hexahydrobenzylcarbonate

Selectively reduces the binding of adenosine diphosphate receptor on platelets and activation receptor glycoprotein IIb / IIIa by the action, reducing platelet aggregation. Decreases platelet aggregation induced by other agonists by preventing activation  released does not affect the activity of phosphodiesterase . It binds irreversibly to platelet ADP receptors which remain impervious to hexahydrobenzylcarbonate stimulation throughout life cycle (approximately 7 days). Platelet Aggregation Inhibition is observed after 2 hours after administration (40% inhibition) of the initial dose of 400 mg. The maximum effect (60% inhibition of aggregation) develops after 4-7 days of continuous use at a dose of 50-100 mg / day. Antiplatelet effect lasts the entire period of the life of platelets (7-10 days).

. Pharmacokinetics
After a single dose and at course taken orally at a dose of 75 mg per day, clopidogrel is rapidly absorbed.
The absorption and bioavailability – high. However, the concentration of the starting material is low in the plasma and in 2 hours after taking the measurement reaches the limit (0.025 mg / l). Relationship to plasma proteins – 98-94%. It is a prodrug.
Clopidogrel is rapidly metabolized in the liver. The active metabolite in the blood can not be detected. Mainly determined metabolite – inactive derivative of a carboxylic acid, the time to reach maximum concentration (the TC max ) which after repeated oral doses of 75 mg is reached after 1 h, the maximum concentration (the C max ) -. About 3 mg / l
About 50% of the drug is excreted by the kidneys, and about 46% intestines 120 hours after administration. The half-life (T1 / 2) of the main metabolite after single and repeated administration is 8 hours. Concentrations of metabolites excreted by the kidneys -. 50% of the
concentration of the main metabolite in plasma after administration of 75 mg / d lower in patients with severe chronic renal impairment (creatinine clearance (CC) 5-15 ml / min) compared with patients with chronic renal insufficiency of moderate severity (CC from 30 to 60 ml / min), and hexahydrobenzylcarbonate healthy individuals.

Indications.
Prevention of thrombotic complications in patients with myocardial infarction, ischemic stroke or peripheral arterial occlusive disease.
In combination with acetylsalicylic acid (ASA) for the prevention of thrombotic complications of acute coronary syndrome: ST-segment elevation at the possibility of thrombolytic therapy; without ST-segment elevation (unstable angina or myocardial infarction without tooth Q), including in patients undergoing stenting.

Contraindications.
– Hypersensitivity to the active or any subsidiary component of the drug.
– Lactose intolerance, lactase deficiency and syndrome of glucose-galactose malabsorption.
– Age 18 years (effectiveness and safety have not been established).
– Severe hepatic impairment.
– Acute bleeding (in including peptic ulcer or intracranial hemorrhage).
– Pregnancy and lactation.

Be wary.
Moderate hepatic insufficiency, chronic liver failure (CRF), pathological conditions increase the risk of bleeding (including trauma, surgery), a tendency to bleeding, concomitant use of ASA, warfarin, non-steroidal anti-inflammatory drugs (NSAIDs) (including inhibitors COX-2), heparin, glycoprotein IIb / IIIa, an inherited reduction isoenzyme CYP2C19 function.

Pregnancy and lactation.
In view of the lack of data, clopidogrel is not recommended during pregnancy and lactation.

. Dosing and Administration
Inside, regardless of meals.
For the prevention of thrombotic complications in patients with myocardial infarction, ischemic stroke or peripheral arterial occlusive disease -. 75 mg 1 time per day
in patients with myocardial infarction, treatment can begin from the first day on 35 th day of myocardial infarction and in patients with ischemic stroke -. in the period from 7 days to 6 months after an ischemic stroke
for the prevention of thrombotic complications of acute coronary syndrome without ST-segment elevation (unstable angina, myocardial infarction without tooth Q) – start with single dose loading dose – 300 mg, and then take 75 mg / day (in combination with ASA in doses of 75-325 mg / day, the recommended dose – 100 mg / day). The maximum beneficial effect occurs within 3 months. The course of treatment up to 1 year.
For the prevention of thrombotic complications of acute coronary syndrome segment elevation ST (acute myocardial infarction with ST-segment elevation) – 75 mg / day with an initial single dose loading dose in combination with ASA and thrombolytics (or without thrombolytics) .
Combination therapy is started as soon as hexahydrobenzylcarbonate possible after the onset of symptoms, and continued for at least 4 weeks. In patients older than 75 years treated with clopidogrel should start without receiving its loading dose.
In patients with a genetically determined reduction function isoenzyme CYP2C19 may decrease the effects of clopidogrel. The optimal dosing regimen in such patients is not established.
The experience of use in patients with chronic renal failure or moderate hepatic insufficiency is limited.

Side effects.
The bleeding – the most common reaction that occurs during the first month of treatment. Cases of major bleeding reported in patients taking clopidogrel along with ASA or clopidogrel with ASA and heparin (see “Special Instructions” section.).
The frequency of side effects is determined according to the following definitions: very often – more than 1/10, often – more than 1/100 and less than 1/10, rarely – more than 1/1000 and less than 1/100, rarely – more than 1/10000 and less than 1/1000, very rare – less than 1/10000, including isolated cases. Within each frequency class undesirable effects are presented in order of decreasing severity.

From the side of hematopoiesis: rarely – thrombocytopenia, leukopenia, eosinophilia; rarely – neytropepiya, including expressed; very rarely – thrombotic thrombocytopenic purpura, anemia including aplastic, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia. From the nervous system: rarely – headache, dizziness, paresthesia, intracranial bleeding, including fatal; very rare – confusion, hallucinations, disturbance of taste. From the sensory organs: rarely – a hemorrhage in the conjunctiva, the eye, the retina; . rare – vertigo Since the cardiovascular system: often – hematoma; very rarely – severe bleeding, bleeding from the surgical wound, vasculitis, decreased blood pressure. The respiratory system: very often – nosebleeds; very rarely – bronchospasm, interstitial pneumonitis, pulmonary hemorrhage, hemoptysis. From the digestive system: often – diarrhea, abdominal pain, indigestion, bleeding from the gastrointestinal tract; infrequently – gastric ulcer and 12 duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence; rarely – retroperitoneal bleeding; very rarely – pancreatitis, colitis, including ulcerative or lymphocytic stomatitis, acute liver failure, hepatitis, violation of liver function tests, bleeding from the gastrointestinal tract with a fatal outcome. For the skin: often – subcutaneous hemorrhage; seldom – a skin rash, pruritus, purpura; very rarely – angioedema, urticaria, erythematous rash, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, eczema, lichen planus. From the musculoskeletal system: very rarely – hemarthrosis, arthritis, arthralgia, myalgia. From the urogenital system: rarely – hematuria; very rarely – glomerulonephritis, hypercreatininemia. Allergic reactions: very rare – anaphylactic reaction, serum sickness. Laboratory findings: Infrequent – lengthening of bleeding time, violations hexahydrobenzylcarbonate of liver function tests, increase in serum creatinine concentration. Others – very rare: fever.

 

Overdose.
Overdose clopidogrel may lead to a lengthening of bleeding time and subsequent bleeding complications. If there is bleeding should be applied to the appropriate treatment.
There were no antidotes pharmaceutical activity of clopidogrel.
If you need a quick correction to lengthen bleeding time, platelet transfusion is recommended.