Плагрил®

General characteristics. Structure:

Active agent: klopidogret hydrosulphate - 97,875, 75 mg of a klopidogrel are equivalent.
Excipients: cellulose microcrystallic (Avicel PH 112), Mannitolum, croscarmellose sodium, silicon dioxide colloid, magnesium stearate. Cover: dye of Opadray pink 03B54202 (gipromelloza, titanium dioxide, macrogoal-400, dye ferrous oxide red).

Description: round, biconvex tablets, film coated pink color, with a stamping "C 127" on one party.

Pharmacological properties:

Pharmacodynamics. Specific and active inhibitor of aggregation of thrombocytes; has coronarodilator effect. Selectively reduces linkng of adenosinediphosphate (ADF) with receptors on thrombocytes and activation of receptors of GPIIb/IIIa under the influence of ADF, weakening, thus, 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 h 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. Aggregation of thrombocytes and a bleeding time are returned to initial level, on average, in 5 days after the treatment termination.
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. Absorption and distribution

Absorption and bioavailability high; concentration in plasma low and in 2 h after reception does not reach a measurement limit (0,025 mkg/l). Klopidogrel and the main metabolite reversibly contact proteins of a blood plasma (98% and 94% respectively).

Metabolism

It is metabolized in a liver. The main metabolite - inactive derivative carboxyl acid, making about 85% of the connection circulating in plasma. Time of achievement of peak concentration (TCmax) of a metabolite, after repeated peroral doses of a klopidogrel of 75 mg, is reached in an hour (peak concentration (Cmax) - about 3 mg/l).
Klopidogrel is a predecessor of active ingredient. Its active metabolite, tiolny derivative, is formed by oxidation of a klopidogrel in 2-oxo-klopidogrel and the subsequent hydrolysis. Oxidizing process is regulated, first of all, by isoenzymes of P450 2B6 and 3A4 cytochrome, and, to a lesser extent, - 1A1, 1A2 and 1C19. An active tiolny metabolite quickly it is also irreversible contacts platelet receptors, suppressing, thus, aggregation of thrombocytes. This metabolite in plasma is not found.

Removal

Removal: kidneys - 50%, intestines - 46% (during 120 h after introduction). An elimination half-life (T1/2) of the main metabolite, after one-time and repeated reception, - 8 h. Concentration of the metabolites allocated by kidneys - 50%.

Pharmacokinetics in special clinical cases

Concentration of the main metabolite in plasma, after reception of a klopidogrel in a dose of 75 mg/days, is lower at patients with a serious illness of kidneys (the clearance of creatinine (CC) of 5-15 ml/min.), in comparison with patients with diseases of moderately severe kidneys (KK from 30 to 60 ml/min.) and healthy faces.
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 extended as well, as well as at the healthy volunteers receiving klopidogret 75 mg/days in a dose.
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 klopidogret, both after reception of a single dose, and in an equilibrium state, was many times higher at patients with cirrhosis, than at healthy faces.

Indications to use:

Prevention of ischemic disturbances (a myocardial infarction, a stroke, thrombosis of peripheral arteries, sudden vascular death) at patients with atherosclerosis, including: after the had myocardial infarction, an ischemic stroke or against the background of the diagnosed diseases of peripheral arteries;
at an acute coronary syndrome without raising of a segment of S-T (unstable stenocardia or a myocardial infarction without formation of a tooth of Q), in combination with acetylsalicylic acid).
at an acute coronary syndrome with raising of a segment of ST (an acute myocardial infarction), in a combination with acetylsalicylic acid, receiving drug treatment with possible use of thrombolytic therapy.

Route of administration and doses:

Inside, irrespective of meal.

For prevention of ischemic disturbances at patients after the had myocardial infarction, an ischemic stroke or against the background of the diagnosed diseases of peripheral arteries adult (including to elderly patients) appoint 75 mg of 1 times/days. Treatment should be begun in terms up to 35 days after the postponed Q-forming myocardial infarction and from 7 days to 6 months - after an ischemic stroke.

At an acute coronary syndrome without raising of a segment of S-T (unstable stenocardia or a myocardial infarction without formation of a tooth of Q) treatment it is necessary to begin 300 mg with purpose of a single load dose, then to continue use of drug in a dose of 75 mg of 1 times/days (with a concomitant use of acetylsalicylic acid in a dose of 75-325 mg/days). As use of acetylsalicylic acid in high doses is connected with big risk of bleedings, the recommended dose has to be not higher than 100 mg. A course of treatment - till 1 year.

