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

sheath: Winkout brown (hypromellose 6,60 mg, triacetin 1,56 mg, ethyl cellulose 1,875 mg, titanium dioxide 4,125 mg, talc 0,645 mg, iron oxide red 0,195 mg) 15,00 mg.

Description:

Round tablets covered with a film membrane from light pink to pink, two layers are visible on the fracture; the core is light yellow in color.

Pharmacotherapeutic group:antiplatelet agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

Pharmacodynamics:

Clopidogrel - an inhibitor of platelet aggregation, is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. The active metabolite of clopidogrel selectively decreases the binding of ADP (adenosine diphosphate) to platelet receptors and the activation of receptors GPIIb/IIIa under the action of ADP, weakening the aggregation of platelets.

Clopidogrel reduces platelet aggregation caused by other agonists, preventing their activation by liberated ADP, does not affect the activity of phosphodiesterase (PDE). Irreversibly binds to the platelet ADP receptors that remain impervious to ADP stimulation throughout the life cycle (about 7 days).

Due to the fact that isoenzymes of the cytochrome P450 system, some of which are polymorphous or are capable of being inhibited by other drugs, participate in the formation of the active metabolite of clopidogrel, not all patients have adequate platelet suppression.

If there is an atherosclerotic lesion of the vessel clopidogrel prevents the development of atherothrombosis, regardless of the localization of the vascular process (cerebrovascular, cardiovascular or peripheral lesions).

The inhibition of platelet aggregation is observed 2 hours after admission (40% inhibition) of the initial dose of 400 mg. The maximum effect (60% suppression of aggregation) develops after 4-7 days of constant admission in a dose of 50-100 mg / day. Antiaggregant effect persists throughout the life span of platelets (7-10 days).

The results of a small comparative study of the pharmacodynamic properties of clopidogrel in men and women showed that less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in bleeding time elongation. In a large controlled study CAPRIE (clopidogrel in comparison with acetylsalicylic acid in patients at risk of development of ischemic events), the frequency of clinical outcomes, other adverse reactions and violations of clinical and laboratory parameters was the same for both men and women.

Pharmacokinetics:

Clopidogrel is rapidly absorbed after repeated administration of 75 mg per day.

Bioavailability is high. However, the concentration of the starting material in the plasma is low and does not reach the measurement limit (0.025 μg / l) within 2 hours after administration. The connection with plasma proteins of clopidogrel is 98% and its inactive metabolite is 94%.

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo Clopidogrel is metabolized in two ways: the first by means of esterases followed by hydrolysis with the formation of an inactive derivative of carboxylic acid (85% of the circulating metabolites), the second pathway by cytochrome P450 isoenzymes.

at first clopidogrel is metabolized to 2-oxoklopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxoclopidogrel 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 P450, CYP3A4, CYP2C19, CYP1A2 and CYP2B6. With the help of the CYP2C19 isoenzyme, both an active metabolite and an intermediate metabolite, 2-oxoclopidogrel, are formed.

Excretion. About 50% of clopidogrel is excreted by the kidneys and approximately 46% by the intestine within 120 hours after ingestion. The half-life (T_1/2) clopidogrel after a single dose of 75 mg is approximately 6 hours. T_1/2the main inactive metabolite after a single and repeated administration is 8 hours.

Pharmacokinetics in special clinical cases

Patients with severe renal disease (creatinine clearance 5 to 15 ml / min) after repeated clopidogrel administration at a dose of 75 mg per day, the initiation of ADP-induced platelet aggregation was lower (25%) than that of healthy volunteers, but the lengthening of bleeding time was similar that of healthy volunteers who received clopidogrel in a dose of 75 mg per day.

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

Prevalence of alleles of isoenzyme genes CYP2C9, responsible for the intermediate and reduced metabolism, is different in representatives of different ethnic groups. There are very small literary data among representatives of the Mongoloid race, which does not allow to assess the importance of genotyping isoenzyme CYP2C19 on the clinical outcome of events.

The volunteers of the elderly (over 75 years) when compared with volunteers of young age, there was no difference in platelet aggregation and bleeding time. No dose adjustment is required in elderly patients.

Pharmacokinetics of clopidogrel in children not studied.

Pharmacogenetics

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. Gene allele CYP2C19 * 1 corresponds to fully functional metabolism, whereas gene alleles CYP2C19 * 2 and СУР2С19 * 3 are non-functional. Alleles of genes CYP2C19 * 2 and CYP2C19 * 3 cause a decrease in metabolism in the majority of representatives of the Caucasoid (85%) and Mongoloid races (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 CYP2C19 * 4, * 5, * 6, * 7 and * 8. Patients, which are weak metabolizers, should have the two alleles of the gene with loss of function indicated above.

Published frequency of occurrence of phenotypes of weak metabolizers CYP2C19 are 2% in Caucasians, 4% in blacks and 14% in Mongolian races. There are tests for determining the genotype of the isoenzyme CYP2C19. In individuals with reduced isoenzyme metabolism CYP2C19, there was a decrease in the maximum concentration and area under the concentration-time curve (AUC) active metabolite by 30-50% after taking a loading dose of 300 mg or 600 mg and the subsequent maintenance dose of 75 mg. Reduced activity of the metabolite clopidogrel may lead to a lesser degree of platelet inhibition or to their increased reactivity.

