Клопидекс

General characteristics. Structure:

Active agent: klopidogret (in the form of a klopidogrel of hydrosulphate a form-I) - 75,00 mg;

Excipients: a hypro rod - 6,125 mg, Mannitolum - 120,175 mg, cellulose microcrystallic - 17,150 mg, a macrogoal-6000 - 2,450 mg, the castor oil hydrogenated - 1,225 mg;

Tablet cover: опадрай pink (lactoses monohydrate - 2,800 mg, a gipromelloza (15 CPS) - 1,921 mg, titanium dioxide (E171) of-1,656 mg, triacetin - 0,560 mg, ferrous oxide red (E172) - 0,063 mg) - 7,000 mg.

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 adenosinediphosphate (ADF) with his receptor on 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, usually, within 5 days.

Pharmacokinetics. Absorption. After intake in a dose of 75 mg a day it is quickly soaked up, characterized by high absorption and bioavailability. However concentration of initial substance in plasma low and in 2 h after reception does not reach a measurement limit (0,025 mkg/l).
According to renal secretion of metabolites of a klopidogrel 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.

Metabolism. Klopidogrel is actively metabolized in a liver, and the main metabolite - inactive derivative carboxyl acid, makes about 85% of the substance circulating in a blood plasma. Time of achievement of the maximum concentration (TCmax) of this metabolite (Cmax - about 3 mg/l after multiple dose inside in a dose of 75 mg) is reached in 1 h after intake.
Active metabolite - tiolny derivative klopidogret - it is formed by oxidation of a klopidogrel to 2-oxo-klopidogrela and the subsequent hydrolysis. In vitro this way of metabolism occurs by means of isoenzymes of P450, CYP2C19, CYP1A2 and CYP2B6. The active tiolny metabolite of a klopidogrel allocated to in vitro quickly it is also irreversible contacts receptors of thrombocytes, blocking aggregation of thrombocytes.

Removal. About 50% of drug are removed by kidneys and about 46% intestines during 120 h after intake. After a single dose in a dose of 75 mg the elimination half-life (T1/2) of a klopidogrel makes about 6 h. The elimination half-life of the main circulating inactive metabolite after one-time and repeated reception makes 8 h.
Concentration of the main circulating metabolite in plasma after reception of 75 mg a day at patients with a heavy chronic renal failure (the clearance of creatinine (CC) from 5 to 15 ml/min.) is lower in comparison with patients with a moderately severe chronic renal failure (KK from 30 to 60 ml/min.) and healthy volunteers. Though inhibition ADF-indutsirovannoy of aggregation of thrombocytes at patients with a renal failure was lower too, than at healthy volunteers, lengthening of a bleeding time was same, as well as at the healthy volunteers accepting 75 mg of a klopidogrel a day. Besides, all patients had a good clinical portability.
At patients with cirrhosis reception of a klopidogrel in a daily dose of 75 mg within 10 days was safe and was well transferred. Cmax of a klopidogrel at single and repeated use for patients with cirrhosis was much higher, than at healthy volunteers. However, plasma concentration of the main circulating metabolite and ADF-indutsirovannaya aggregation of thrombocytes, and also a bleeding time were comparable in both groups.

Pharmacogenetics. Several polymorphic enzymes of the P450 system participate in activation of a klopidogrel. The isoenzyme of SUR2S19 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 the allele 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, * 6, * 7 and * 8, but they seldom meet in the general population.

Separate groups of patients. The pharmacokinetics of an active metabolite of a klopidogrel at separate groups of patients is not studied.
Advanced age
Distinctions in indicators of aggregation of thrombocytes and a bleeding time between elderly people (75 years are more senior) and young volunteers were not observed. Dose adjustment for elderly people is not required.
Renal failure
After repeated receptions of a klopidogrel in a dose of 75 mg/days at patients with heavy renal failures (KK from 5 to 15 ml/min.) inhibition ADF-indutsirovannoy aggregations of thrombocytes are 25% lower, than at healthy volunteers; lengthening of a bleeding time is identical in comparison with healthy volunteers, the accepting 75 mg of a klopidogrel a day.
Abnormal liver function
The average time of bleeding and inhibition ADF-indutsirovannoy of aggregation at use of a klopidogrel in a dose of 75 mg/days within 10 days at patients with severe damage of a liver is comparable to healthy volunteers.

