Плавикс®

General characteristics. Structure:

Active agent: klopidogret hydrosulphate in a form II - 97,875 mg (in terms of klopidogret - 75,0 mg);
  excipients: Mannitolum, a macrogoal-6000, cellulose microcrystallic (with the low content of water, 90 microns), the hypro rod low-replaced the castor oil hydrogenated опадрай pink *, wax of karnaubskiya. * - опадрай pink contains lactoses monohydrate, a gipromelloza, titanium dioxide (Е 171), triacetin, dye ferrous oxide red (Е 172).

Description: Round, slightly biconvex tablets, film coated pink color, with an engraving "75" on one party and "I I 7 I" on other party.

Pharmacological properties:

Pharmacodynamics. Klopidogrel is pro-medicine, one of active metabolites of which is inhibitor of aggregation of thrombocytes. The active metabolite of a klopidogrel selectively inhibits linkng of ADF with P2Y12 a receptor of thrombocytes and the subsequent ADF-oposredovannuyu activation of the GPIIb/IIIa complex, leading to suppression of aggregation of thrombocytes. Thanks to irreversible binding, thrombocytes remain unreceptive to stimulation of ADF during all remaining period of the life (about 7-10 days), and recovery of normal function of thrombocytes happens to speed, the corresponding speed of updating of thrombocytes.
The aggregation of thrombocytes caused by the agonists other than ADF is also inhibited due to blockade of the strengthened activation of thrombocytes by the released ADF.
As formation of an active metabolite happens by means of P450 system enzymes some of which can differ in polymorphism, or can be inhibited by other drugs, not at all patients perhaps adequate suppression of thrombocytes.
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 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 aggregation of thrombocytes is suppressed on average for 40-60%. After the termination of reception aggregation of thrombocytes and a bleeding time gradually klopidogret are returned to initial level, on average, within 5 days.
In a small research, the comparing pharmakodinamichesik of property of a klopidogrel at men and women, smaller inhibition ADF-indutsirovannoy of aggregation of thrombocytes was observed at women, but there were no distinctions on lengthening of a bleeding time. In the big controlled research CAPRIE (klopidogret in comparison with acetylsalicylic acid at patients with risk of development of ischemic events), the frequency of clinical outcomes, other side effects and abnormal clinical laboratory parameters was identical both at men, and at women.

Pharmacokinetics.

Absorption. At course intake, in a dose of 75 mg a day, klopidogret quickly it is soaked up.
Average peak concentration of not changed klopidogrel in a blood plasma (about 2,2-2,5 ng/ml after intake of a single dose of 75 mg) are reached approximately in 45 minutes after reception. According to excretion of metabolites of a klopidogrel with urine its absorption makes about 50%.

Distribution
In vitro klopidogret and its main inactive metabolite circulating in blood reversibly contact proteins of plasma (for 98% and 94%, respectively) and this communication is not saturable up to concentration of 100 mg/l.
Metabolism
Klopidogrel is intensively metabolized in a liver. In vitro and in vivo klopidogret is metabolized in two ways: the first - through esterases and the subsequent hydrolysis with education inactive derivative carboxyl acid (85% of the circulating metabolites), and the second way - through system of P450 cytochrome. In the beginning klopidogret it is metabolized to 2-oxo-klopidogrela, being an intermediate metabolite. The subsequent metabolism 2-oxo-klopidogrela leads to formation of an active metabolite of a klopidogrel - a tiolny derivative klopidogrel. In vitro this way of metabolism occurs by means of isoenzymes of P450, CYP2C19, CYP1A2 and SUR2V6. An active tiolny metabolite of a klopidogrel which was allocated in the researches in vitro quickly and it is irreversible contacts receptors of thrombocytes, blocking, thus, aggregation of thrombocytes.
Removal
Within 120 hours after intake by the person of a 14C-marked klopidogrel about 50% of radioactivity are allocated with urine and about 46% of radioactivity - with a fecal masses. After a single dose in a dose in 75 mg the elimination half-life of a klopidogrel makes about 6 hours. After a single dose and reception of repeated doses the elimination half-life of the main inactive metabolite circulating in blood makes 8 hours.

