Aspigrel

General characteristics. Structure:

Active ingredients: 75 mg клопидогреля (in the form of a klopidogrel of bisulphate), 75 mg of ascorbic acid.

Excipients for клопидогреля: beta cyclodextrin, talc, silicon colloid anhydrous, starch corn, microcrystallic cellulose.

Excipients for a tablet of the slowed-down effect of acetylsalicylic acid – starch, microcrystallic cellulose, the talc purified lemon acid, stearic acid, aerosil.

The medicinal antitrombotichesky drug used in cardiology for treatment of unstable stenocardia and a myocardial infarction.

Pharmacological properties:

Pharmacodynamics. Aspigrel is the combined drug which effect is caused by pharmacological properties клопидогреля and acetylsalicylic acid, being its part. Klopidogrel selectively blocks linkng of adenosinediphosphate (ADF) with a receptor on surfaces of a thrombocyte and activation of the GPIIb/IIIa complex under the influence of ADF, suppressing thus aggregation of thrombocytes. It also suppresses the aggregation of thrombocytes caused by other agonists, way of blockade of activity of thrombocytes the released ADF. Klopidogrel brings to irreversible change of a receptor of ADF. Therefore, the thrombocytes which entered with it interaction remain unreceptive to action of ADF during all term of their life, however normal function of thrombocytes is recovered with a speed, the corresponding speed of updating of thrombocytes.

Dozozavisimy suppression of aggregation of thrombocytes under influence клопидогреля is observed in 2 hours after reception of the first dose of Asp_irel, and permanent decrease in aggregation of thrombocytes is established between 3 and 7 days of administration of drug.

Acetylsalicylic acid in small doses has antiagregantny effect, in higher doses febrifugal and antiinflammatory action is shown. The main mechanism of effect of acetylsalicylic acid is the irreversible inactivation of enzyme of cyclooxygenase, as a result of it synthesis of prostaglandins, простациклінів by endothelial cells (in doses more than 300 mg) and A2 thromboxane in thrombocytes is broken. Irreversible disturbance of synthesis in thrombocytes of A2 thromboxane causes antiagregantny effect of acetylsalicylic acid. So, Aspigrel who is a combination клопидогреля and acetylsalicylic acid, brings to the expressed antitrombotichesky effect by simultaneous blockade of two different ways of aggregation of thrombocytes.

Pharmacokinetics. Klopidogrel. After oral administration of a dose of 75 mg a day клопидогрель it is quickly absorbed, however concentration of the main connection in plasma is small and in 2 hours after reception does not reach a measurement limit (0,00025 mg/l). On the basis of definition of excretion of metabolites of a klopidogrel with urine it is possible to claim that its absorption makes about 50%. Klopidogrel is metabolized in a liver. Its main metabolite (carboxyflax derivative) is inactive and makes 85% circulating in plasma of initial connection. The maximum concentration of this metabolite in plasma (about 3 mg/l after use of repeated peroral doses in 75 mg) is observed approximately in 1 hour after reception.

Klopidogrel is a predecessor of active ingredient. Its active metabolite (thiol derivative) is formed by oxidation in 2-oxo-klopidogrel with the subsequent hydrolysis. The Okisnyuvalny stage is regulated, first of all, by isoenzymes of P450 2B6 and 3A4 cytochrome and to a lesser extent – 1A1, 1A2 and 1C19. An active thiol metabolite which was allocated to in vitro quickly and it is irreversible contacts platelet receptors, suppressing aggregation of thrombocytes. This metabolite in plasma is not found. The kinetics of the main metabolite has linear dependence (increase in concentration in plasma depending on doses) within doses from 50 to 150 mg клопидогреля. Klopidogrel and the main circulating metabolite reversibly contact proteins of human in vitro plasma (98 and 94% respectively). Time of semi-removal of the main circulating metabolite makes 8 hours after single and repeated use, 50% are allocated with kidneys, 46% – intestines.

Acetylsalicylic acid. After oral administration acetylsalicylic acid turns into the main active metabolite - salicylic acid. Absorption of acetilsalicylic and salicylic acids comes from a GIT quickly and completely. The maximum level of concentration in a blood plasma is reached in 10-20 min. (acetylsalicylic acid) or in 45-120 min. (the general salicylate). Extent of linkng with proteins depends on concentration and makes for acetylsalicylic acid 49-70%, for salicylic – 66-98%. Acetylsalicylic acid for 50% is metabolized at the first passing through a liver. Gentisic acid and it глицинконъюгат is a metabolite of acetylsalicylic acid, together with salicylic acid, глицинконъюгат salicylic acid. Acetylsalicylic acid is removed in the form of metabolites preferential by kidneys. The elimination half-life of acetylsalicylic acid makes about 20 minutes. The elimination half-life of salicylic acid increases in proportion to the accepted dose and makes 2, 4 and 20 hours. Acetylsalicylic acid gets into breast milk, cerebrospinal fluid, synovial fluid and through a blood-brain barrier.

