Klopidogrel-LF

General characteristics. Structure:

Active ingredient: 75 mg of a klopidogrel (in the form of a klopidogrel of hydrosulphate - 97,875 mg).

Excipients: cellulose microcrystallic, the hydroxypropyl cellulose low-replaced talc, a mannitol.

Structure of a cover of a gelatin capsule: gelatin, titanium dioxide (E-171), crimson 4R (E-124), quinolinic yellow (E-104), orange yellow (E-110), patent blue V (E-131).

Modern antiagregantny means.

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 with 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:

The route of administration also dozyklopidogret - LF should be accepted inside, irrespective of meal.

Adults and elderly people with normal activity of an isoenzyme of CYP2C19

Myocardial infarction, ischemic stroke and the diagnosed occlusal disease of peripheral arteries

Drug is accepted on 75 mg (1 capsule) once a day.

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 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 was observed by third month of treatment.

Acute coronary syndrome with raising of a segment of ST (an acute myocardial infarction with raising of a segment of ST). Klopidogrel it is necessary to accept once in days in a dose 75 mg with an initial single dose of a load dose of a klopidogrel of 300 mg in a combination with acetylsalicylic acid in combination with trombolitika or without combination to trombolitika. At patients it has to is more senior 75 years treatment klopidogrely 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, four weeks. Efficiency of use of a combination klopidogret and acetylsalicylic acid at this indication 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 klopidogrely 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, then it is necessary to accept immediately passed drug dose, and then in the following doses to accept in usual time;

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

Patients with genetically caused reduced activity of an isoenzyme of CYP2C19. Low activity of an isoenzyme of CYP2C19 is associated with reduction of antiagregantny action of a klopidogrel. The mode of use of higher doses (600 mg - a load dose, then 150 mg once a day daily) at patients with low activity of an isoenzyme of CYP2C19 increases antiagregantny action of a klopidogrel (see the section "Pharmacokinetics"). However, at the moment the clinical trials considering clinical outcomes the optimum mode of dosing of a klopidogrel for patients with his reduced metabolism because of genetically caused low activity of an isoenzyme of CYP2C19 is not set.

Features of use:

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 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 since 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.

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 з patients regarding an exception of symptoms of bleeding, including, and hidden.

Due to the risk of development of bleeding and hematologic undesirable effects, in case of emergence during treatment of the clinical symptoms indicating developing of bleeding it is necessary to make precisely 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 IIb/IIIa.

Combined use of a klopidogrel with warfarin can strengthen risk of bleeding therefore it is necessary to be careful at combined use of a klopidogrel with warfarin. If planned surgery is necessary to the patient, and at the same time there is no need for antithrombocytic effect, then in 5-7 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). Klopidogret drugs which can cause injuries of a mucous membrane of digestive tract (such as acetylsalicylic acid, non-steroidal anti-inflammatory drugs) in the patients receiving, it is necessary to use with care. Patients have to be warned that at acceptance 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 trombotichesky Werlhof's disease (TWD) 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 (since there are no data on its use at this state).

Klopidogrel does not influence or exerts insignificant impact on ability to drive the car or other means of transport and to use mechanisms.

Side effects:

Klopidogrel's safety was investigated more than at 44 000 patients, including more than at 12 000 patients receiving treatment within a year or more. In general Klopidogrel's portability in a dose of 75 mg/days in the research CAPRIE corresponded to portability of acetylsalicylic acid in a dose of 325 mg/days, irrespective of age, sex and race of patients. Clinically significant undesirable effects observed in five big clinical trials are listed below: CAPRIE, CURE, CLARITY, COMMIT, ACTIVE A. Except experience of development of undesirable reactions in clinical trials there were spontaneous messages on emergence of undesirable reactions.

In clinical trials and at use of drug after its entry into the market it was most often reported about development of bleedings, mainly, within the first month of use of drug.

In clinical trial of CAPRIE the general frequency of all bleedings at the patients receiving either Klopidogrel or acetylsalicylic acid, made 9,3%. Frequency of heavy bleedings or Klopidogrel's use and acetylsalicylic acid was identical.

