Klopidogrel

General characteristics. Structure:

Active ingredient: 75 mg of a klopidogrel (in the form of hydrosulphate) in 1 tablet.

Excipients: cellulose microcrystallic, starch prezhelatinizirovanny, stearic acid, silicon dioxide colloid.

Cover: Опадрай II (polyvinyl alcohol, titanium dioxide, macrogoal, talc, dye red charming, dye quinolinic yellow, indigo carmine).

Pharmacological properties:

Pharmacodynamics. Inhibitor of aggregation of thrombocytes. Klopidogrel is pro-medicine, one of metabolites of which is inhibitor of aggregation of thrombocytes. Klopidogrel selectively inhibits linkng of adenosinediphosphate (ADF) with his trombrotsitarny receptor of P2Y12 and the subsequent, caused ADF, activation of the glycoprotein IIb/IIIa complex, suppressing thereby aggregation of thrombocytes.

Owing to irreversibility of binding the thrombocytes which were affected are damaged on all remaining period of their life (about 7-10 days), and recovery of normal function of thrombocytes happens to the speed corresponding to a platelet cycle. The aggregation of thrombocytes caused by the agonists other than ADF is suppressed by blocking of strengthening of the activation of thrombocytes happening under the influence of the released ADF too. As the active metabolite of a klopidogrel is formed with the participation of an isoenzyme of CYP2C19 which has polymorphism or can be inhibited by other medicines, not at all patients suppression of thrombocytes happens sufficient. Klopidogrel is capable to prevent development of an aterotromboz at any localizations of atherosclerotic defeat of vessels, in particular, at damages of cerebral, coronary or peripheral arteries.

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

Pharmacokinetics. Absorption and distribution: at regular intake of a klopidogrel in a dose of 75 mg/days it is quickly soaked up. However its concentration in a blood plasma is insignificant and in 2 hours after reception does not reach a measurement limit (0,25 mkg/l). Proceeding from data on removal of a metabolite klopidogret kidneys, absorption of a klopidogrel makes not less than 50%.

In vitro klopidogret and the main metabolite reversibly contact proteins of a blood plasma (98% and 94%, respectively), this communication is not saturable with the broad range of concentration.

Metabolism: the main metabolite of a klopidogrel (carboxyl derivative) makes about 85% of the metabolites of a klopidogrel circulating in a blood plasma and has no pharmacological activity, however is capable in vitro to inhibit activity of an isoenzyme 2C9 of family of P450 cytochrome. Cmax (the maximum concentration) of this metabolite in a blood plasma after repeated administrations of drug in a dose of 75 mg makes about 3 mg/l and is observed approximately in 1 hour after intake. The pharmacokinetics of the main metabolite is linear (plasma concentration increase in proportion to a dose) at use of a klopidogrel in the range of doses from 50 to 150 mg.

Being pro-medicine, klopidogret intensively it is metabolized in a liver. Its active metabolite, derivative thiol, is formed by oxidation of a klopidogrel in 2-oxo-klopidogrel with the subsequent hydrolysis. Oxidation of a klopidogrel happens generally with the participation of isoenzymes of system of P450 2B6 and ZA4 cytochrome, and to a lesser extent - isoenzymes of IA1, IA2 and 2S19. An active tiolny metabolite which was removed in the researches in vitro quickly and it is irreversible contacts platelet receptors, suppressing, thus, aggregation of thrombocytes. This metabolite in a blood plasma is not found.

Removal: within 120 hours after intake by the person of a 14C-mechenny klopidogrel about 50% of a dose are removed by kidneys and about 46% - through intestines. The elimination half-life of the main circulating metabolite makes 8 hours after single and repeated receptions.

Pharmacogenetics. By means of an isoenzyme of CYP2C19 both the active metabolite, and an intermediate metabolite 2-oxo-klopidogrel is formed. The pharmacokinetics and antiagregantny action of an active metabolite of a klopidogrel, at a research of aggregation of thrombocytes ех vivo, vary depending on CYP2C19 isoenzyme genotype. The allele of a gene of CYP2C19*1 corresponds to completely functional metabolism whereas alleles of genes of CYP2C19*2 and CYP2C19*3 are nonfunctional. Alleles of genes of CYP2C19*2 and CYP2C19*3 are the reason of decrease in metabolism at most of representatives Caucasian (85%) and Mongoloid race (99%). Other alleles which absence or decrease in metabolism contacts meet less often and include, but are not limited to alleles of genes of CYP2C19M, * 5, * 6, * 7 and * 8. Patients with low activity of an isoenzyme of CYP2C19 have to possess two gene alleles stated above with function loss. The published frequencies of occurrence of phenotypes of persons with low activity of an isoenzyme of CYP2C19 make 2% at persons of Caucasian race, persons of negroid race have 4% and Chinese have 14%.