Pharmacogenetics. Several polymorphic enzymes of the P450 system participate in activation of a klopidogrel. The isoenzyme of CYP2C19 is involved in formation of 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% among 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, * 6, * 7 and * 8, but they seldom meet in the general population. The published data on the frequency of occurrence of a phenotype and genotype of an isoenzyme of CYP2C19 are presented in the table.
                            Frequency of occurrence of a phenotype and genotype of an isoenzyme of CYP2C19

    Frequency,
Types of metabolism of an isoenzyme of CYP2C19  Caucasians (n=1356)  Negroids (n=966) Mongoloids (n=573)
Intensive metabolism of an isoenzyme                                            74 66                38
CYP2C19*1/*1                         
Intermediate metabolism of an isoenzyme                                        26 29                50
CYP2C19*1/*2 or * 1/*3 
Reduced metabolism of an isoenzyme                                                2 4                 14
CYP2C19*2/*2 either * 2/*3 or * 3/*3 

Influence of a genotype of an isoenzyme of CYP2C19 on pharmacokinetics of an active metabolite of a klopidogrel it was investigated at 227 people in 7 published researches. At persons with reduced metabolism of an isoenzyme of CYP2C19 reduction of the maximum concentration (Stakh) and the areas under a curve "concentration time" (AUC) of an active metabolite for 30-50% after reception of a load dose in 300 mg or 600 mg and the subsequent maintenance dose in 75 mg was observed. Reduced activity of a metabolite of a klopidogrel can lead to smaller degree of inhibition of a thrombocyte, or to their hyperreactivity. At the moment the weakened antithrombocytic response to reception of a klopidogrel was described for persons with intermediate and reduced metabolism in 21 researches on 4520 subjects. The relative difference in the antithrombocytic answer between groups with a different genotype differed on researches because of use of various methods of assessment of the answer, but there were more than 30%.
Communication between a genotype of an isoenzyme of CYP2C19 and the result of therapy klopidogrely was estimated in two post-registration clinical trials (the research CLARITY-TIMI 28 (n=465) and TRITON-TIMI 38 (n=1477) and 5 cohort researches (n=6489). In CLARITY-TIMI 28 and in one of cohort researches (Trenk, n=765) the frequency of cardiovascular events significantly did not differ depending on a genotype. In TRITON-TIMI 38 and three cohort researches (Collet, Sibbing, Giusti, n=3516) patients with intermediate and reduced metabolism had the big frequency of cardiovascular events (death, a myocardial infarction, a stroke) or stent thrombosing in comparison with patients with good metabolism. In the fifth cohort research (Simon, n=2208) increase in frequency of cardiovascular events was observed only at patients with reduced metabolism.
Pharmacogenetic testing allows to define a genotype with variability of activity of an isoenzyme of CYP2C19.
Also genetic options of other enzymes of the P450 system with effects on ability of formation of active metabolites of a klopidogrel are possible.
Separate groups of patients
The pharmacokinetics of an active metabolite of a klopidogrel at separate groups of patients is not studied.
Elderly people
At volunteers of advanced age (75 years are more senior) when comparing with young volunteers distinctions on indicators of aggregation of thrombocytes and a bleeding time were not received. Dose adjustment for elderly people is not required.
Persons of children's age
Data are absent.
Renal failure
After repeated receptions of a klopidogrel in a dose of 75 mg/days at patients with severe damage of kidneys (clearance of creatinine from 5 to 15 ml/min.) inhibition ADF-indutsirovannoy of aggregation of thrombocytes was lower (25%) in comparison with that at healthy volunteers, however, lengthening of a bleeding time was similar to that at the healthy volunteers receiving klopidogret in a dose 75 mg a day.
Abnormal liver function
After daily, within 10 days of reception of a klopidogrel in a daily dose of 75 mg at patients with severe damage of a liver inhibition ADF-indutsirovannoy of aggregation of thrombocytes was similar to that at healthy volunteers. The average time of bleeding was also comparable in both groups.
Ethnic origin
Prevalence of alleles of genes of an isoenzyme of CYP2C19 which are responsible for intermediate and reduced metabolism is excellent at representatives of various ethnic groups. There are very small literary data among representatives of Mongoloid race that does not allow to estimate value of genotyping of an isoenzyme CYP2C19 on a clinical outcome of events. 

