medicalmeds.eu Medicines Antiagregantny means. Зилт®

Зилт®

Producer: Krka Slovenia

Code of automatic telephone exchange: B01AC04

Release form: Firm dosage forms. Tablets.

Indications to use: Acute myocardial infarction. Ischemic stroke. Occlusion of arteries. Acute coronary syndrome.

General characteristics. Structure:

Active ingredient: 97,875 mg of a klopidogrel of hydrosulphate (that corresponds to 75 mg of a klopidogrel).

Excipients: lactose anhydrous, cellulose microcrystallic, starch prezhelatinizirovanny, a macrogoal 6000, the castor oil hydrogenated.

Cover: gipromelloza 6 Wednesday, titanium dioxide, talc, dye ferrous oxide red (E 172), propylene glycol.

Pharmacological properties:

Pharmacodynamics. Klopidogrel selectively inhibits binding adenosine of diphosphate (ADF) with his receptor on thrombocytes and the subsequent activation of the GPIIb/IIIa complex, thus, preventing ADF-indutsiruyemuyu aggregation of thrombocytes. Biotransformation of a klopidogrel is necessary for development of action. Klopidogrel also inhibits the aggregation of thrombocytes caused by other agonists, blocking activation of thrombocytes the released ADF. Klopidogrel acts is irreversible due to change of a configuration of a receptor of ADF. Therefore the thrombocytes treated to action of a klopidogrel remain inactivated during the entire period of their life; and recovery of normal function of thrombocytes is possible with a speed, the corresponding speed of updating of thrombocytes.

At daily reception of a klopidogrel in a dose of 75 mg from the first day of reception considerable suppression ADF-indutsiruyemoy of aggregation of thrombocytes which gradually increases within 3-7 days is noted and then reaches constant level (at achievement of an equilibrium state). In an equilibrium state at reception of a dose of 75 mg a day aggregation of thrombocytes is suppressed on average for 40% - 60%. Aggregation of thrombocytes and a bleeding time gradually are returned to reference values usually in 5 days after treatment cancellation.

Pharmacokinetics. Klopidogrel is quickly soaked up at course reception in a dose of 75 mg a day. However plasma concentration of not changed drug in 2 hours very low, below a definition threshold (0,00025 mg/l). Absorption makes not less than 50% according to renal secretion of metabolites of a klopidogrel.

Klopidogrel is actively metabolized in a liver, and the main metabolite, pharmacological inactive – derivative carboxyl acid, makes about 85% of the substance circulating in plasma. The maximum plasma levels of this metabolite (about 3 mg/l after multiple dose inside in a dose of 75 mg) are reached approximately in 1 hour after reception.

Klopidogrel - pro-medicine. The active metabolite, thiol derivative, is formed by oxidation of a klopidogrel to 2-oxo-klopidogrela and the subsequent hydrolysis. Oxidation of a klopidorel happens preferential to the help of isoenzymes 2B6 and 3A4 of P450 cytochrome and to a lesser extent - isoenzymes 1A1, 1A2 and 2C19. The active thiol metabolite allocated to in vitro quickly it is also irreversible contacts receptors of thrombocytes, suppressing their aggregation. This metabolite in plasma is not defined.

The pharmacokinetics of the main circulating metabolite has linear in the range of doses of a klopidogrel from 50 to 150 mg.

Klopidogrel and the main circulating in vitro metabolite reversibly contact proteins of plasma (98% and 94%, respectively). This binding not saturable in the big range of concentration.

Within 120 hours after intake of a 14C-mechenny klopidogrel about 50% also 46% - intestines are removed by kidneys. An elimination half-life of the main circulating metabolite after reception of one dose and reception of repeated doses – 8 hours.

After repeated use of 75 mg of a klopidogrel a day plasma levels of the main circulating metabolite at patients with heavy damage of kidneys (clearance of creatinine from 5 to 15 ml/min.) below, than at patients with moderately severe damages of kidneys (clearance of creatinine from 30 to 60 ml/min.) and at healthy faces. Though inhibition ADF-indutsirovannoy of aggregation of thrombocytes at patients with a renal failure too was lower (25%), than at healthy faces, lengthening of a bleeding time was same, as well as at the healthy faces accepting 75 mg of a klopidogrel a day. Besides, all patients had a good clinical portability.

