Klopidogrel

General characteristics. Structure:

Active ingredient: a klopidogrela of hydrosulphate – 0,097875 g,

in terms of klopidogret – 0,075000 g;

excipients: lactoses monohydrate – 0,186275 g, povidone (polyvinylpirrolidone low-molecular) – 0,001850 g, cellulose of microcrystallic 0,044400 g, talc – 0,011100 g, croscarmellose sodium (primelloza) – 0,014800 g, magnesium stearate – 0,003700 g;

excipients of a film cover: Опадрай the II Pink – 0,0097 g (polyvinyl alcohol, titanium dioxide, talc, a macrogoal (polyethyleneglycol), dye a carmine red (E120), an aluminum varnish on the basis of dye of a sunset of yellow (E110), an aluminum varnish on the basis of dye of red charming (E129), an aluminum varnish on the basis of dye of quinolinic yellow (E104)), a silicone emulsion – 0,0003 g.

Description.

Round biconvex tablets, film coated, pink color. On cross section color of a kernel of a tablet white or white with a yellow shade.

Pharmacological properties:

Pharmacodynamics. Klopidogrel specific and active inhibitor of aggregation of thrombocytes. Selectively reduces linkng of adenosinediphosphate (ADF) with receptors on thrombocytes and activation of receptors of a glycoprotein of IIb/IIIa under the influence of ADF, weakening aggregation of thrombocytes.

Reduces the aggregation of thrombocytes caused by other agonists, preventing their activation by the released ADF, does not influence activity of phosphodiesterase (FDE). It is irreversible contacts ADF-receptors of thrombocytes which remain unreceptive to stimulation of ADF throughout a life cycle (about 7 days).

Braking of aggregation of thrombocytes is observed in 2 hours after reception (40% inhibition) an initial dose of 400 mg. The maximum effect (60% aggregation suppression) develops in 4-7 days of constant reception in a dose of 50-100 mg/days Antiagregantny effect the entire period of life of thrombocytes (7-10 days) remains.

In the presence of atherosclerotic defeat of a vessel interferes with development of an aterotromboz irrespective of localization of vascular process (cerebrovascular, cardiovascular or peripheral defeats).

Pharmacokinetics. Klopidogrel is quickly soaked up after numerous reception on 75 mg a day.

Bioavailability – high. However concentration of initial substance in plasma low and in 2 hours after reception does not reach a measurement limit (0,025 mkg/l). Communication with proteins of plasma - 98-94%.

Klopidogrel is quickly metabolized in a liver. An active metabolite – inactive derivative carboxyl acid which time of achievement of the maximum concentration (TCmax), after repeated peroral doses of 75 mg, is reached in 1 hour (average maximum concentration (Cmax) - about 3 mg/l).

About 50% of drug are removed by kidneys and about 46% intestines within 120 hours after introduction. The elimination half-life (T1/2) of the main metabolite after one-time and repeated reception makes 8 hours. Concentration of the metabolites allocated by kidneys - 50%.

Concentration of the main metabolite in plasma after reception of 75 mg/days is lower at patients with a serious illness of kidneys (the clearance of creatinine (CC)
5-15 ml/min.) in comparison with patients with a disease of moderately severe kidneys (KK from 30 to 60 ml/min.) and healthy faces.

Indications to use:

Prevention of trombotichesky complications at patients with a myocardial infarction, an ischemic stroke or occlusion of peripheral arteries.

In a combination with Acetylsalicylic acid for prevention of trombotichesky complications at an acute coronary syndrome: with raising of a segment of ST at a possibility of performing thrombolytic therapy; without raising of a segment of ST (unstable stenocardia or a myocardial infarction without Q tooth), including at the patients who are exposed to stenting.

Route of administration and doses:

Inside, irrespective of meal.

For prevention of trombotichesky complications at patients with a myocardial infarction, an ischemic stroke or occlusion of peripheral arteries - on 75 mg of 1 times a day.

At patients with a myocardial infarction treatment can 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 trombotichesky complications 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/days (in combination with ASK in doses
75-325 mg/days, the recommended dose - 100 mg/days). The maximum favorable effect occurs in 3 months. A course of treatment till 1 year.

For prevention of trombotichesky complications 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/days 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  during   , 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 at an injury, surgical intervention, 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 inhibitors), heparin or inhibitors of a glycoprotein IIb/IIIa. 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 is not recommended as it can strengthen bleeding.

In case of 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 klopidogrel arising against the background of use (in combination with ASK or without it) bleeding demands bigger time, they have to report to the doctor about each case of bleeding. Patients have to inform also the doctor on administration of drug if operative measures are coming them.

After reception of a klopidogrel the trombotichesky Werlhof's disease (TWD) was found very seldom, sometimes after short-term use. This state is characterized by thrombocytopenia and mikroangiopatichesky hemolitic anemia in combination with neurologic signs, a renal failure or fever. TTP - potentially deadly state demanding immediate treatment including using a plasma exchange.

Due to the lack of data klopidogret it is impossible to recommend at acute (less than 7 days) ischemic strokes.

Experience of use of a klopidogrel for patients with   a renal failure is limited therefore this patient klopidogret it is necessary to appoint with care.

At heavy abnormal liver functions it is necessary to remember risk of development of hemorrhagic diathesis, experience of use of drug for patients with a moderate  abnormal liver function, it is limited therefore to these patients klopidogret it is necessary to appoint with care.

Side effects:

Bleeding – the most frequent reaction 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 (see the section "Special Instructions").

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. Within each class of frequencies undesirable effects are presented as severity reduction.

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

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

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 an eye conjunctiva, a retina; seldom - вертиго. 

From cardiovascular system: often - a hematoma; very seldom - heavy bleedings, bleeding from an operational wound, a vasculitis, decrease in the ABP. 

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 a GIT; 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 a GIT 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. 

Laboratory indicators: infrequently - lengthening of a bleeding time. 

Other - is very rare: arthralgia, arthritis, mialgiya, anaphylactoid reactions, serum disease, temperature increase, disturbances of functional trials of a liver, increase in concentration of creatinine of blood, glomerulonephritis, fever, hemarthrosis, gematouriya.

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, ASK, heparin together with klopidogrely increases risk of development of bleedings. 

At simultaneous use with NPVP the risk of bleedings can increase. 

The concomitant use with CYP2C19 inhibitors (for example, омепразол)  is not recommended. 

The active metabolite of a klopidogrel inhibits activity of an isoenzyme of CYP2C9 therefore concentration of Phenytoinum, Tolbutamidum and NPVP in plasma can increase.

Contraindications:

Hypersensitivity to active or any auxiliary component of drug.

Deficit of lactase, lactose intolerance, glyukozogalaktozny malabsorption.

Age up to 18 years (efficiency and safety of use are not established).

Heavy liver failure.

Active pathological bleeding (round ulcer or intracraneal hemorrhage).

Pregnancy and period of a lactation.

Overdose:

The overdose klopidogrely can lead to lengthening of a bleeding time and the subsequent complications. At detection of bleeding the corresponding treatment has to be applied.

Antidotes of pharmaceutical activity of a klopidogrel are not revealed.

If bystry correction of the extended bleeding time is necessary, transfusion of a platelet concentrate is recommended.

Storage conditions:

In the dry, protected from light place, 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 7 and 10 tablets in a blister strip packaging.

On 1, 2, 3 or 4 blister strip packagings together with the application instruction in a pack from a cardboard.