At an acute coronary syndrome with raising of a segment of ST (an acute myocardial infarction) drug appoint in a dose 75 mg of 1 times/days, with use of an initial load dose in a combination with acetylsalicylic acid, in a combination or without trombolitik. For patients it has to is aged more senior 75 years treatment klopidogrely to be carried out without use of a load dose. The combination therapy is begun as soon as possible after emergence of symptoms and continued within at least 4 weeks.

Features of use:

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 drug of bleeding arising against the background of use demands bigger 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 are coming them or if the doctor appoints new to the patient of medicines.

During treatment it is necessary to control indicators of system of a hemostasis (AChTV, number of thrombocytes, tests of functional activity of thrombocytes); it is regular to investigate functional activity of a liver.

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

Influence on ability to driving of motor transport and to control of mechanisms

Signs of deterioration in ability of driving or reduction of mental working capacity after reception it was revealed not.

Side effects:

Depending on the frequency of emergence allocate the following groups of side effects: frequent - more than 1%, infrequent - 0,1-1%, rare - 0,01-0,1%, very rare - less than 0,01%.

From coagulant system of blood:
often - gastrointestinal bleedings; infrequently - a hemorrhagic stroke, lengthening of a bleeding time, nasal bleedings; seldom - hematomas, a hamaturia, and conjunctive bleedings.

From system of a hemopoiesis:
infrequently - thrombocytopenia; infrequently - a neutropenia, a leukopenia, an eosinophilia; very seldom - a Werlhof's disease; granulocytopenia, agranulocytosis, anemia and aplastic anemia.

From TsNS and peripheral nervous system: infrequently - a headache, dizziness, paresthesia; seldom - вертиго; very seldom - confusion of consciousness, a hallucination.

From cardiovascular system: very seldom - a vasculitis, a lowering of arterial pressure.

From respiratory system: very seldom - a bronchospasm, an intersticial pneumonitis.

From the alimentary system: often - dyspepsia, diarrhea, abdominal pains; infrequently - nausea, gastritis, a meteorism, a lock, vomiting, an ulceration of a mucous membrane of digestive tract; aggravation of a peptic ulcer of a stomach and duodenum; very seldom - colitis (including ulcer or lymphocytic colitis), pancreatitis, change of flavoring feelings, stomatitis, hepatitis, an acute liver failure, increase in activity of liver enzymes.

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

From an urinary system: very seldom - a glomerulonephritis.

Dermatological reactions: infrequently - an itch; very seldom - violent rash (a mnogoformny erythema, Stephens-Johnson's syndrome, a toxic epidermal necrolysis), erythematic rash, eczema, flat deprive.

Allergic reactions: very seldom - a Quincke's disease, a small tortoiseshell, anaphylactoid reactions, a serum disease.

Others: very seldom - temperature increase, increase in creatinine of blood.

Interaction with other medicines:

Strengthens antiagregantny effect of acetylsalicylic acid, heparin, indirect anticoagulants, non-steroidal anti-inflammatory drugs, at combined use increases risk of development of bleedings from digestive tract.

Inhibiting activity of one of CYP2C9 cytochrome enzymes, increases concentration of the medicines which are metabolized by means of CYP2C9 (Phenytoinum, Tolbutamidum).

Clinically significant pharmakodinamichesky interaction at use of a klopidogrel together with atenololy, nifedipine, phenobarbital, Cimetidinum, estrogen, digoxin, theophylline, Tolbutamidum, antiacid means is noted.

Contraindications:

Hypersensitivity to drug components; heavy liver failure; a hemorrhagic syndrome, acute bleeding (including intracraneal hemorrhage) and the diseases contributing to its development (a peptic ulcer of a stomach and a 12-perstny gut in aggravation stages, nonspecific ulcer colitis, tuberculosis, tumors of lungs, a hyper fibrinolysis); pregnancy, period of a lactation (breastfeeding); children's age up to 18 years (safety and efficiency of use are not established).

With care
Moderate liver and/or renal failure, injuries, states increasing risk of development of bleeding (including an injury, operations), a concomitant use of acetylsalicylic acid, non-steroidal anti-inflammatory drugs (including TsOG-2 inhibitors), heparin and inhibitors of a glycoprotein IIb/IIIa.

Overdose:

Symptoms: At one-time oral administration of 600 mg of a klopidogrel (the quantity equivalent to 8 standard tablets of 75 mg) to healthy people, by-effects were not. The bleeding time was extended by 1,7 times that corresponds to the size registered after reception of a therapeutic dose (75 mg a day).

Treatment: transfusion of a platelet concentrate. The specific antidote is absent.

Storage conditions:

List B. In the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children! Period of validity 2 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 75 mg. On 10 tablets in PVC/PVDH / the aluminum blister. On 3, 10 blisters together with the application instruction in a pack cardboard.