In clinical trial of CURE at the patients who stopped administration of drug more than in 5 days prior to aortocoronary shunting increase of cases of development of large bleedings within 7 days after intervention was not noted. At the patients continuing antithrombocytic therapy during the last 5 days before aortocoronary shunting, the frequency of these events after intervention made 9,6% (Klopidogrel + acetylsalicylic acid) and 6,3% (placebo + acetylsalicylic acid).

In clinical trial of CLARITY the general increase in frequency of bleedings in group Klopidogrel + acetylsalicylic acid in comparison with group of placebo + acetylsalicylic acid was observed. Frequency of large bleedings was identical in both groups. It was identical in subgroups of the patients allocated according to initial characteristics and by the form fibrinolitic or heparin therapy.

In clinical trial of COMMIT the general frequency of not cerebral large bleedings or cerebral bleedings was low and identical in both groups (Klopidogrel + acetylsalicylic acid and placebo + acetylsalicylic acid)

In clinical trial of ACTIVE A the frequency of development of large bleedings in group Klopidogrel + acetylsalicylic acid was higher, than in group of placebo + acetylsalicylic acid (6,7% against 4,3%). Large bleedings generally were extracranial in both groups (5,3% against 3,5%), mainly, gastrointestinal bleedings were observed (3,5% against 1,8%). In group Klopidogrel + acetylsalicylic acid of intracraneal hemorrhages was more, than in group with placebo (1,4% against 0,8%). There were no statistically significant distinctions between these groups of treatment in the frequency of developing of fatal bleedings (1,1% against 0,7%) and a hemorrhagic stroke (0,8% against 0,6%).

Frequency of undesirable reactions which were observed or during conduct of clinical trials or were received from spontaneous messages on development of undesirable reactions is defined as follows: often (> 1/100 - <1/10); infrequently (> 1/1000 - <1/100); seldom (> 1/10 000 - <1/1000); very seldom (<1/10 000). In each system and organ class undesirable reactions are presented in decreasing order of their weight.

Disturbances from blood and lymphatic system. Infrequently: thrombocytopenia, leukopenia, eosinophilia. Seldom: a neutropenia, including a heavy neutropenia. Very seldom: trombotichesky Werlhof's disease, aplastic anemia, pancytopenia, agranulocytosis, heavy thrombocytopenia, granulocytopenia, anemia.

Disturbances from immune system. Very seldom: serum disease, anaphylactoid reactions.

Disturbances of mentality. Very seldom: hallucinations, confusion of consciousness.

Disturbances from a nervous system. Infrequently: intracranial hemorrhages (it was reported about several cases from the death), a headache, paresthesia, dizziness. Very seldom: disturbances of flavoring perception.

Disturbances from organs of sight. Infrequently: eye hemorrhages (conjunctival, in fabrics and a retina of an eye).

Disturbances from acoustic organs and labyrinth disturbances. Seldom: вертиго.

Disturbances from vessels. Often: hematoma. Very seldom: serious bleeding from an operational wound, a vasculitis, a lowering of arterial pressure.

Disturbances from respiratory system, bodies of a thorax and a mediastinum. Often: nasal bleeding. Very seldom: bleeding from respiratory tracts (a pneumorrhagia, pulmonary bleeding), a bronchospasm, intersticial pneumonia.

Disturbances from a GIT. Very often: gastrointestinal bleeding, diarrhea, abdominal pains, dyspepsia. Infrequently: stomach ulcer and 12-perstny gut, vomiting, nausea, lock, abdominal distention. Seldom: retroperitoneal hemorrhage. Very seldom: gastrointestinal bleeding and a retroperitoneal hemorrhage from the death, pancreatitis, colitis (including nonspecific ulcer colitis or lymphocytic colitis), stomatitis.

Disturbances from a liver and biliary tract. Very seldom: acute liver failure, hepatitis, aberration of indicators of function of a liver.

Disturbances from skin and hypodermic fabrics. Often: hypodermic bruises. Infrequently: rash, itch, purpura (hypodermic hemorrhage). Very seldom: violent dermatitis (a toxic epidermal necrolysis, Stephens-Johnson's syndrome, a mnogoformny erythema), a Quincke's disease, erythematic rash, a small tortoiseshell, eczema, flat deprive.