Pharmacokinetics in special clinical cases. Concentration of the main circulating metabolite in a blood plasma at regular reception in a dose of 75 mg/days were lower at patients with a renal failure of heavy degree (clearance of creatinine (KK of 5-15 ml/min.) in comparison with patients with a moderately severe renal failure (KK of 30-60 ml/min.) and healthy volunteers. Though the inhibiting effect on ADF-indutsirovannuyu aggregation of thrombocytes was reduced (25%) in comparison with the same effect at healthy volunteers, the bleeding time was increased as well, as well as at the healthy volunteers receiving klopidogret 75 mg/days in a dose.

At patients with cirrhosis (a class A or B on a scale of Chayld-Pyyu) daily reception of a klopidogrel within 10 days in a dose of 75 mg/days was safe and also was well transferred, as well as at healthy volunteers. At patients with cirrhosis (a class A or B on a scale of Chayld-Pyyu) Cmax klopidogret after its single dose inside and clearance of creatinine after reception of the next dose of drug against the background of course treatment were many times higher, than at patients without cirrhosis. However klopidogrely ADF-indutsirovannoy aggregations of thrombocytes, and also a bleeding time patients with cirrhosis and without it had a comparable plasma concentration of the main metabolite circulating in blood and extent of suppression.

Separate groups of patients. The pharmacokinetics of an active metabolite klopidogret at patients of advanced age and children, patients with diseases of kidneys and a liver is not studied.

Indications to use:

Prevention of aterotrombotichesky complications:

- at adult patients with a myocardial infarction (with prescription from several days to 35 days), an ischemic stroke (with prescription from 7 days to 6 months) or the diagnosed occlusal disease of peripheral arteries;

- at adult patients with an acute coronary syndrome: without raising of a segment of ST (unstable stenocardia or a myocardial infarction without Q tooth), including patients to whom stenting at transdermal coronary intervention was carried out (in a combination with acetylsalicylic acid); with raising of a segment of ST (an acute myocardial infarction) at drug treatment and a possibility of carrying out a thrombolysis (in a combination with acetylsalicylic acid).

Prevention of aterotrombotichesky and tromboembolic episodes, including a stroke, at fibrillation of auricles (ciliary arrhythmia).

At patients with fibrillation of auricles (ciliary arrhythmia) which have at least one risk factor of development of vascular complications cannot accept indirect anticoagulants and have low risk of development of bleeding (in a combination with acetylsalicylic acid).

Route of administration and doses:

Klopidogrel is recommended to accept inside irrespective of meal time.

To adults and patients of advanced age with normal activity of an isoenzyme of CYP2C19. A myocardial infarction, an ischemic stroke and the diagnosed occlusal disease of peripheral arteries

Drug is accepted on 75 mg once a day.

Acute coronary syndrome without raising of a segment of ST (unstable stenocardia, a myocardial infarction without Q tooth). Treatment by drug Klopidogrel has to be begun with a single dose of the load dose making 300 mg. And then it is continued by reception of a dose of 75 mg once a day (in combination with acetylsalicylic acid in doses of 75-325 mg a day). As use of higher doses of acetylsalicylic acid is connected with increase in risk of bleedings, the dose of acetylsalicylic acid recommended at this indication should not exceed 100 mg. The optimum duration of treatment is officially not determined. Data of clinical trials support administration of drug up to 12 months, and the maximum favorable effect is observed by third month of therapy.

Acute coronary syndrome with raising of a segment of ST (an acute myocardial infarction with raising of a segment of ST). Drug Klopidogrel should be accepted once in days in a dose of 75 mg with an initial single dose of a load dose of Klopidogrel of 300 mg in a combination with acetylsalicylic acid in combination with trombolitika or without combination to trombolitika. At patients 75 years treatment by drug Klopidogrel have to is more senior to begin without reception of its load dose. The combination therapy is begun as soon as possible after emergence of symptoms, and continued within, at least, 4 weeks. Efficiency of use of a combination of Klopidogrel and acetylsalicylic acid according to this indication lasting over 4 weeks was not studied.

Fibrillation of auricles (ciliary arrhythmia). Klopidogrel it is necessary to accept in a dose 75 mg once a day. In a combination with Klopidogrel it is necessary to begin and then to continue reception of acetylsalicylic acid (75-100 mg/days).

