Agregal - instructions for use, dose, side effects, contraindications

Excipients: potato starch 0.0109 g, lactose (milky sugar) 0.0547 g,cellulose microcrystalline 0.008 g, hypromellose (hydroxypropylmethylcellulose) 0.001 g, macrogol 6000 (polyethylene glycol 6000) 0.0038 g, stearic acid 0.0018 g, magnesium stearate 0.0018 g; shell: hypromellose (hydroxypropylmethylcellulose) 0.00398 g, titanium dioxide 0.00098 g, macrogol 6000 (polyethylene glycol 6000) 0.001 g, ferric oxide red dye 0.00004 g.

Description:

The tablets covered with a film membrane pink-creamy color, round, biconcave, on a cross-section are visible two layers.

Pharmacotherapeutic group:antiplatelet agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

Pharmacodynamics:

Clopidogrel is a pro-drug, 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 P2Y12platelet receptor and subsequent ADP-mediated activation of the complex GPIIb/IIIa, leading to suppression of platelet aggregation. Irreversibly binds to ADP-receptor platelets, and platelets remain immune to stimulation of ADP for the rest of their life (about 7-10 days), and the 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 the active metabolite occurs with the enzymes of the cytochrome P450 system, which may differ in polymorphism or 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 lesions, in particular 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 baseline levels on average for 5 days.

In patients with a risk of developing ischemic events, the frequency of clinical outcomes, side effects and deviations of clinical and laboratory parameters is the same for both men and women.

Pharmacokinetics:

Suction. After oral administration in a dose of 75 mg clopidogrel quickly absorbed from the gastrointestinal tract, while the maximum concentration (C_mOh) of unchanged clopidogrel in blood plasma (about 2.2-2.5 ng / ml) is achieved approximately 45 minutes after administration. Based on the data on urinary excretion of clopidogrel metabolites, its absorption is at least 50%.

Distribution. In vitro Clopidogrel and its main circulating in the blood are 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 intensively metabolized in the liver. In vitro and in vivo Clopidogrel is metabolized in two ways, the first through esterases and subsequent hydrolysis with the formation of an inactive derivative of a carboxylic acid (85% of circulating metabolites), the second through the cytochrome P450 system. at first clopidogrel is metabolized to 2-oxoklopidogrel (intermediate metabolite), the subsequent metabolism leads to the formation of an active metabolite - the thiol clopidogrel derivative. In vitro metabolism along this path is carried out with the participation of isoenzymes CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite of clopidogrel, which was isolated in studies in vitro, quickly and irreversibly binds to platelet receptors, thus blocking platelet aggregation. FROM_max active metabolite of clopidogrel after a single loading dose of clopidogrel 300 mg is 2 times higher than after taking a dose of 75 mg for 4 days.

Excretion. Within 120 hours after ingestion ¹⁴C-labeled clopidogrel about 50% of the radioactivity is excreted by the kidneys and approximately 46% through the intestine. The half-life of clopidogrel after a single dose of 75 mg is 6 hours, the main inactive metabolite after a single and repeated administration is 8 hours.

Pharmacogenetics

In the activation of clopidogrel, several polymorphic isoenzymes participate (CYP) of the cytochrome P450 system. CYP2C19 is involved in the formation of both an active metabolite and an intermediate metabolite of clopidogrel.Pharmacokinetics and antiplatelet effects of the active metabolite of clopidogrel, studied by platelet aggregation ex vivo, differ depending on the genotype CYP2C19. Gene allele CYP2C19 * 1 is responsible for the normally functioning metabolism, whereas the alleles of the isoenzyme gene CYP2C19 * 2 and CYP2C19 * 3 are responsible for reduced metabolism. These alleles are responsible for a decrease in metabolism in about 85% of the representatives of the Caucasoid race and 99% in the representatives of the Mongoloid race. Other alleles associated with reduced metabolism are represented by isoenzymes CYP2C19 * 4, * 5, * 6, * 7 and * 8, but they are rarely found in the general population. Frequency of occurrence of genotypes with reduced metabolism CYP2C19 among Caucasians is about 2%, among Negroids - 4%, Mongoloids - 14%.

Special patient groups

The pharmacokinetics of the active metabolite of clopidogrel in certain groups of patients has not been studied.

Elderly patients. There was no difference in platelet aggregation and bleeding time in elderly people (over 75 years) and younger. In elderly patients, dose adjustment is not required.

Patients with impaired renal function. After repeated use of clopidogrel at a dose of 75 mg / day in patients with severe renal impairment (creatinine clearance from 5 to 15 ml / min), inhibition of ADP-induced platelet aggregation is lower (25%) than in healthy individuals, and lengthening of time bleeding similar to that of healthy individuals who received clopidogrel in a dose of 75 mg per day.