Indications to use:

- Prevention of aterotrombotichesky events at patients with a myocardial infarction, an ischemic stroke or with the diagnosed occlusal disease of peripheral arteries.
- Prevention of aterotrombotichesky events (in a combination with acetylsalicylic acid) at 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;
• with raising of a segment of ST (an acute myocardial infarction) at drug treatment and a possibility of carrying out a thrombolysis.

Route of administration and doses:

Adults and elderly people
Klopidogrel it is necessary to accept inside, irrespective of meal.
Myocardial infarction, ischemic stroke and the diagnosed occlusal disease of peripheral arteries.
Drug is accepted on 75 mg once a day.
At patients with the myocardial infarction (MI) treatment can be begun from the first days till 35 in the afternoon with IT, and at patients with the ischemic stroke (IS) - in terms from 7 days up to 6 months after AI.
Acute coronary syndrome without raising of a segment of ST (unstable stenocardia, a myocardial infarction without Q tooth).
Treatment klopidogrely has to be begun with a single dose of the load dose making 300 mg and then 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 maximum favorable effect is observed by third month of treatment. A course of treatment till 1 year.
Acute coronary syndrome with raising of a segment of ST (an acute myocardial infarction with raising of a segment of ST)
Klopidogrel is appointed once in a dose of 75 mg with an initial single dose of a load dose in a combination with acetylsalicylic acid and trombolitikam once a day (or without trombolitik). The combination therapy is begun as soon as possible after emergence of symptoms, and continued within, at least, four weeks. At patients it has to is more senior 75 years treatment klopidogrely to begin without reception of its load dose.
Patients with genetically caused CYP2C19 isoenzyme depression of function
Weakening of metabolism by means of an isoenzyme of CYP2C19 can lead to reduction of effect of a klopidogrel. The optimum mode of dosing for patients with the weakened metabolism by means of CYP2C19 isoenzyme still is not set yet.

Features of use:

At treatment klopidogrely, especially within the first weeks of treatment 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, and hidden.
Due to the risk of development of bleeding and hematologic undesirable effects (see. "Side effect") in case of emergence during treatment of clinical symptoms, suspicious on developing of bleeding, it is necessary to make urgently clinical blood test, to define AChTV, quantity of thrombocytes, indicators of functional activity of thrombocytes and to conduct other necessary researches.
Klopidogrel, as well as other antithrombocytic drugs, it is necessary to apply with care at the patients having the increased risk of development of bleeding connected with injuries, surgical interventions or other morbid conditions and also at the patients receiving acetylsalicylic acid, non-steroidal anti-inflammatory drugs, including, TsOG-2 inhibitors, heparin or inhibitors of a glycoprotein of IIb/Sha.
Combined use of a klopidogrel with warfarin can increase intensity of bleedings (see. "Interaction with other medicines"), therefore, except for special rare clinical situations (such as existence of the floating blood clot in a left ventricle, stenting at patients with a ciliary arrhythmia), combined use of Plaviks and warfarin is not recommended.
If planned surgery is necessary to the patient, and at the same time there is no need for antithrombocytic effect, then in 7 days prior to operation reception of a klopidogrel should be stopped.
Klopidogrel extends a bleeding time and has to be applied with care at patients with the diseases contributing to development of bleedings (especially, gastrointestinal and intraocular).
Patients have to be warned that at reception of a klopidogrel (one or in a combination with acetylsalicylic acid) for a stop of bleeding more time can be required, and also that, in case of emergence at them unusual (on localization or duration) bleedings, they should report about it to the attending physician. Before any forthcoming operation and before reception of any new medicine patients have to report to the doctor (including the stomatologist) about reception of a klopidogrel.
Very seldom after use of a klopidogrel (sometimes even short) cases of development of the Werlhof's trombogemolitichesky disease (WTD) which is characterized by the thrombocytopenia and mikroangiopatichesky hemolitic anemia which are followed by neurologic frustration, a renal failure and fever were noted. TTP is potentially life-threatening state demanding immediate treatment including a plasma exchange.
During treatment it is necessary to control functional activity of a liver. At severe damages of a liver it is necessary to remember risk of development of hemorrhagic diathesis.
Reception of a klopidogrel is not recommended at an acute stroke with prescription less than 7 days (as there are no data on its use at this state).
Плавикс patients should not accept with rare hereditary intolerance of a galactose, deficit of lactase and a sprue of glucose galactose (watch "Structure").
Influence on ability to drive the car and to work with mechanisms
Плавикс has no significant effect on the abilities necessary for driving or work with mechanisms.