Admission of reception of the next dose
- if there passed less than 12 hours after the admission of reception of the next dose of drug, then it is necessary to accept immediately passed drug dose, and then to accept the following doses in usual time;

- if there passed more than 12 hours after the admission of reception of the next dose of drug, then the patient has to accept the following dose in usual time (it is not necessary to double a dose).

Patients with genetically caused reduced activity of an isoenzyme of CYP2C19
Low activity of an isoenzyme of CYP2C19 is associated with decrease in antiagregantny action of Klopidogrel. The mode of use of higher doses (600 mg - a load dose, and then 150 mg once a day daily) at patients with low activity of an isoenzyme of CYP2C19 increases antiagregantny action of Klopidogrel.

Now in the clinical trials considering clinical outcomes the optimum mode of dosing of Klopidogrel for patients with reduced metabolism because of genetically caused low activity of an isoenzyme of CYP2C19 is not set.

Special groups of patients. Patients of advanced age. Dose adjustment is not required.

Patients with a renal failure. Experience of use is limited at patients with a moderate or heavy renal failure.

At patients with moderated (KK of 30-60 ml/min.) or heavy (KK of 5-15 ml/min.) a renal failure braking of ADF-of the induced aggregation of thrombocytes decreases, however lengthening of a bleeding time is similar to that at healthy faces. Data on correction of doses are absent.

Patients with an abnormal liver function. At patients with easy and moderate (a class A or B on Chayld-Pyyu) a liver failure inhibition ADF-indutsirovannoy of aggregation of thrombocytes is close to that at healthy faces. The average time of bleeding is comparable in both groups. Correction of doses with slight and moderate hepatic dysfunction is not required from patients.

As drug is metabolized in a liver and patients with diseases of a liver are predisposed to coagulative frustration, monitoring of side effects is recommended.

Ethnic origin. Prevalence of alleles of genes of an isoenzyme of CYP2C19 which are responsible for intermediate and reduced metabolism of a klopidogrel to its active metabolite differs at representatives of various ethnic groups. There are limited data for representatives of Mongoloid race on CYP2C19 isoenzyme genotype impact assessment on clinical outcomes.

Patients women's and male. In the small research comparing pharmakodinamichesky properties of a klopidogrel at men and women at women smaller inhibition ADF-indutsirovannoy of aggregation of thrombocytes was observed, but distinctions in lengthening of a bleeding time were not. In the big controlled research CAPRIE (klopidogret in comparison with acetylsalicylic acid at patients with risk of development of ischemic complications), the frequency of clinical outcomes, other side effects and aberrations of clinical laboratory indicators was identical both at men, and at women.

Features of use:

Pregnancy. As a precautionary measure drug use Klopidogrel is not recommended during pregnancy due to the lack of clinical data on its use by pregnant women though researches on animals and did not reveal either direct, nor indirect adverse effects on the course of pregnancy, embryonic development, childbirth and post-natal development.

Breastfeeding period. It is unknown whether it is allocated klopidogret in breast milk, in researches on rats it was shown that klopidogret and/or its metabolites are allocated in milk of the lactating rats. During treatment by drug Klopidogrel feeding by a breast needs to be stopped.

At Klopidogrel's use, especially within the first weeks of therapy and/or after the invasive cardiological procedures / surgical intervention, it is necessary to conduct careful observation of patients regarding an exception of symptoms of bleeding including hidden.

In case of the planned surgical interventions if antiagregantny action is undesirable, the course of treatment should be stopped in 7 days prior to operation.

Patients should be warned that as the stop of the drug of bleeding arising against the background of use demands big time, they have to report to the doctor about each case of unusual bleeding. Patients have to inform also the doctor on administration of drug if operative measures (including dental), and also in case of a drug combination with acetylsalicylic acid, heparin, inhibitors of a glycoprotein IIb/IIIa, NPVP are coming them (including with TsOG-2 inhibitors).

During treatment it is necessary to control indicators of system of a hemostasis (the activated partial tromboplastinovy time (APTT), number of thrombocytes, tests of functional activity of thrombocytes), to regularly investigate functional activity of a liver.

At heavy abnormal liver functions it is necessary to remember risk of development of hemorrhagic diathesis.

It is not recommended to appoint to patients with an ischemic stroke prescription less than 7 days.

