheduled surgical intervention, and there is no need for an antiplatelet effect, then 7 days before the operation, taking the drug Clopidogrel should be discontinued.

Clopidogrel prolongs 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 the drug Clopidogrel (alone or in combination with acetylsalicylic acid) to stop bleeding may take longer, and that if they have unusual (localized or prolonged) bleeding, they should inform their doctor about it. Before any upcoming operation and before starting any new drug, patients should inform the doctor (including the dentist) about taking the drug Clopidogrel.

Very rarely, after using the drug Clopidogrel (sometimes even briefly), there have been cases of thrombocytopenic thrombohemolytic purpura (TTP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever. TTP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis. During the treatment it is necessary to monitor the functional activity of the liver. In case of severe violations of liver function, one should remember about the risk of hemorrhagic diathesis.

Reception of the drug Clopidogrel It is not recommended for acute stroke less than 7 days old (as there is no data on its use in this condition).

Clopidogrel should not be taken to patients with a rare hereditary intolerance to galactose, a deficiency of lactase and a glucose-galactose malabsorption syndrome (see the "Composition" section).

Effect on the ability to drive transp. cf. and fur:

Clopidogrel does not significantly affect the ability to drive vehicles or work with machinery.

Form release / dosage:

Tablets coated with a film coating, 75 mg.

Packaging:

For 10, 14 or 30 tablets in a planar cell package.

For 30 tablets in a plastic can or in a polymer bottle.

3, 6 contour cell packs of 10 tablets, 1, 2, 4 contourcell packs of 14 tablets, 1, 2, 3 contourcell packs of 30 tablets, a can or bottle together with instructions for use in a cardboard pack.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001884

Date of registration:24.10.2012

The owner of the registration certificate:NORTH STAR, CJSC NORTH STAR, CJSC Russia

Manufacturer: & nbsp

NORTH STAR, CJSC Russia

Representation: & nbspNORTH STAR CJSC NORTH STAR CJSC Russia

Information update date: & nbsp02.08.2015

Illustrated instructions

Instructions

Clopidogrel-SZ (Clopidogrel-SZ)