The pharmacodynamics and pharmacokinetics of a klopidogrel were estimated in researches with single and repeated doses at healthy faces and at patients with cirrhosis (Child Pugh the class A or B). Daily reception within 10 days of a klopidogrel in a dose of 75 mg/days was safe and it was well transferred. The maximum concentration of a klopidogrel (at single use and at repeated use) at patients with cirrhosis were many times higher, than at healthy faces. Nevertheless, plasma concentration of the main circulating metabolite and ADF-indutsirovannaya aggregation of thrombocytes, and also a bleeding time were comparable between groups.

Pharmacogenetics. Several polymorphic enzymes of the P450 system participate in activation of a klopidogrel. The isoenzyme of CYP2C19 is involved in education, both an active metabolite, and an intermediate metabolite — a 2-oksoklopidogrel. The pharmacokinetics and antithrombocytic effects of an active metabolite of a klopidogrel investigated by means of aggregation of thrombocytes of ex vivo differ, depending on CYP2C19 isoenzyme genotype. The allele of a gene of CYP2C19*1 is responsible for normally functioning metabolism whereas alleles of a gene of an isoenzyme of CYP2C19*2 and an isoenzyme of CYP2C19*3 are responsible for reduced metabolism. These alleles are responsible for decrease in metabolism approximately at 85% of representatives of Caucasian race and in 99% — among representatives of Mongoloid race. Other alleles connected with reduced metabolism are presented by isoenzymes of CYP2C19*4, * 5, *, * 7, * 8, but they seldom meet in the general population.

Indications to use:

Зилт it is applied to prevention of aterotrombotichesky events at adult patients with a myocardial infarction, an ischemic stroke (prescription from 7 days to 6 months) or the diagnosed occlusal disease of peripheral arteries, and also at patients with an acute coronary syndrome (with rise and without raising of a segment of ST).

Route of administration and doses:

Inside, irrespective of meal.

After the had myocardial infarction, an ischemic stroke, with the established disease of peripheral arteries drug is accepted on 75 mg (1 tablet) a day. At an acute coronary syndrome: 300 mg (once), then - 75 mg once a day in combination with acetylsalicylic acid (75-325 mg a day).

Features of use:

bleedings, connected with injuries, surgical interventions or other morbid conditions, and also the patients receiving ASK, heparin, inhibitors of a glycoprotein have IIb/IIIa or NPVP, including TsOG 2 inhibitors. It is necessary to conduct careful observation regarding symptoms of bleeding, including hidden, especially within the first weeks of therapy and/or after the invasive cardiological procedures or surgical interventions.

Simultaneous use of a klopidogrel and the anticoagulants accepted inside is not recommended because of possible strengthening of intensity of bleeding (see the section "Interaction with Other Medicines").

If to the patient invasive intervention is planned, and the antithrombocytic effect is temporarily undesirable, reception of a klopidogrel needs to be cancelled in 7 days prior to operation. Patients have to inform doctors (including the stomatologist) on reception of a klopidogrel before carrying out any invasive operation and before reception of any new drugs. Klopidogrel extends a bleeding time and therefore it has to be applied with care at patients with the diseases contributing to development of bleeding (especially, digestive tract and intraocular).

Patients need to be warned that against the background of reception of a klopidogrel (independently or in a combination with ASK) more time for a bleeding stop, and that it is necessary to report to the doctor about any unusual (on localization or duration) bleeding can be required.

Seldom or never against the background of reception of a klopidogrel (sometimes even short) the trombotichesky Werlhof's disease (TWD) developed. TTP is characterized by thrombocytopenia and mikroangiopatichesky hemolitic anemia in combination with neurologic frustration, a renal failure or fever. TTP – a state, potentially life-threatening and demanding immediate therapy, including a plasmapheresis.

Klopidogrel do not recommend during the first 7 days after an acute ischemic stroke (not enough data).

Experience of use of a klopidogrel for patients with diseases of kidneys is limited. Therefore at such patients klopidogret it is necessary to apply with care.

Experience of use of a klopidogrel for patients with a moderate liver failure (risk of development of hemorrhagic diathesis) is also limited. Therefore to these patients klopidogret it is necessary to take with caution.