Very seldom against the background of reception Klopidogrela developed a trombotichesky Werlhof's disease, sometimes after short-term use. The state is characterized by the thrombocytopenia and mikroangiopatichesky hemolitic anemia associated with neurologic disturbances, damage of kidneys and fever. The Trombotichesky Werlhof's disease - potentially zhizneugrozhayushchy state demanding immediate treatment including a plasma exchange.

Patients should appoint drug with care with renal failures.

Influence on ability to manage vehicles and mechanisms. Klopidogrel has no significant effect on the abilities necessary for control of motor transport or work with mechanisms. However, considering side effects of drug, patients have to be careful at control of motor transport and work with mechanisms.

Side effects:

Frequency of undesirable reactions is presented according to the following frequency of development: very often - more than 1/10, it is frequent - more than 1/100 and less than 1/10, infrequently - more than 1/1000 and less than 1/100, is rare - more than 1/10000 and less than 1/1000, is very rare - less than 1/10000, including isolated cases.

From bodies of a hemopoiesis: infrequently - thrombocytopenia, a leukopenia, an eosinophilia; seldom - a neytropepiya, including heavy; very seldom - a trombotichesky Werlhof's disease, anemia, including aplastic, a pancytopenia, an agranulocytosis, heavy thrombocytopenia, a granulocytopenia.

From coagulant system of blood: often - a hematoma, nasal bleeding, gastrointestinal bleeding, bruises, bleeding on site punctures; sometimes - intracranial bleeding, a hematopsia (conjunctival, ocular, retinal), lengthening of a bleeding time; seldom - retroperitoneal bleeding; very seldom - heavy bleeding from an operational wound, bleeding from a respiratory organs (a pneumorrhagia, pulmonary bleeding), a hemarthrosis.

Allergic reactions: very seldom - anaphylactic reactions, a serum disease. From a nervous system: infrequently - a headache, dizziness, paresthesias, intracraneal hemorrhage, including with a lethal outcome; very seldom - confusion of consciousness, a hallucination, disturbance of flavoring perception.

From an organ of sight: infrequently - eye hemorrhages (konjyuktivalny, in fabrics and a retina of an eye).

From an acoustic organ: seldom - вертиго.

From cardiovascular system: often - a hematoma; very seldom - heavy bleedings, bleeding from an operational wound, a vasculitis, a lowering of arterial pressure.

From respiratory system: often - nasal bleeding; very seldom - a bronchospasm, an intersticial pneumonitis, pulmonary bleeding, a pneumorrhagia.

From the alimentary system: very often - diarrhea, an abdominal pain, dyspepsia, bleeding from digestive tract; infrequently - stomach ulcer and a 12-perstny gut, gastritis, vomiting, nausea, a lock, a meteorism; seldom - a retroperitoneal hemorrhage; very seldom - pancreatitis, colitis, including ulcer or lymphocytic, stomatitis, an acute liver failure, hepatitis, disturbance of functional trials of a liver, bleeding from digestive tract with a lethal outcome.

From integuments: often - hypodermic hemorrhages; infrequently - skin rash, an itch, a purpura (hypodermic hemorrhage); very seldom - a Quincke's disease, a small tortoiseshell, erythematic rash, violent dermatitis (a mnogoformny erythema, Stephens-Johnson's syndrome, a toxic epidermal necrolysis), eczema, flat deprive.

From a musculoskeletal system: very seldom - a hemarthrosis, arthritis, an arthralgia, a mialgiya.

From urinogenital system: infrequently - a hamaturia; very seldom - a glomerulonephritis, a giperkreatininemiya.

Local reactions: often - bleedings in the place of an injection.

Laboratory indicators: infrequently - lengthening of a bleeding time, decrease in neutrophils, thrombocytes.

Others: very seldom - fever.

Interaction with other medicines:

The concomitant use of warfarin with klopidogrely can increase intensity of bleedings therefore use of this combination is not recommended.

Purpose of inhibitors of a glycoprotein of IIb/IIIa along with klopidogrely demands care, especially patients with the increased risk have development of bleeding (at injuries and surgical interventions or other morbid conditions). Acetylsalicylic acid does not change the inhibiting effect of a klopidogrel on ADF-indutsirovannuyu aggregation of thrombocytes, but Klopidogrel exponentiates effect of acetylsalicylic acid on collagen - the induced aggregation of thrombocytes. Nevertheless, reception, simultaneous with klopidogrely, acetylsalicylic acid on 500 mg 2 times a day within 1 day did not cause essential increase in the bleeding time caused klopidogrely. Between acetylsalicylic acid and klopidogrely perhaps pharmakodinamichesky interaction which leads to increase in risk of bleeding. Therefore at their simultaneous use it is necessary to be careful though in clinical trials patients received a combination therapy klopidogrely and acetylsalicylic acid during 1 year.