Side effects:

The undesirable effects observed during clinical trials
Safety of a klopidogrel was investigated more than at 42000 patients, including, more than at 9000 patients receiving treatment within a year or more.  Clinically significant  undesirable effects  observed  in four big clinical trials are listed below: CAPRIE, CURE, CLARITY and COMMIT. Portability of a klopidogrel in a dose of 75 mg/days in testing of CAPRIE corresponded to portability of acetylsalicylic acid in a dose of 325 mg/days. The general portability of a klopidogrel was similar to portability of acetylsalicylic acid, irrespective of age, sex and race of patients.

Bleedings
• In clinical trial of CAPRIE
The general frequency of all bleedings at the patients receiving or klopidogret or acetylsalicylic acid, made 9,3%. Frequency of heavy bleedings at use of a klopidogrel made 1,4%, and at use of an atsetisalitsilovy okislota - 1,6%.
At the patients receiving klopidogret, and at the patients receiving acetylsalicylic acid, gastrointestinal bleedings met respectively in 2,0% and 2,7% of cases, and hospitalization was required in 0,7% and 1,1% of cases. Frequency of other bleedings was higher at the patients receiving klopidogret, than at the patients receiving acetylsalicylic acid (7,3% against 6,5%, respectively). However the frequency of heavy bleedings in both groups was identical (0,6% against 0,4%). Most often in both groups observed purpuras/bruises and nasal bleedings. Less often hematomas, a hamaturia and eye hemorrhages met (generally conjunctive).
Frequency of intracraneal hemorrhages made 0,4% at the patients receiving klopidogret, and 0,5% - at the patients receiving acetylsalicylic acid.