Зилт patients should not accept with rare hereditary intolerance of a galactose, deficit of lactase of Lapp or with a glucose galactose sprue.

Зилт contains the hydrogenated castor oil which can cause dyspepsia or diarrhea.

As clinical data on use of a klopidogrel during pregnancy are absent, as a precautionary measure drug is not recommended to be used during pregnancy. Researches on animals did not reveal a direct or indirect adverse effect on pregnancy, development of an embryo/fruit, the course of childbirth or post-natal development.

Whether it is excreted klopidogret in breast milk of the person, it is unknown. In researches on animals penetration of a klopidogrel into breast milk was proved. Therefore in need of therapy klopidogrely it is recommended to stop breastfeeding.

Klopidogrel has no significant effect on the abilities necessary for driving.

Side effects:

From bodies of a hemopoiesis and lymphatic system: not often - thrombocytopenia, a leukopenia, an eosinophilia; seldom - a neutropenia, including heavy; very seldom - the trombotichesky Werlhof's disease (TWD), aplastic anemia, a pancytopenia, an agranulocytosis, heavy thrombocytopenia, a granulocytopenia, anemia.

From the central and peripheral nervous system: not often - intracraneal hemorrhages (there are messages on several cases with a lethal outcome), a headache, paresthesias, dizziness; very seldom - hallucinations, the confused consciousness.

From cardiovascular system: often – a hematoma; very seldom - hemorrhages, bleeding of postoperative wounds, a vasculitis, arterial hypotension.

From a respiratory organs: often - a phlegm with blood; very seldom - bleedings from respiratory tracts (a pneumorrhagia, pulmonary bleedings), a bronchospasm, an intersticial pneumonitis.

From digestive organs: often - gastrointestinal bleedings, diarrhea, an abdominal pain, dyspepsia; not often - stomach ulcer and a duodenum, gastritis, vomiting, nausea, locks, a meteorism; seldom - retroperitoneal bleedings; very seldom - gastrointestinal and retroperitoneal bleedings with a lethal outcome, pancreatitis, colitis (including ulcer or lymphocytic colitis), stomatitis, disturbances of indicators of function of a liver, hepatitis, an acute liver failure.

From skin and hypodermic cellulose: often – bruises; not often - rash, a skin itch, skin hemorrhages (purpura); seldom - violent dermatitis (a toxic epidermal necrolysis, Stephens-Johnson's syndrome, a multiformny erythema), a Quincke's disease, erythematic rash, a small tortoiseshell, eczema, flat deprive.

From bodies of a musculoskeletal system: seldom - skeletal and muscular bleedings (hemarthrosis), arthritis, an arthralgia, a mialgiya.

From urinogenital system: not often – a hamaturia; seldom - a glomerulonephritis, increase in creatinine of blood.

From a sense body: not often - eye hemorrhages (conjunctival, ocular, retinal); seldom – вертиго.

Laboratory indicators: not often - lengthening of a bleeding time, a neutropenia, thrombocytopenia.

Allergic reactions: very seldom - a serum disease, anaphylactoid reactions.

Others: often - bleeding in the place of a puncture; seldom – fever.

Interaction with other medicines:

Due to the risk of bleedings and other hematologic undesirable effects against the background of therapy klopidogrely at emergence of clinical symptoms, suspicious on developing of bleeding, it is necessary to make urgently clinical blood test, to define the activated partial tromboplastinovy time (APTT); quantity of thrombocytes, indicators of functional activity of thrombocytes and to conduct other necessary researches.

Klopidogrel it is necessary to apply with care at patients with the increased risk Peroral anticoagulants: simultaneous use of a klopidogrel and peroral anticoagulants is not recommended (possibly strengthening of intensity of bleedings).

IIb/IIIa glycoprotein inhibitors: co-administration of a klopidogrel and inhibitors of a glycoprotein IIb/IIIa demands care from patients with the increased risk of bleedings (at injuries, surgical interventions or at other morbid conditions demanding a concomitant use of inhibitors of a glycoprotein of IIb/IIIa) (see the section "Special Instructions").