Indications to use:

- An acute coronary syndrome (unstable stenocardia, a myocardial infarction without Q2 tooth, a myocardial infarction with raising of a segment of ST), including when carrying out transdermal coronary interventions.

- Long secondary prevention of an acute coronary syndrome after the transdermal coronary interventions (TCI), both with stenting, and without it.

Route of administration and doses:

Adults and patients of advanced age. Aspigrel appoint on 1 capsule irrespective of meal once a day.

Acute coronary syndrome. Aspigrel appoint from the first day of development of the acute coronary syndrome (ACS) in independence of its option. At Construction Department without raising of a segment of ST (unstable stenocardia, a myocardial infarction without Q tooth) for the purpose of strengthening antitrombotichesky actions along with Aspigrel appoint not fractional heparin or low-molecular heparins, at the same time give preference of an enoksaparin (for example, Ekleks_i). At Construction Department with raising of a segment of ST (a myocardial infarction with raising of a segment of ST), except purpose of heparins, along with Aspigrel fibrinolitikam carry out thrombolytic therapy fibrinspetsifichesky (for example, an alteplaza) or fibrinnespetsifichesky (for example, to Streptaliza). At purpose of heparins and thrombolytic therapy it is necessary to consider the corresponding contraindications.

At Construction Department without raising of a segment of ST therapy by Aspigrel has to continue within 12 months, at Construction Department with raising of a segment of ST – within 1 month. Efficiency of longer therapy клопидогреля and acetylsalicylic acid in controlled clinical trials was not estimated by a combination, however it can be reasonable for further secondary prevention of an acute coronary syndrome. The decision on expediency of continuation of therapy of more above-stated terms by Aspigrel is made by the doctor individually in each case.

Long secondary prevention of an acute coronary syndrome after intradermal coronary interventions (ChKV). Aspigrel appoint with the preventive purpose after ChKV, both with stenting, and without it, within 12 months. At the same time therapy by Aspigrel has to continue surely not less than 1 month after establishment of a metal stent.

Features of use:

At Aspigrel's use blood test needs to be carried out within the first week of treatment. As well as other antitrombotichesky drugs, Aspigrel it is necessary to apply with care at patients with the increased risk of bleedings owing to injuries, surgical interventions or other morbid conditions.

The combined use to Aspigrel with anticoagulants, trombolitika, antithrombocytic drugs is followed by the increased risk of development of bleedings. In case of surgical interventions if antiagregantny action is undesirable, the course of treatment Aspigrel should be stopped in 7 days prior to operation.

Careful observation of patients is necessary for identification of symptoms of bleeding, including the concealed hemorrhages, especially within the first weeks of treatment and/or after the invasive cardial procedures or surgical intervention.

Aspigrel extends a bleeding time and has to be applied with care to treatment of patients with risk of bleedings (especially gastrointestinal and intraocular). Patients should be warned that the stop of bleeding, caused by Aspigrel's use, demands bigger time. Patients have to report to the doctor about each case unusual (from the point of view of the place and/or duration) bleedings. Patients have to inform the doctor and the stomatologist on administration of drug before an operative measure or if the doctor appoints medicine, new to the patient.

Aspigrel it is necessary to appoint with care the patient with moderate abnormal liver functions at which developing of hemorrhagic diathesis is possible and at a renal and liver failure.

With care Aspigrel it is necessary to appoint at gout, a hyperuricemia, and also to the patients having in the anamnesis of the instruction on cankers of digestive tract or gastrointestinal bleedings, bronchial asthma, chronic diseases of a respiratory organs, hay fever, polyposes of a mucous membrane of a nose, allergic reactions to medicines at deficit of vitamin K and glyukozo-6-fosfatdegidrogenazy.

Patients of advanced age can have a hypersensitivity to pharmacological effect of drug. Therefore for this group of patients drug needs to be used with care.