• In clinical trial of CURB
Use of a combination of a klopidogrel with acetylsalicylic acid in comparison with use of a combination of placebo with acetylsalicylic acid did not lead to statistically reliable increase in frequency of life-threatening bleedings (2,2% and 1,8%, respectively) and lethal bleedings (0,2% and 0,2%, respectively). However, at use of a combination klopidogret + acetylsalicylic acid the risk of large, small and other bleedings was authentically above: not life-threatening large bleedings, mainly, gastrointestinal and in the place of punctures (1,6% - klopidogret + acetylsalicylic acid against 1,0% - placebo + acetylsalicylic acid) and small bleedings (5,1% - klopidogret + acetylsalicylic acid against 2,4% - placebo + acetylsalicylic acid). Frequency of intracraneal hemorrhages in both groups made 0,1%.
Frequency of large bleedings at use of a combination klopidogret + acetylsalicylic acid depended on a dose of the last (<100 mg - 2,6%; 100-200 mg of-3,5%,> 200 mg - 4,9%), the same as their frequency at use of one acetylsalicylic acid (<100 mg - 2,0%, 100-200 mg - 2,3%,> 200 mg - 4,0%). During the research the risk of the bleedings (posing hazard to life, large, small, other) decreased as at reception of a combination klopidogret also acetylsalicylic acid, and at reception only of one acetylsalicylic acid, making respectively 9,6% (599/6259) and 6,6% (413/6303) (0-1 month of treatment), 4,5% (276/6123) and 2,3% (144/6168) (1 - 3 month of treatment), 3,8% (228/6037) and 1,6% (99/6048) (3 - 6 month of treatment), 3,2% (162/5005) and 1,5% (74/4972) (6 - 9 month of treatment), 1,9% (73/3841) and 1,0% (40/3844) (9 - 12 month of treatment).
At the patients who stopped administration of drug more than in 5 days prior to aortocoronary shunting increase of cases of large bleedings within 7 days after this intervention (4,4% was not noted at reception of a klopidogrel + acetylsalicylic acid against 5,3% at reception of one acetylsalicylic acid). At the patients remaining on antiagregantny therapy during the last five days before aortocoronary shunting, the frequency of these events after intervention made 9,6% (klopidogret + acetylsalicylic acid) and 6,3% (one acetylsalicylic acid).
• In clinical trial of CLARITY
Observed the general increase in frequency of bleedings in group klopidogret + acetylsalicylic acid (17,4%) in comparison with group of placebo + acetylsalicylic acid (12,9%). Frequency of large bleedings was in both groups similar (1,3% and 1,1% in groups klopidogret + acetylsalicylic acid and placebo + acetylsalicylic acid, respectively) and practically did not depend from on initial patients of characteristics and a type of fibrinolitic or heparin therapy. Frequency of lethal bleedings (0,8% and 0,6% in groups klopidogret + acetylsalicylic acid and placebo + acetylsalicylic acid, respectively) and intracraneal hemorrhages (0,5% and 0,7% in groups klopidogret + acetylsalicylic acid and placebo + acetylsalicylic acid, respectively) was low and authentically did not differ in both groups of treatment.
• In clinical trial of COMMIT
The general frequency of not cerebral large bleedings or cerebral bleedings was low and authentically did not differ in both groups (0,6% and 0,5% in groups klopidogret + acetylsalicylic acid and placebo + acetylsalicylic acid, respectively).
Hematologic disturbances
• In clinical trial of CAPRIE
The heavy neutropenia (<0,45Õ109/l) was observed at 4 patients (0,04%) receiving klopidogret, and at 2 patients (0,02%) receiving acetylsalicylic acid. At two of 9599 patients receiving klopidogret, the number of neutrophils was equal to zero and at one of 9586 patients receiving acetylsalicylic acid, such extent of decrease in quantity of neutrophils was not noted. During treatment klopidogrely one case of aplastic anemia was observed.
Frequency of heavy thrombocytopenia (<80Õ109/l) made 0,2% in group of a klopidogrel and 0,1% in group of acetylsalicylic acid.
• In clinical trials of CURB and CLARITY
The number of patients with thrombocytopenia or a neutropenia in both groups was identical.
Other clinically significant side effects
The side effects observed in clinical trials of CAPRIE, CURE, CLARITY and COMMIT with a frequency> 0,1%, and also all serious side effects, are given below, according to classification of side effects of WHO. Their frequency is defined as follows: often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); seldom (> 1/10000, <1/1000).
Disturbances from the central and peripheral nervous system
- Infrequently: headache, dizziness and paresthesia.
- Seldom: вертиго.
Disturbances from digestive tract
- Often: diarrhea, abdominal pains, dyspepsia.
- Infrequently: stomach ulcer and duodenum, gastritis, vomiting, nausea, lock, meteorism.
Disturbances from a hemostasis
- Infrequently: lengthening of a bleeding time. Disturbances from a hemopoiesis
- Infrequently: thrombocytopenia, leukopenia, neutropenia and eosinophilia.

Disturbances from skin and its appendages
- Infrequently: rash and itch.
The undesirable effects observed in the post-marketing period
Bleedings
Messages on development of bleedings which were most often observed in the first month of treatment were the most frequent messages on adverse effects. Several cases of bleedings with a lethal outcome, mainly, intracranial, gastrointestinal and retroperitoneal were registered. There are messages on hard cases of hemorrhages in tissue of skin (purple), hemorrhages in joints and muscles (a hemarthrosis, a hematoma), eye hemorrhages (conjunctival, in fabrics and a retina of an eye), nasal bleedings, bleedings from a respiratory organs (a pneumorrhagia, pulmonary bleeding), a hamaturia and bleedings from an operational wound. At the patients accepting klopidogret along with acetylsalicylic acid, or along with acetylsalicylic acid and heparin, cases of heavy bleedings were noted (see. "Interaction with other medicines" and "Special instructions").
Other side effects
In addition to the side effects revealed during clinical trials and which are listed above by results of spontaneous messages the side effects given below divided into groups on systems of bodies were registered (on classification of MedDRA). In each group side effects are given with the indication of frequency of occurrence (the term "very seldom" corresponds to frequency <1/10000). In each frequency group of side effects the last are presented as reduction of their severity.
Disturbances from a hemopoiesis
- Very seldom: a Werlhof's trombogemolitichesky disease (1:200000 treated patients), heavy thrombocytopenia (number of thrombocytes <30x10/l), an agranulocytosis, a granulocytopenia, aplastic anemia (pancytopenia), anemia.
Disturbances from immune system
- Very seldom: anaphylactoid reactions, serum disease. Mental disorders
- Very seldom: confusion of consciousness, hallucination. Disturbances from a nervous system
- Very seldom: changes of flavoring feelings.
- Disturbances from vascular system
- Very seldom: vasculitis, hypotension. Disturbances from a respiratory organs
- Very seldom: bronchospasm, intersticial pneumonitis.
Disturbances from digestive tract
- Very seldom: pancreatitis, colitis (including, ulcer or lymphocytic colitis), stomatitis.
Disturbances from gepato-biliary system
- Very seldom: acute liver failure, hepatitis. Disturbances from skin and hypodermic fabrics
- Very seldom: the Quincke's disease, a small tortoiseshell, erythematic rash (connected with klopidogrely or acetylsalicylic acid).
- Very seldom: violent dermatitis (a mnogoformny erythema, Stephens-Johnson's syndrome, a toxic epidermal necrolysis), eczema and flat deprive.
Disturbances from a musculoskeletal system
- Very seldom: arthralgia, arthritis, mialgiya. Disturbances from kidneys and urinary tract
- Very seldom: glomerulonephritis. General disturbances
- Very seldom: fever. Changes of laboratory indicators
- Very seldom: change of hepatic tests, increase in concentration of serumal creatinine.