At simultaneous use with heparin, according to the clinical trial conducted on healthy volunteers at reception of a klopidogrel dose adjustment of heparin was not required and its anticoagulating action did not change. Simultaneous use of heparin did not change an inhibiting effect of a klopidogrel to aggregation of thrombocytes. Between klopidogrely and heparin perhaps pharmakodinamichesky interaction which can increase risk of development of bleedings therefore at use of this combination it is necessary to be careful.

Safety of simultaneous use klopidogret, fibrinspetsifichesky or fibrinnespetsifichesky thrombolytic drugs and heparin was investigated at patients with an acute myocardial infarction. Frequency of clinically significant bleedings was similar that that it was observed in case of simultaneous use of thrombolytic means and heparin with acetylsalicylic acid.

Purpose of non-steroidal anti-inflammatory drugs (NPVP) (including TsOG-2 inhibitors) along with klopidogrely demands care. In the clinical trial conducted with participation of healthy volunteers, simultaneous use of a klopidogrel and Naproxenum increased the hidden losses of blood through digestive tract. However due to the lack of researches on interaction of a klopidogrel with NPVP it is unknown now whether there is an increased risk of gastrointestinal bleedings at reception of a klopidogrel along with other NPVP.

A number of clinical trials with klopidogrely and other at the same time appointed drugs for the purpose of studying of possible pharmakodinamichesky and pharmacokinetic interaction which showed the following was carried out:

At use of a klopidogrel with atenololy, nifedipine or with both drugs of at the same time clinically significant pharmakodinamichesky interaction it was not observed.

Simultaneous use of phenobarbital, Cimetidinum and estrogen had no significant effect on a pharmacodynamics of a klopidogrel.

Pharmacokinetic indicators of digoxin and theophylline did not change at their simultaneous use with klopidogrely.

Antiacid means did not reduce absorption of a klopidogrel.

Phenytoinum and Tolbutamidum can be applied safely along with klopidogrely in spite of the fact that the data obtained during the researches with microsomes of a liver of the person demonstrate that the carboxyl metabolite of a klopidogrel can inhibit activity of an isoenzyme of CYP2C19 that can lead to increase in concentration in a blood plasma of some medicines (Phenytoinum, Tolbutamidum and some NPVP) which are metabolized by means of CYP2C19 isoenzyme.

In clinical trials clinically significant undesirable interaction of a klopidogrel with inhibitors of an angiotensin-converting enzyme, diuretics, beta adrenoblockers, blockers of "slow" calcium channels, hypolipidemic means, vazodilatator, hypoglycemic means (including with insulin), antiepileptic means, drugs for gormonozamestitelny therapy, with antagonists of a glycoprotein of IIb/IIIa was not revealed.

Contraindications:

- hypersensitivity to drug components;

- heavy liver failure;

- acute bleeding (including, at a peptic ulcer of a stomach or duodenum or intracraneal hemorrhage);

- pregnancy and period of a lactation (breastfeeding);

- age up to 18 years.

With care:
- a moderate liver failure at which predisposition to bleeding is possible (experience of a clinical use is limited);

- a chronic renal failure (clinical experience of use is limited);

- injuries, surgical interventions;

- diseases at which there is a predisposition to development of bleedings (especially gastrointestinal or intraocular);

- at simultaneous use of non-steroidal anti-inflammatory drugs (NPVP) (including inhibitors of cyclooxygenase-2 (TsOG-2)), heparin, warfarin, IIb/IIIa glycoprotein inhibitors;

- at hypersensitivity to other thienopyridines (a tiklodipina, a prasugrela);

- patients with genetically caused depression of function of an isoenzyme have CYP2C19 (there are literary data indicating that patients with genetically caused depression of function of an isoenzyme of CYP2C19 are exposed to smaller system exposure by an active metabolite of a klopidogrel and have less expressed antiagregantny effect of drug, besides at them the big frequency of cardiovascular complications after a myocardial infarction in comparison with patients with normal function of an isoenzyme CYP2C19 can be observed).

Overdose:

Symptoms: lengthening of a bleeding time, hemorrhagic complications.

Treatment: bleeding stop, transfusion of a platelet concentrate. The antidote of a klopidogrel is not established.

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to use after expiry date.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 75 mg. Packaging: on 14 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 14 or 28 tablets in bank polymeric. On 1 either 2 blister strip packagings or 1 bank polymeric together with the application instruction in a pack from a cardboard.