Patients with impaired liver function. In patients with severe liver damage after taking clopidogrel at a daily dose of 75 mg for 10 days, inhibition of ADP-induced platelet aggregation is similar to that of healthy volunteers. The average bleeding time is also comparable.

Patients of different ethnicity. Prevalence of alleles of isoenzyme genes CYP2C19, responsible for an intermediate or decreased metabolism, is different in representatives of different ethnic groups. The available limited data on the representatives of the Mongoloid race do not allow one to assess the value of the genotyping of the isoenzyme CYP2C19 for the clinical outcome of events.

Indications:

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

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.

Prevention of atherothrombotic and thromboembolic events, including stroke (in combination with acetylsalicylic acid), in adults with atrial fibrillation who have at least one risk factor for cardiovascular complications and who can not be treated with vitamin K antagonists (provided there is a low risk of bleeding) .

Contraindications:

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

- severe hepatic impairment;

- acute bleeding, eg bleeding from peptic ulcers or intracranial hemorrhage;

- rare hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption (the preparation contains lactose);

- 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);

- injuries, surgical interventions;

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

- simultaneous administration of non-steroidal anti-inflammatory drugs (NSAIDs), 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.

Pregnancy and lactation:

Taking clopidogrel during pregnancy is not recommended in connection withlack of clinical data, although animal studies have not shown adverse effects on fertility, pregnancy, embryonic development, childbirth and postnatal development. Action category for the fetus by FDA - AT.

It is not known whether clopidogrel with human breast milk. In animal studies, it was shown that clopidogrel and / or its metabolites are excreted into breast milk. If you need to use the drug Agregal during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Clopidogrel should be taken orally regardless of food intake, preferably at the same time.

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

Take once 75 mg (1 tablet) per day. Treatment should be started within a few days to 35 days in patients after myocardial infarction and from 7 days to 6 months in patients after ischemic stroke.

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

Treatment begins with a single dose of a loading dose of clopidogrel 300 mg (4 tablets of the drug Agregal),and then take 75 mg (1 tablet of the drug Agregal) 1 time per day in combination with acetylsalicylic acid at a dose 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 does not exceed 100 mg. The maximum favorable effect is observed by the third month of treatment. The course of treatment is 1 year (the safety of longer-term combined use of clopidogrel and acetylsalicylic acid has not been studied).

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

Clopidogrel is prescribed in a daily dose of 75 mg once a day with an initial single dose 300 mg loading dose in combination with acetylsalicylic acid and thrombolytic agents (or without thrombolytics). Combination therapy is started as soon as possible after the onset of symptoms and continues for at least 4 weeks. The advantage of using a combination of clopidogrel with acetylsalicylic acid for more than 4 weeks at this indication has not been studied. In patients older than 75 years, treatment with clopidogrel is performed without taking a loading dose.

In patients with atrial fibrillation

Clopidogrel is prescribed in a daily dose of 75 mg in combination with acetylsalicylic acid 75-100 mg per day.

In case of missed time of taking a regular dose of clopidogrel:

- if less than 12 hours have passed, the missed dose of clopidogrel should be taken immediately, and the next dose taken at the usual time;

- if more than 12 hours have passed, you should skip this and take another dose of clopidogrel at the usual time (without doubling it!).

Application in special patents groups

Patients with renal insufficiency. The clinical experience of the application is limited, so in patients with renal insufficiency clopidogrel should be used with caution.

Patients with hepatic insufficiency. Clinical application experience is limited; In patients with moderate hepatic impairment, a predisposition to bleeding is possible (use with caution).

Patients with a genetically determined decrease in function CYP2C19. Weakening of metabolism with the help of isoenzyme CYP2C19 can lead to a decrease in the effect of clopidogrel. For patients with reduced isoenzyme activity CYP2C19 the optimal dosing regimen is not installed.

Side effects:

The incidence of adverse events is classified according to the recommendations of the World Health Organization: Often - more than 10%; often - more than 1% and less than 10%; infrequently - more than 0,1% and less than 1%; rarely - more than 0,01% and less than 0,1%; rarely - less than 0.01%, including individual cases.

Violations of the blood and lymphatic system: infrequently - thrombocytopenia, leukopenia, eosinophilia; rarely - neutropenia (including severe); very rarely thrombotic thrombocytopenic purpura, aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anemia.

Immune system disorders: very rarely - serum sickness, anaphylactic reactions.

Disorders of the psyche: very rarely - hallucinations, confusion.