Interaction with other medicines:

Warfarin: the concomitant use together with klopidogrely can increase intensity of bleedings therefore use of this combination is not recommended.
Blockers of IIb/IIIa-receptors: purpose of blockers of IIb/IIIa-receptors together with klopidogrely demands care from the patients having the increased risk of development of bleeding (at injuries and surgical interventions or other morbid conditions) (see. "Special instructions").
Acetylsalicylic acid: acetylsalicylic acid does not change effect of the klopidogrel inhibiting ADF-indutsiruyemuyu aggregation of thrombocytes, but klopidogret exponentiates influence of acetylsalicylic acid on collagen - the induced aggregation of thrombocytes. Nevertheless, reception of acetylsalicylic acid, simultaneous with klopidogrely, on 500 mg 2 times a day within 1 day did not cause essential increase in the bleeding time caused by reception of a klopidogrel. Between klopidogrely and acetylsalicylic acid 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 up to one year.
Heparin: according to the clinical testing which is carried out with participation of healthy faces at reception of a klopidogrel change of a dose of heparin was not required and its anticoagulating action did not change. Simultaneous use of heparin did not change antiagregantny effect of a klopidogrel. Between Plaviks and heparin perhaps pharmakodinamichesky interaction which can increase risk of development of bleedings therefore simultaneous use of these drugs demands care.
Trombolitiki: safety of combined use klopidogret, fibrinspetsifichesky or fibrinne-specific thrombolytic drugs and heparin was investigated at patients with an acute myocardial infarction. Frequency of clinically significant bleedings was similar to that which was observed in case of combined use of thrombolytic means and heparin with acetylsalicylic acid.
Non-steroidal anti-inflammatory drugs (NPVP): in the clinical trial conducted with participation of healthy volunteers, combined use of a klopidogrel and Naproxenum increased the hidden losses of blood through a GIT. However, due to the lack of researches on interaction of a klopidogrel with other NPVP, it is not known now whether there is an increased risk of gastrointestinal bleedings at reception of a klopidogrel together with other NPVP. Therefore purpose of NPVP, including TsOG-2 inhibitors in combination with klopidogrely, it is necessary to carry out with care (see. "Special instructions").
Other combination therapy
As klopidogret it is metabolized before formation of the active metabolite partially by means of the CYP2C19 system, use of the drugs inhibiting this system can lead to decrease in level of an active metabolite of a klopidogrel and reduction of its clinical performance. The concomitant use of the drugs inhibiting the CYP2C19 system (for example, омепразол), is not recommended.
A number of clinical trials with klopidogrely and another, at the same time appointed drugs, for the purpose of studying of possible pharmakodinamichesky and pharmacokinetic interactions which showed that was carried out:
- at use of a klopidogrel together 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 combined use with klopidogrely;
- antiacid means did not reduce absorption of a klopidogrel;
- Phenytoinum and Tolbutamidum can be applied with safety along with klopidogrely (research CAPRIE) 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 2C9 of family of P450 cytochrome that can lead to increase in plasma concentration of some medicines (Phenytoinum, Tolbutamidum and some NPVP) which are metabolized by means of an isoenzyme 2C9 of family of P450 cytochrome;
- APF inhibitors, diuretic, beta adrenoblockers, blockers of "slow" calcium channels, hypolipidemic means, coronary vazodilatator, hypolipidemic means (including insulin), antiepileptic means, gormonozamestitelny therapy and blockers of GPIIb/IIIa-receptors: in clinical trials clinically significant undesirable interactions were not revealed.