Indications to use:

- Prevention of aterotrombotichesky events at the patients who had 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 (ASK)) 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 performing thrombolytic therapy.
- 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:

Inside, irrespective of meal.
For prevention of aterotrombotichesky events at patients with a myocardial infarction, an ischemic stroke or the diagnosed occlusion of peripheral arteries - on 75 mg of 1 times a day. At patients with a myocardial infarction treatment should be begun from the first days to the 35th day of a myocardial infarction, and at patients with an ischemic stroke - in terms from 7 days up to 6 months after an ischemic stroke.
For prevention of aterotrombotichesky events at an acute coronary syndrome without raising of a segment of ST (unstable stenocardia, a myocardial infarction without Q tooth) - begin with a single dose of a load dose - 300 mg, and then accept 75 mg a day (in combination with ASK in doses of 75-325 mg a day, the recommended dose - 100 mg a day). The maximum favorable effect occurs in 3 months. A course of treatment till 1 year.
For prevention of aterotrombotichesky events at an acute coronary syndrome with raising of a segment of ST (an acute myocardial infarction with raising of a segment of ST) - on 75 mg a day with an initial single dose of a load dose in a combination with ASK and trombolitikam (or without trombolitik).
The combination therapy is begun as soon as possible after emergence of symptoms and continued within, at least, 4 weeks. At patients it has to is more senior 75 years treatment klopidogrely to begin without reception of its load dose.
At patients with genetically caused depression of function of an isoenzyme of CYP2C19 reduction of effect of a klopidogrel is possible. The optimum mode of dosing at such patients is not set.
Experience of use for patients with HPN or moderate degree of a liver failure is limited.

Features of use:

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); it is regular to investigate functional activity of a liver.
Klopidogrel it is necessary to apply with care at patients with risk of the expressed bleeding connected with injuries, surgical interventions at the patients having the damages inclined to bleeding (especially gastrointestinal and intraocular), and also at the patients receiving ASK, non-steroidal anti-inflammatory drugs (including TsOG-2), heparin or inhibitors of a glycoprotein of IIb/Sha. It is necessary to watch patients carefully for identification of any symptoms of bleeding, including hidden, especially for the first weeks of use of drug and/or after the invasive procedures on heart or surgeries.
Simultaneous use of a klopidogrel and warfarin can increase intensity of bleeding 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 with warfarin is not recommended.
In case of surgical interventions if antiagregantny action is undesirable, the course of treatment should be stopped in 7 days prior to operation.
Patients have to be warned that at reception of a klopidogrel (one or in a combination with ASK) 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 inform on it the doctor. Patients have to inform also the doctor on administration of drug if operative measures are coming them (including dental).
Very seldom against the background of reception of a klopidogrel the trombotichesky Werlhof's disease (TWD), sometimes after short-term use developed. This state is characterized by thrombocytopenia and mikroangiopatichesky hemolitic anemia in combination with neurologic signs, damage of kidneys and fever. The Trombotichesky Werlhof's disease - potentially zhizneugrozhayushchy state demanding immediate treatment including a plasma exchange.
Due to the lack of data it is not recommended to appoint klopidogret to patients with an acute ischemic stroke prescription less than 7 days.
At heavy abnormal liver functions it is necessary to remember risk of development of hemorrhagic diathesis therefore these patients should appoint with care klopidogret because of limited experience of use of drug for these patients.
Experience of use of a klopidogrel for patients with a renal failure is limited therefore to these patients klopidogret it is necessary to appoint with care. The dosage forms containing the hydrogenated castor oil can cause dyspepsia and diarrhea.
The drug Klopideks® contain lactose therefore patients should not use drug with hereditary intolerance of a galactose, deficit of lactase or a sprue of glucose and a galactose.

Influence on ability of control of vehicles and mechanisms
Klopidogrel does not influence ability to control of vehicles and mechanisms.