Use of acetylsalicylic acid can cause a bronchospasm in patients with bronchial asthma, hay fever, polipozy a mucous membrane of a nose, chronic respiratory diseases, allergic reactions to other medicines (in the form of skin reactions, an itch, small tortoiseshell). Acetylsalicylic acid in small doses can provoke development of gout in predisposed patients (with reduced removal of uric acid from an organism).

Ability to influence the speed of reactions at control of motor transport or work with other mechanisms. Any signs of deterioration in ability to drive the car or deterioration in work with mechanisms and reduction of mental working capacity after Aspigrel's use are noted.

Use during pregnancy or feeding by a breast. Aspigrel is contraindicated during pregnancy and feeding by a breast.

Children. Safety and efficiency of drug at persons under 18 are not established.

Side effects:

According to WHO recommendations, the frequency of side effects is classified as follows: often – 1-10%, infrequently – 0.1-1%, is rare – 0.01-0.1%, is very rare – less than 0.01%.

Klopidogrel. Hemorrhagic disturbances. Bleedings are the most frequent side effect клопидогреля. Separate cases of heavy bleedings, including with a lethal outcome (especially intracranial, gastrointestinal and retroperitoneal bleedings), hard cases of skin bleedings (purple), musculoskeletal bleedings (a hemarthrosis, a hematoma), eye bleedings (conjunctive,-point, retinal), nasal bleedings, bleedings from a respiratory path (a pneumorrhagia, pulmonary bleeding), a hamaturia and bleedings from an operational wound are recorded. In most cases bleedings were observed within the first month of treatment. At patients who stopped reception клопидогреля more than in 5 days prior to surgical intervention, increase in frequency of large bleedings within 7 days after operation of coronary shunting was not noted.

Hematologic disturbances. Very seldom – heavy thrombocytopenia (quantity of thrombocytes less 30Ε109/л), an agranulocytosis, anemia and aplastic anemia / pancytopenia, a heavy neutropenia (less than 0,45Õ09/l). Extremely seldom after use of a klopidogrel cases of the trombotichesky Werlhof's disease (TWD) were observed. The Chamber of Commerce and Industry is characterized by thrombocytopenia and mikroangiopatichesky hemolitic anemia with neurologic disturbances, dysfunction of kidneys and a hyperthermia. TTP is a state which demands immediate intervention, including a plasma exchange.

Renal failure. Very seldom – increase in level of creatinine, a glomerulonephritis.

Abnormal liver function. Very seldom – changes in laboratory indicators of function of a liver (increase in level of transaminases) and hepatitis.

Disturbances of the central and peripheral nervous system. Infrequently - a headache, dizziness, paresthesias. Very seldom - confusion of consciousness and a hallucination.

Gastrointestinal frustration. Often - abdominal pain, dyspepsia, a diarrhea. Infrequently - nausea, heartburn, vomiting, stomach ulcer and a duodenum, a lock, a meteorism and gastritis. Very seldom – pancreatitis, colitis (including ulcer), stomatitis.

Allergic reactions. Infrequently – rash, an itch. Very seldom - hypersensitivity reactions in the form of a small tortoiseshell, a Quincke's edema, violent rash, a multimorfny erythema, a bronchospasm, a Quincke's disease, anaphylactic reactions, temperature increase, arthralgias and arthritis.

Others. Extremely seldom – disturbance of flavoring feelings.

Acetylsalicylic acid. The most frequent side reactions – nausea, anorexia, pain in epigastric area. Seldom - especially at prolonged use of the raised doses of acetylsalicylic acid, erosive cankers of bodies of digestive tract, the gastric bleeding which is followed by a melena are possible. At patients with individual hypersensitivity to salicylates development of allergic reactions in the form of skin rashes, at patients with bronchial asthma – increase in frequency of emergence of attacks of a bronchospasm is possible. Abnormal liver functions, heavy reactions are very seldom possible from skin, up to development of a multimorfny erythema, a renal failure, a hypoglycemia.

Interaction with other medicines:

Warfarin. Simultaneous use is not recommended to Asp_grel with warfarin as such combination can strengthen risk and intensity of bleeding. However some patients can have it reasonable, for example, in the presence of fibrillation of auricles or venous thromboses and thromboembolisms. The decision about simultaneous use Asp_grelya with warfarin is made by the doctor individually in each case.

Nefrakts_yovany heparin and low-molecular heparins. Asp_grel and heparins are usually used together at treatment of an acute coronary syndrome, however it is necessary to remember that this combination can strengthen risk of bleeding.