Disturbances from the nervous system: infrequently - intracranial bleeding, headache, paresthesia, dizziness; very rarely - a violation of taste.

Disturbances on the part of the organ of sight: infrequently - intraocular bleeding (hemorrhage in the conjunctiva, eyeball, retina).

Hearing disorders and labyrinthine disturbances: rarely - vertigo.

Vascular disorders: often - hematoma; very rarely - heavy bleeding, bleeding from the operating wound, vasculitis, arterial hypotension.

Disturbances from the respiratory system, chest and mediastinal organs: often - epistaxis; very rarely - hemoptysis, pulmonary hemorrhage, bronchospasm, interstitial pneumonitis.

Disorders from the gastrointestinal tract: often - gastrointestinal bleeding, diarrhea, abdominal pain, indigestion; infrequently - peptic ulcer of the stomach and duodenum, gastritis, nausea, vomiting, constipation, flatulence; rarely - retroperitoneal bleeding; very rarely - fatal gastrointestinal and retroperitoneal bleeding, pancreatitis, colitis (including ulcerative or lymphocytic), stomatitis.

Disturbances from the liver and bile ducts: very rarely - acute liver failure, hepatitis, a violation of functional liver tests.

Disturbances from the skin and subcutaneous tissues: often - bruising; infrequently - a rash, itching, bleeding in the skin (purpura); very rarely - bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), angioedema, erythematous rash, urticaria, eczema, lichen planus.

Disturbances from musculoskeletal and connective tissue: very rarely - hemarthrosis, arthritis, arthralgia, myalgia.

Disorders from the kidneys and urinary tract: infrequently - hematuria; very rarely - glomerulonephritis, hypercreatininaemia.

General disorders and disorders at the site of administration: often bleeding at the injection site; very rarely - a fever.

Laboratory and instrumental data: infrequently - prolongation of bleeding time, decrease in the number of neutrophils, platelets.

Overdose:

Symptoms. An overdose of clopidogrel may lead to an increase in the time of bleeding followed by a complication of bleeding.

Treatment. There is no specific antidote. When bleeding occurs, appropriate treatment is required. If it is necessary to quickly correct the increased bleeding time, a transfusion of platelet mass is recommended.

Interaction:

Oral anticoagulants (warfarin). Joint use is not recommended, since it can lead to increased bleeding intensity.

Inhibitors of glycoprotein IIb/IIIa. Joint use requires caution in patients,having an increased risk of bleeding (with trauma, surgical interventions, other pathological conditions).

Acetylsalicylic acid does not alter the ADP-induced platelet aggregation inhibition mediated by clopidogrel. But clopidogrel enhances the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, simultaneous with clopidogrel, acetylsalicylic acid at a dose of 500 mg twice a day for 1 day did not significantly increase bleeding time caused by clopidogrel. Between clopidogrel and acetylsalicylic acid, pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, simultaneous use requires caution.

Heparin. When combined with clopidogrel, healthy subjects did not require a change in the dose of heparin, and its anticoagulant effect did not change; Heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation. Possible pharmacodynamic interaction of clopidogrel and heparin, which can lead to an increased risk of bleeding.Therefore, simultaneous use requires caution.

Thrombolytics. With the combined use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic drugs and heparin in patients with acute myocardial infarction, the frequency of clinically significant bleeding was the same as in the joint use of thrombolytic agents and heparin with acetylsalicylic acid.

Non-steroidal anti-inflammatory drugs (NSAIDs). With the combined use of clopidogrel and naproxen in healthy individuals, there was an increase in latent blood loss through the gastrointestinal tract. It is not known whether there is a similar risk with the combined use of clopidogrel with other NSAIDs. Therefore, with caution should be used NSAIDs, including inhibitors of cyclooxygenase-2, in combination with clopidogrel.

Other concomitant therapy

Inhibitors CYP2CI9. Because the clopidogrel metabolized into an active metabolite with the participation of CYP2C19, the use of drugs that inhibit the activity of this isoenzyme may lead to a decrease in the formation of an active metabolite of clopidogrel.The clinical significance of this interaction is not fully understood. As a precaution, joint use of clopidogrel with strong or moderate inhibitors of CYP2C19 (omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol).

Proton Pump Inhibitors. Omeprazole in a dose of 80 mg reduced the concentration of the active metabolite of clopidogrel in blood plasma (by 45% and 40% with loading and maintenance doses of clopidogrel, respectively) and reduced the inhibition of platelet aggregation (by 39% and 21%, respectively). These effects were noted both with the simultaneous administration of omeprazole and clopidogrel, and when taken at an interval of 12 hours. For esomeprazole, a similar interaction with clopidogrel is possible. As a precaution, it is recommended to avoid the combined use of clopidogrel with omeprazole or esomeprazole.