Indications:

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

Prevention of atherothrombotic events (in combination with acetylsalicylic acid (ASA)) 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 the active or any auxiliary component of the drug;

- age to 18 years (efficacy and safety of use not established);

- severe hepatic impairment;

- active pathological bleeding (peptic ulcer or intracranial hemorrhage);

- pregnancy and lactation.

Carefully:

Moderate hepatic insufficiency, chronic renal failure (CRF), pathological conditions that increase the risk of bleeding (including trauma, surgery), simultaneous intake of acetylsalicylic acid, non-steroidal anti-inflammatory drugs (NSAIDs) (including cyclooxygenase (COX-2) inhibitors, heparin and glycoprotein inhibitors IIb/IIIa.

In patients who are weak СУР2С19-metabolizers (t.p.they clopidogrel when the recommended doses are fewer active metabolite of clopidogrel and weaker expressed its antiplatelet effect; weak metabolizers receiving clopidogrel the recommended doses for acute coronary syndrome or percutaneous coronary intervention, may have a higher incidence of cardiovascular complications than patients with normal function isoenzyme CYP2C19).

Pregnancy and lactation:

Due to lack of data, it is not recommended to take Tromborele during pregnancy and lactation.

Dosing and Administration:

Inside of meals, adult (including elderly) Tromborel drug should be taken 75 1 mg once a day.

Treatment should be started within the period of a few days up to 35 days in patients after myocardial infarction and from 7 days to 6 months - in patients after ischemic stroke.

In acute coronary syndrome without ST segment elevation (Unstable angina or myocardial infarction without tooth Q) Tromborelem treatment should be initiated single loading dose of 300 mg (4 tablets of 75 mg), and then continue the dose of 75 mg once a day (with acetylsalicylic acid (ASA) - 75-325 mg per day).Since the use of high dosages of ASA is associated with a high risk of bleeding, the recommended dose should not exceed 100 mg.

In patients with acute myocardial infarction with ST segment elevation the drug is prescribed once a day at a dose of 75 mg with a single loading dose of 300 mg clopidogrel (4 tablets of 75 mg) in combination of ASA in a combination of thrombolytic agents or without thrombolytics.

For patients older than 75 years treatment Thromborelem should be performed without the use of a loading dose. Combination therapy should begin as soon as possible after the development of symptoms and last at least four weeks.

In patients with a genetically determined decrease in the function of the isoenzyme СUR2С19 decrease in metabolic rate by isoenzyme CYP2C19 can lead to a decrease in the effectiveness of clopidogrel. Optimum dosage regimen for patients with metabolic isozyme reduction CYP2C19 has not been established to date.

Side effects:

Bleeding is the most frequent reaction that occurs during the first month of taking the drug. Cases of severe bleeding are documented in patients taking clopidogrel simultaneously with ASA or with ASA and heparin (see Fig.See "Precautions for Use").

The frequency of side effects is determined according to the following definitions: often (> 1/100 - <1/10), infrequently (> 1/1 000 - <1/100) and rarely (> 1/10 000 - <1/1 000), very rarely corresponds (<1/10 000).

From the central nervous system: infrequently - headache, dizziness and paresthesia, intracranial hemorrhage; rarely - systemic dizziness; very rarely - hallucinations, confusion, a disorder of taste sensations.

From the gastrointestinal tract: often - gastrointestinal bleeding, diarrhea, abdominal pain, indigestion; infrequently - a stomach ulcer, a duodenal ulcer, a gastritis, a vomiting, a nausea, a constipation, a meteorism; rarely - retroperitoneal hemorrhages; very rarely - pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis, acute liver failure, hepatitis, abnormal liver function tests, gastrointestinal bleeding and retroperitoneal hemorrhages with fatal outcome.

From the side of the vascular system and the organs of hematopoiesis: often - hematoma; infrequently - an increase in bleeding time and a decrease in the number of platelets (thrombocytopenia),leukopenia, eosinophilia; rarely - neutropenia, including severe; very rarely vasculitis, lowering of arterial pressure, thrombotic thrombocytopenic purpura (TTP) (see "Precautions for use"), expressed thrombocytopenia, agranulocytosis, granulocytopenia, aplastic anemia / pancytopenia, anemia, severe bleeding, bleeding in the operating wound.

From the skin: often - a bruise; infrequently - skin rash, skin itch, bleeding in the skin (purpura); very rarely angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), urticaria, erythematous rash, eczema and flatulence.

On the part of the respiratory system: often - epistaxis; very rarely - bronchospasm, interstitial pneumonitis, bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage).

From the musculoskeletal system: very rarely - arthralgia, arthritis, myalgia, hemarthrosis.

From the side of the urinary system: infrequently - hematuria; very rarely - glomerulonephritis, increased serum creatinine.

Allergic reactions: very rarely - anaphylactoid reactions, serum sickness.