Blockers of gl_koprote_novy receptors of IIb/IIIa. Simultaneous use with Asp_grel is possible, however it is necessary to remember that this combination can strengthen risk of bleeding.

Trombolitiki. Aspigrel and trombolitik are used together at treatment of an acute myocardial infarction with raising of a segment of ST, however it is necessary to remember that this combination can strengthen risk of bleeding.

Digoxin. Aspigrel increases concentration of digoxin in a blood plasma and strengthens its effects due to decrease in its removal.

Methotrexate. At combined use acetylsalicylic acid strengthens effect of a methotrexate due to decrease in its renal clearance and replacement from bonds with proteins of a blood plasma that is followed by the increased frequency of development of side effects from bodies of a hemopoiesis. Therefore the combined use of Aspigrel with a methotrexate in a dose of 15 mg a week and is not recommended any more.

Hypoglycemic drugs. At simultaneous use of acetylsalicylic acid and peroral anti-diabetic drugs from group of derivatives of sulphonylurea the hypoglycemic effect of the last amplifies.

Uricosuric drugs. Acetylsalicylic acid weakens action of uricosuric means.

Non-steroidal anti-inflammatory drugs (NPVS). Simultaneous use клопидогреля and Naproxenum increased quantity of the concealed gastrointestinal hemorrhages. Owing to lack of researches concerning interaction of a klopidogrel with other NPVS it is not found out for today whether there is an increased risk of gastrointestinal bleedings at a combination therapy клопидогреля with all NPVP. At simultaneous use of acetylsalicylic acid and NPVS therapeutic and side effects of the last amplify. The ibuprofen suppresses antitrombotichesky activity of acetylsalicylic acid. Thus, care at the combined use of non-steroidal anti-inflammatory drugs is necessary and Aspigrelya.

Glucocorticoid means (GKZ). At the combined use of glucocorticoid means (GKZ) and acetylsalicylic acid the risk of development of gastrointestinal bleeding increases.

Other forms of the combined use of drugs. Clinically significant pharmakodinamichesky interaction at use клопидогреля along with atenololy, nifedipine, phenobarbital, Cimetidinum and estrogen is not revealed. The data obtained during the researches with microsomes of a liver of the person demonstrate to what клопидогрель can block activity of P4502C9 cytochrome that can lead to increase in level in plasma of such medicines as Phenytoinum and Tolbutamidum, NPVS which are metabolized by means of P4502C9 cytochrome. Despite it, data of clinical trial of CAPRIE demonstrate that Phenytoinum and Tolbutamidum can safely be applied along with klopidogrely.

Contraindications:

• The increased individual sensitivity to клопидогрелю or acetylsalicylic acid.
• The expressed liver failure.
• Acute bleeding, including, gastrointestinal bleeding.
• Intracraneal hemorrhage.
• Hemorrhagic diathesis.
• The bronchial asthma induced by use of salicylates and non-steroidal anti-inflammatory drugs, "an aspirinovy triad" (a combination of bronchial asthma, the nose recuring a polypose and okolonosovy bosoms and sensitivity to acetylsalicylic acid).
• Pregnancy and period of feeding by a breast.
• Children's age up to 18 years.

Overdose:

At Aspigrel's overdose increase in a bleeding time can be observed. The antidote of pharmacological activity клопидогреля is not found. If bystry correction of duration of bleeding is necessary that it was extended, клопидогреля it can be terminated by transfusion of a platelet concentrate.

At overdose of acetylsalicylic acid there can be such symptoms: at overdose of moderate severity – nausea, vomiting, a sonitus, deterioration in hearing, dizziness, confusion of consciousness, at heavy degree – fever, a hyperventilation, ketoacidosis, a respiratory alkalosis, a coma, cardiovascular and respiratory insufficiency, the expressed hyperglycemia. The overdose is most probable at patients of advanced age.

Treatment. Absorbent carbon, a gastric lavage, definition of indicators of acid-base balance, the alkaline and forced alkaline diuresis, a hemodialysis, infusional therapy, a symptomatic treatment. It is necessary to carry out an alkaline diuresis until PH value within 7,5-8 is reached. The forced alkaline diuresis should be carried out at concentration of salicylates in plasma more than 500 mg/l (3,6 mmol/l).

Storage conditions:

To store in the place, dry, unavailable to children, at a temperature not over 25 ºС. Period of validity 2 years.

Issue conditions:

According to the recipe

Packaging:

On 10 capsules in the blister, on 10 blisters in a cardboard pack.