Contraindications:

- Hypersensitivity to a klopidogrel or any of drug excipients.
- Heavy liver failure.
- Acute bleeding, for example, bleeding from a round ulcer or intracraneal hemorrhage.
- Rare hereditary lactose intolerance, deficit of lactase and glyukozo-galaktozny malabsorption.
- Pregnancy and the period of a lactation (see. "Pregnancy and lactation").
- Children's age up to 18 years (safety and efficiency of use are not established).

With care at:
- a moderate liver failure at which predisposition to bleeding (limited clinical experience of use) is possible;
- renal failure (limited clinical experience of use);
- injuries, surgical interventions (cm "Special instructions");
- diseases at which there is a predisposition to development of bleedings (especially gastrointestinal or intraocular);
- concomitant use of non-steroidal anti-inflammatory drugs, including, and the selection inhibitors of cyclooxygenase-2 (TsOG-2);
- simultaneous purpose of warfarin, heparin, inhibitors of a glycoprotein of IIb/Sha;
- patients with genetically caused depression of function of an isoenzyme have CYP2d9 (there are literary data indicating that patients with genetically caused depression of function of an isoenzyme of CYP2d9 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 CYP2d9 can be observed).
Pregnancy and lactation
As a precautionary measure reception of a klopidogrel is not recommended during pregnancy due to the lack of clinical data on its reception 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.
Feeding by a breast in case of treatment klopidogrely should be stopped as in researches on rats it was shown that klopidogret and/or its metabolites are excreted in breast milk. Whether gets klopidogret in breast milk of the person - it is unknown.
Route of administration and doses
Adults and elderly people
Klopidogrel it is necessary to accept inside, irrespective of meal.
Myocardial infarction, ischemic stroke and the diagnosed occlusal disease of peripheral arteries
Drug is accepted on 75 mg once a day.
At patients with the myocardial infarction (MI) treatment can be begun from the first days till 35 in the afternoon with IT, and at patients with the ischemic stroke (IS) - in terms from 7 days up to 6 months after AI.
Acute coronary syndrome without raising of a segment of ST (unstable stenocardia, a myocardial infarction without Q tooth)
Treatment klopidogrely has to be begun with a single dose of the load dose making 300 mg and then 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 maximum favorable effect is observed by third month of treatment. A course of treatment till 1 year.
Acute coronary syndrome with raising of a segment of ST (an acute myocardial infarction with raising of a segment of ST)
Klopidogrel is appointed once in a dose of 75 mg with an initial single dose of a load dose in a combination with acetylsalicylic acid and trombolitikam once a day (or without trombolitik). The combination therapy is begun as soon as possible after emergence of symptoms, and continued within, at least, four weeks. At patients it has to is more senior 75 years treatment klopidogrely to begin without reception of its load dose.
Patients with genetically caused CYP2C19 isoenzyme depression of function
Weakening of metabolism by means of an isoenzyme of CYP2C19 can lead to reduction of effect of a klopidogrel. The optimum mode of dosing for patients with the weakened metabolism by means of CYP2C19 isoenzyme still is not set yet.

Overdose:

Symptoms: The overdose of a klopidogrel can lead to increase in a bleeding time with the subsequent complications in the form of development of bleedings.
Treatment: At emergence of bleeding holding the relevant medical activities is required. The antidote of a klopidogrel is not established. If bystry correction of the extended bleeding time is necessary, then carrying out transfusion of a platelet concentrate is recommended.

Storage conditions:

To store at a temperature not above 30 °C. To store in the place, unavailable to children. List B.
Period of validity 3 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 75 mg.
On 7, 10 or 14 tablets in the blister from PVH/PVDH and aluminum foil or PAS / It is scarlet / PVC and aluminum foil.
On 1, 2 or 3 blisters together with the application instruction in a cardboard pack.