Disturbances from skeletal and muscular and connecting fabric. Very seldom: hemorrhages in muscles and joints, arthritis, an arthralgia, a mialgiya.

Disturbances from kidneys and urinary tract. Infrequently: hamaturia. Very seldom: a glomerulonephritis, increase in concentration of creatine in blood.

The general frustration and disturbances in an injection site. Often: bleeding from the place of puncturation of vessels. Very seldom: fever.

Laboratory and tool data. Infrequently: increase in a bleeding time, reduction of quantity of neutrophils, reduction of quantity of thrombocytes in peripheral blood.

Interaction with other medicines:

Warfarin: though reception of a klopidogrel of 75 mg/days did not change warfarin pharmacokinetics (CYP2C9 isoenzyme substrate) or INR (the international normalized relation) at patients, is long receiving treatment by warfarin, the concomitant use of a klopidogrel increases risk of bleeding in connection with its independent additional influence on coagulability of blood. Therefore it is necessary to be careful at a concomitant use of warfarin and a klopidogrel.

Blockers of IIb/IIIa-receptors: purpose of blockers 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).

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 influence 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 trial conducted 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 klopidogrely and heparin perhaps pharmakodinamichesky influence which can increase risk of development of bleedings therefore simultaneous use of these drugs demands care.

Trombolitiki: safety of combined 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 which was observed in case of combined use of thrombolytic means and heparin with acetylsalicylic acid.

Non-steroidal anti-inflammatory drugs (NPVS): 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 NPVS, it is not known now whether there is an increased risk of gastrointestinal bleedings at reception of a klopidogrel together with other NPVS. Therefore purpose of NPVS, including TsOG-2 inhibitors in combination with klopidogrely, it is necessary to carry out with care.

Interaction with other medicines: since 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. Clinical value of this interaction is not established. It is necessary to avoid simultaneous use with klopidogrely strong or moderate inhibitors of an isoenzyme CYP2C19 (for example, an omeprazola). If inhibitors of a protonew pomp have to be accepted along with klopidogrely, it is necessary to use inhibitor of a protonew pomp with the smallest inhibition of an isoenzyme of CYP2C19, such as пантопразол.

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). It is improbable that klopidogret can influence metabolism of other medicines, such as Phenytoinum and Tolbutamidum, and also NPVS which are metabolized by means of an isoenzyme of CYP2C9 of family of P450 cytochrome;
- APF inhibitors, diuretic, beta adrenoblockers, blockers of "slow" calcium channels, hypolipidemic means, coronary vasodilators, hypoglycemic 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;
- pregnancy and period of feeding by a breast;
- children's age up to 18 years.

With care:
- at a moderate renal failure at which predisposition to bleeding (organic clinical experience of use) is possible;
- at a renal failure (organic clinical experience of use);
- at injuries, surgical interventions;
- at diseases at which there is a predisposition to development of bleedings (especially gastrointestinal or intraocular);
- at a concomitant use of non-steroidal anti-inflammatory drugs, including, and the selection inhibitors of cyclooxygenase-2 (TsOG-2);
- at co-administration of warfarin, heparin, IIb/IIIa glycoprotein inhibitors;
- at patients with low activity of an isoenzyme of CYP2C19 (as at them at use of a klopidogrel in the recommended doses less active metabolite of a klopidogrel is formed more weakly its antiagregantny action is expressed) at reception of usually recommended doses of a klopidogrel, at an acute coronary syndrome or transdermal coronary intervention higher frequency of cardiovascular complications is possible, than patients with normal activity of an isoenzyme have CYP2C19.

Overdose:

Symptoms. Klopidogrel's overdose can lead to increase in a bleeding time with the subsequent complications in the form of razvitiyakrovotecheniye.

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 in the place protected from moisture and light at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity 2 years.

Issue conditions:

According to the recipe

Packaging:

On 10 capsules in a blister strip packaging from a film of polyvinyl chloride and aluminum foil. On 2 or 3 blister strip packagings together with the application instruction in a pack from a cardboard.