Other: often bleeding at injection sites; infrequently - eye hemorrhages, including conjunctivitis, in the tissues of the eye; very rarely - a fever.

Overdose:

An overdose of clopidogrel can lead to bleeding, prolongation of bleeding time and subsequent complications in the form of bleeding. If a bleeding is detected, appropriate treatment should be applied.

Antidotes of the pharmaceutical activity of clopidogrel have not been found.

If rapid correction of prolonged bleeding time is necessary, transfusion of platelet mass is recommended.

Interaction:

Strengthens the antiplatelet effect ASA, heparin, thrombolytics, indirect anticoagulants, NSAIDs (naproxen, COX-2 inhibitors), increases the risk of bleeding, incl. from the gastrointestinal tract, so the simultaneous use of these funds requires caution.

Thromboreal should be used with caution in patients who may have a risk of increased bleeding in case of trauma or surgery in case of simultaneous administration inhibitors of glycoprotein IIb/IIIa.

The simultaneous use of clopidogrel and warfarin is not recommended, as it may increase bleeding (see also "Precautions for Use").

There were no clinically significant pharmacodynamic interactions in cases of simultaneous use of thromboplast with atenolol, nifedipine, or a combination of atenolol with nifedipine. In addition, the pharmacodynamic activity of clopidogrel did not change significantly with simultaneous application phenobarbital, cimetidine or estrogens.

Pharmacokinetic parameters digoxin and theophylline did not change when they were used together with clopidogrel.

Antacid agents did not reduce the absorption of clopidogrel.

Phenytoin and tolbutamide can be safely used simultaneously with clopidogrel, even though the carboxylic metabolite clopidogrel can inhibit the activity of the isoenzyme CYP2C9, and this can lead to an increase in plasma concentrations of certain drugs (phenytoin, tolbutamide and some NSAIDs) that are metabolized by isoenzyme CYP2C9.

Because the clopidogrel metabolized to the formation of its active metabolite partially by means of the system CYP2C19, the use of drugs that inhibit this system may result in lower levels of the active metabolite of clopidogrel. The clinical significance of this interaction is not established. The simultaneous use of potent or moderate inhibitors with clopidogrel should be avoided CYP2C19 (e.g., omeprazole). If it is necessary to use proton pump inhibitors, the drug with the lowest inhibitory activity in relation to CYP2C19 (e.g., pantoprazole).

In clinical trials, there was no clinically relevant undesirable interaction of clopidogrel with ACE inhibitors, diuretics, β-blockers, blockers "slow" calcium channels, hypolipidemic agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, drugs for hormone replacement therapy with blockers glycoprotein IIb / IIIa- receptors.

Special instructions:

The period of treatment is necessary to control hemostatic parameters (activated partial thromboplastin time (APTT), platelet count,tests of the functional activity of thrombocytes); regularly investigate the functional activity of the liver.

Thromborele should be used with caution in patients at risk of severe bleeding in trauma, surgery, in patients with injuries prone to bleeding (especially gastrointestinal and intraocular), as well as in patients receiving ASA, NSAIDs (incl. inhibitors of COX-2), heparin or glycoprotein inhibitors IIb/IIIa. Patients should be monitored carefully to identify any signs of bleeding, incl. especially during the first weeks of application of the drug and / or after invasive procedures on the heart or surgical operations. The simultaneous use of thrombore and warfarin is not recommended; it can increase bleeding.

In the case of surgical interventions, if antiaggregant effect is undesirable, the course of treatment should be discontinued 7 days before the operation. Patients should be warned that because the stoppage of the bleeding that occurs when the drug is used (in combination with or without ASA) takes longer, they should inform the doctor of every case of bleeding.Patients should also inform the doctor about taking the drug if they are to be promptly operated.

After taking clopidogrel preparations, thrombotic thrombocytopenic purpura (TTP) was rarely detected, sometimes after short-term use. This condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia in combination with neurological signs, impaired renal function or fever. TTP is a potentially life-threatening condition requiring immediate treatment, incl. with the use of plasmapheresis.

Due to the lack of data, thromboreol can not be recommended for acute (less than 7 days) ischemic stroke.

The experience of using clopidogrel in patients with impaired renal function is limited, so these patients should be prescribed with caution.

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

Clopidogrel is not affected or slightly affected by the inability to drive vehicles and work with mechanisms.

Form release / dosage:

Tablets coated with a film coating, 75 mg.

Packaging:

For 10 and 14 tablets in Al / Al blister.

For 1, 2, 3 and 10 blisters of 10 tablets, together with the instructions for use are placed in a cardboard box.

By 1, 2, 4 and 6 blisters for 14 tablets together with the instruction for use are placed in a cardboard box.

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:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-002151

Date of registration:19.07.2013

The owner of the registration certificate:Edge Pharma Private LimitedEdge Pharma Private Limited India

Manufacturer: & nbsp

EDGE PHARMA PRIVATE, Limited India

Representation: & nbspEdge Pharma Private Limited Edge Pharma Private Limited India

Information update date: & nbsp05.08.2015

Illustrated instructions

Instructions

Thromboreal (Tromborel)