Side effects:

Frequency of side effects is determined according to the following definitions: 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.
The most often appearing reaction - bleeding which meets for the first month of administration of drug. Cases of severe bleeding are registered at the patients accepting klopidogret along with ASK or klopidogret with ASK and heparin.
From bodies of a hemopoiesis: infrequently - thrombocytopenia, a leukopenia, an eosinophilia; seldom - the neytropepiya including expressed; very seldom - a trombotichesky Werlhof's disease, anemia, including aplastic, a pancytopenia, an agranulocytosis, heavy thrombocytopenia, a granulocytopenia.
From a nervous system: infrequently - a headache, dizziness, paresthesias, intracranial bleeding, including with a lethal outcome; very seldom - confusion of consciousness, a hallucination, taste disturbance.
From sense bodys: infrequently - hemorrhage in a conjunctiva, eyes, a retina; 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: very often - nasal bleeding; very seldom - a bronchospasm, an intersticial pneumonitis, pulmonary bleeding, a pneumorrhagia.
From the alimentary system: 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 - retroperitoneal bleeding; 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; very seldom - a Quincke's disease, a small tortoiseshell, erythematic rash, a mnogoformny erythema, Stephens-Johnson's syndrome, a toxic epidermal necrolysis, eczema, red 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.
Allergic reactions: very seldom - anaphylactic reactions, a serum disease.
Laboratory indicators: infrequently - lengthening of a bleeding time.
Others: very seldom - fever.

Interaction with other medicines:

Simultaneous use of a klopidogrel and warfarin in connection with the increased risk of bleedings is not recommended.
Purpose of inhibitors of a glycoprotein of Ilb/IIIa together with klopidogrely increases risk of development of bleedings therefore it is recommended to be careful at their simultaneous use.
ASK does not change the inhibiting effect of a klopidogrel to ADF the induced aggregation of thrombocytes, but klopidogret strengthens action of ASK on collagen - the induced aggregation of thrombocytes. Combined use of these drugs demands care. However at the patients suffering from an acute coronary syndrome without raising of a segment of ST prolonged combined use клопидогреля and ASK is recommended (till 1 year).
At simultaneous use with NPVP the risk of bleedings therefore it is necessary to be careful at their simultaneous use can increase.
The concomitant use with CYP2C19 inhibitors (for example, омепразол) is not recommended.
The active metabolite of a klopidorgel inhibits activity of an isoenzyme of CYP2C9 therefore concentration of Phenytoinum, Tolbutamidum and NPVP in a blood plasma can increase.
Numerous clinical trials did not reveal significant clinical interaction at co-administration of a klopidogrel and such drugs as атенолол, the APF inhibitors, means reducing the content of cholesterol in blood, nifedipine, digoxin, phenobarbital, Cimetidinum, estrogen, theophylline.
Antacids do not influence absorption of a klopidogrel.

Contraindications:

Hypersensitivity; lactose intolerance, deficit of lactase and syndrome of glyukozo-galaktozny malabsorption; heavy liver failure; acute bleeding (including round ulcer or intracraneal hemorrhage); pregnancy and period of a lactation; children's age up to 18 years.

With care
The moderate liver failure, the chronic renal failure (CRF), morbid conditions increasing risk of development of bleeding (including, an injury, operations), tendency to bleedings, a concomitant use of ASK, warfarin, non-steroidal anti-inflammatory drugs (NPVS) (including the selection TsOG-2 inhibitors), heparin, IIb/IIIa glycoprotein inhibitors, hereditary depression of function of CYP2C19.

Use at pregnancy and during breastfeeding
Pregnancy
As clinical data on use of drug during pregnancy are absent, use of a klopidogrel for pregnant women is not recommended. Drug can be used during pregnancy only in that case when the advantage for mother exceeds potential risk for a fruit.
Tests for animals do not indicate direct or indirect adverse effects on the course of pregnancy, embryonic development, childbirth and post-natal development.
Breastfeeding
In need of therapy klopidogrely it is necessary to stop breastfeeding as tests on rats showed that klopidogret and/or its metabolites are excreted in breast milk. Data on penetration of a klopidogrel into breast milk of the person are not known.

Overdose:

Symptoms: lengthening of a bleeding time and the subsequent complications in the form of development of bleedings is possible.
Treatment: bleeding stop, transfusion of a platelet concentrate.

Storage conditions:

At a temperature not above 25 °C.
To store in the place, unavailable to children!

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated 75 mg
On 15 tablets in PVH/PVDH//the blister Is scarlet. 2 blisters together with the application instruction place in a cardboard pack.