When combined with pantoprazole (does not react with isoenzyme CYP2C19) or lansoprazole a less pronounced decrease in the concentration of the active metabolite clopidogrel.When pantoprazole was administered at a dose of 80 mg, the concentration of the active metabolite of clopidogrel in blood plasma was reduced by 20% h (loading dose) and 14% (maintenance dose), which was accompanied by a 15% and 11% decrease in platelet aggregation inhibition, respectively.

There is no evidence of a decrease in the antiplatelet activity of clopidogrel when combined with other drugs that reduce the acidity of gastric juice, such as antacids and H2-histamine receptor blockers (except for cimetidine, which is an inhibitor of the isoenzyme CYP2C19). Antacids do not change the degree of absorption of clopidogrel.

There was no clinically significant pharmacodynamic interaction with clopidogrel combined with atenolol and / or nifedipine, phenobarbital, cimetidine, estrogens, phenytoin, tolbutamide, Although there is evidence that the carboxylic metabolite of clopidogrel can inhibit activity CYP2C9, contributing to an increase in the concentration of drugs metabolized by the isoenzyme 2C9, for example, phenytoin, tolbutamide, some NLDP.

Pharmacokinetic parameters digoxin and theophylline did not change when combined with clopidogrel.

No clinically significant adverse interactions of clopidogrel with such drugs as ACE inhibitors, diuretics, beta-blockers, slow calcium channel blockers, coronary vasodilators, hypolipidemic agents, hypoglycemic agents (including insulin), antiepileptics, glycoprotein inhibitors IIb/IIIa.

Special instructions:

Bleeding and blood disorders

In the treatment of clopidogrel, especially during the first weeks of therapy and / or after invasive cardiac procedures, surgical intervention, it is necessary to carefully monitor patients for signs of bleeding, including latent. In the case of clinical symptoms appearing on the background, suspicious for the occurrence of bleeding, it is urgent to do a clinical blood test, determine activated partial thromboplastin time (APTT), the number of platelets, tests of the functional activity of platelets and conduct other necessary studies.

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

The combined use of clopidogrel with warfarin is not recommended (except for special rare clinical situations, e.g., the presence of floating thrombus in the left ventricle, stenting for patients with atrial fibrillation), as it can increase the intensity of bleeding (see. "Precautions", "Interaction with other medicaments preparations ").

If the patient will have a planned surgery, and thus there is no need for antiplatelet effect, then 7 days prior to surgery clopidogrel should be discontinued. Clopidogrel It prolongs bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (particularly gastrointestinal and intraocular).

The patient should be warned that taking clopidogrel (alone or in combination with acetylsalicylic acid) may require more time to stop bleeding, and that if they have unusual bleeding (localization and duration), they should be informed of this to your doctor. The patient should inform doctors, including dentists, that he is taking clopidogrel, before any upcoming operation or before starting any new drug.

Thrombotic thrombocytopenic purpura

Very rarely, after the use of clopidogrel (sometimes short), there have been cases of thrombotic thrombocytopenic purpura (TTP), which is characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurological disorders, impaired renal function and fever. TTP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

In patients after acute ischemic stroke Clopidogrel is not recommended for use within the first 7 days (due to lack of application dataat this state).

In patients with a genetically determined decrease in function CYP2C19 Clopidogrel at recommended doses is less metabolized to the active metabolite and has less effect on platelet function. Although the clinical significance of this interaction is not fully understood, joint use of clopidogrel with drugs that are strong or moderate inhibitors should be avoided CYP2C19 (see the section "Interaction with other medicinal products").

If it is necessary to use clopidogrel together with proton pump inhibitors omeprazole or esomeprazole, patients should be carefully observed.

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

Clopidogrel does not significantly affect the ability to drive vehicles and perform activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:

Tablets coated with a film coating, 75 mg.

Packaging:

For 14 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 1 or 2 contour squares with instructions for use in a pack of cardboard.

Storage conditions:

In a dry, protected from light place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 of the year.

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

Terms of leave from pharmacies:On prescription

Registration number:LSR-001516/08

Date of registration:14.03.2008/11.09.2012

Expiration Date:Unlimited

The owner of the registration certificate:NIZHFARM, JSC NIZHFARM, JSC Russia

Manufacturer: & nbsp

OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Representation: & nbspNizhpharm, JSCNizhpharm, JSCRussia

Information update date: & nbsp21.01.2017

Illustrated instructions

Instructions

Agregal (Agregal)