Acetylsalicylic acid (ASK): ASK does not influence the suppression of aggregation of thrombocytes caused klopidogrely induced by ADF, but klopidogret exponentiates action of ASK on collagen - the induced aggregation of thrombocytes. Nevertheless, the concomitant use of 500 mg of ASK two times a day within one day significantly does not extend the bleeding time caused by reception of a klopidogrel. Pharmakodinamichesky interaction between klopidogrely and ASK is possible, and leads to increase in risk of bleedings. Considering it, it is necessary to be careful at a concomitant use of these drugs (see the section "Special Instructions").

Heparin: according to clinical trial change of a dose of heparin was not required from healthy faces at reception of a klopidogrel, and anticoagulating effect of heparin also did not change. Combined use of heparin did not exert impact on suppression of aggregation of thrombocytes klopidogrely. Perhaps pharmakodinamichesky interaction between klopidogrely and heparin, leading to increase in risk of bleeding. Therefore simultaneous use of these drugs demands care (see the section "Special Instructions").

Trombolitiki: safety of simultaneous use of a klopidogrel, fibrinspetsifichesky or nonspecific trombolitik and heparin was estimated at patients with an acute myocardial infarction. Frequency of development of clinically significant bleedings was comparable to that frequency at simultaneous use of trombolitik, heparin with ASK (see the section "Side effect").

Non-steroidal anti-inflammatory drugs (NPVP): according to one clinical trial with participation of healthy volunteers simultaneous use of a klopidogrel and Naproxenum increased the hidden gastrointestinal losses of blood. Nevertheless, in view of a lack of researches on interaction with other NPVP it is not known now whether the risk of gastrointestinal bleedings for all NPVP increases. Therefore simultaneous therapy of NPVP, including TsOG-2 inhibitors, and a klopidogrel should be carried out with care (see the section "Special Instructions").

Other accompanying therapy: several clinical trials with klopidogrely and another at the same time appointed medicinal for the purpose of studying of possible pharmakodinamichesky and pharmacokinetic interactions were conducted.

• at simultaneous use of a klopidogrel with atenololy or nifedipine, and also with atenololy and nifedipine (co-administration) of clinically significant pharmakodinamichesky interactions it was not revealed;
• pharmakodinamichesky activity klopidogret significantly did not change at combined use with phenobarbital, Cimetidinum or estrogen;
• the pharmacokinetics of digoxin or theophylline did not change;
• antacids do not influence extent of absorption of a klopidogrel;
• In one of clinical a research Phenytoinum and Tolbutamidum were safely combined with reception of a klopidogrel. However, the inhibition of activity of P450 2C9 cytochrome a carboxyl metabolite of a klopidogrel is possible. Potentially it can lead to increase in plasma concentration of drugs, such as Phenytoinum and Tolbutamidum, and also NPVP which are metabolized by P450 2C9 cytochrome.
• in addition to specific interactions with the medicines described above other researches were not conducted. Nevertheless, at the patients who are participating in clinical trials with klopidogrely, and at the same time accepting diuretics, beta-blockers, inhibitors of the angiotensin-converting enzyme (ACE), antagonists of calcium, hypolipidemic means, coronary vazodilatator, hypoglycemic means (including insulin), antiepileptic means and antagonists of GPIIb/IIIa clinically significant interactions were not revealed.

Contraindications:

Hypersensitivity to active component or excipients;
heavy liver failure;
acute pathological bleeding, for example bleeding from a round ulcer or intracraneal hemorrhage;
rare hereditary intolerance of a galactose, deficit of lactase of Lapp or sprue of glucose galactose;
pregnancy and period of a lactation;
age up to 18 years.

With care: a moderate liver failure (clinical experience of use is limited), a renal failure (clinical experience of use is limited), injuries, surgical interventions, diseases at which there is a predisposition to development of bleedings (especially, digestive tract or intraocular); co-administration of non-steroidal anti-inflammatory drugs (NPVP), including the selection TsOG-2 inhibitors); co-administration of warfarin, heparin, IIb/IIIa glycoprotein inhibitors, hereditary depression of function of an isoenzyme of CYP2C19.

Overdose:

Symptoms: the overdose of a klopidogrel can lead to lengthening of a bleeding time and the subsequent complications in the form of development of bleedings.

Treatment: for the purpose of correction of the extended bleeding time transfusion of a platelet concentrate is necessary. There is no antidote of a klopidogrel.