The composition and form of issue:
Tablets, film-coated. 1 tablet contains:
clopidogrel hydrosulfate 98,875 mg
(in terms of clopidogrel — 75 mg)
auxiliary substances: lactose, anhydrous — 108,125 mg microcrystalline — 30 mg starch pregelatinization 12 mg macrogol 6000 8 mg castor oil hydrogenated — 4 mg
shell: hypromellose 6.CP — 5,6 mg titanium dioxide (E171) of 1.46 mg dye iron oxide red (E172) — 0.04 mg talc — 0,50 mg propylene glycol — 0.4 mg
blistere in 7 or 10 PCs per cartons 2, 4, 8, 12 blister packs (7 pieces) or 3, 9 blisters (for 10 pieces).
Description pharmaceutical form:
Round, slightly biconvex tablets, film-coated pink.
View in cross section: white or off-white lumpy mass with a film cover pink.
Clopidogrel is rapidly absorbed in a dose of 75 mg per day. However, plasma concentrations of unchanged drug after 2 h is very low, below the threshold (of 2.2–2.5 ng/l). Absorption is at least 50% according to the renal secretion of metabolites of clopidogrel.
Clopidogrel is extensively metabolized in the liver and the main metabolite, is pharmacologically inactive derivative carboxylato acid is about 85% circulating plasma substances. Maximum plasma concentrations of this metabolite (approximately 3 mg/l after repeated oral administration at a dose of 75 mg) achieved approximately 1 hour after ingestion. Clopidogrel is a prodrug. Active metabolite, thiol derivative is formed by oxidation of clopidogrel to 2-oxo-clopidogrel and subsequent hydrolysis. The oxidation of clopidogrel occurs mainly through 2В6 and isoenzymes of cytochrome P450 ZA4, and to a lesser extent, isoenzymes 1A1, 1A2 and 2C19. The active thiol metabolite, isolated in vitro, binds rapidly and irreversibly to receptors on platelets, inhibiting their aggregation. This metabolite in plasma is not defined.
The pharmacokinetics of the main circulating metabolite is linear in the dose range clopidogrel from 50 to 150 mg.
Clopidogrel and the main circulating metabolite bind reversibly in vitro to plasma proteins (98% and 94%, respectively).
Within 120 h after ingestion of 14C-labeled clopidogrel approximately 50% is excreted by the kidneys and 46% — through the intestines.
T1/2 the main circulating metabolite after a single dose and receiving repeated doses is 8 hours.
After repeated application of 75 mg clopidogrel per day, plasma levels of the main circulating metabolite in patients with severe renal impairment (Cl creatinine from 5 to 15 ml/min) is lower than in patients with moderate-to-severe renal impairment (Cl creatinine clearance 30 to 60 ml/min) and healthy volunteers. Although inhibition of ADP-induced platelet aggregation in patients with renal failure was also lower (25%) than in healthy subjects, the prolongation of bleeding time was the same as that of the healthy volunteers who took 75 mg of clopidogrel per day. In addition, clinical tolerance was good in all patients. Pharmacodynamics and pharmacokinetics of clopidogrel was assessed in studies with single and repeated doses in healthy volunteers and patients with cirrhosis (Child-Pugh class A or b). Daily application within 10 days of clopidogrel at a dose of 75 mg/day was safe and well tolerated. Cmax of clopidogrel (with single and repeated application) in patients with liver cirrhosis was much higher than in healthy volunteers. However, the plasma concentrations of the main circulating metabolite and ADP-induced platelet aggregation and bleeding time were comparable between the groups.
Several polymorphic enzymes P450 system involved in the activation of clopidogrel. The isoenzyme CYP2C19 is involved in education, as an active metabolite, and intermediate metabolites — 2-exclamatorily. Pharmacokinetics and antiplatelet effects of the active metabolite of clopidogrel, was investigated by platelet aggregation ex vivo, differ, depending on the genotype of the CYP2C19 isoenzyme. The allele of CYP2C19*1 is responsible for the normal functioning of the metabolism, whereas alleles of the gene for the isoenzyme CYP2C19*2 and CYP2C19 isoenzyme*3 responsible for reduced metabolism. These alleles are responsible for the decrease in metabolism of approximately 85% of Caucasian and 99% among representatives of the Mongoloid race. Other alleles associated with reduced metabolism, represented by the isoenzymes CYP2C19*4, *5, *b, *7, *8, but they are rare in the General population.
A separate group of patients
The pharmacokinetics of the active metabolite in certain groups of patients has not been studied.
Differences in platelet aggregation and bleeding time in elderly and younger patients was observed.
Violation of kidney function
After repeated use of clopidogrel in a dose of 75 mg/day in patients with severe renal impairment (Cl creatinine clearance 5-15 ml / min) inhibition of ADP-reduced platelet aggregation 25% lower than in healthy volunteers, the prolongation of bleeding time equally in comparison with healthy volunteers (dose 75 mg/day).
The average bleeding time and inhibition of ADP-induced platelet aggregation was comparable with healthy volunteers.
Description pharmacological action:
Clopidogrel is a prodrug that selectively inhibits binding of ADP to its receptor on the platelets and subsequent activation of the complex GPIIb/IIIa, thus preventing ADP-induced platelet aggregation. For the development steps are necessary in biotransformation of clopidogrel. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the activation of platelets released ADP. Clopidogrel acts by irreversibly by changing the configuration of the ADP receptor. Therefore, platelets exposed to clopidogrel remain inactivated during the whole period of their lives to the restoration of normal platelet function is possible at a rate corresponding the refresh rate of platelets.
With daily use of clopidogrel in a dose of 75 mg from the first day of admission showed a significant inhibition of ADP-induced platelet aggregation, which gradually increased over 3-7 days and then goes at a constant level (at equilibrium state). In the equilibrium state with the dose 75 mg/day platelet aggregation is suppressed on average by 40-60%. Platelet aggregation and bleeding time gradually return to baseline values, generally within 5 days after discontinuation of treatment.
Application of pregnancy and breast-feeding:
Since clinical data on the use of clopidogrel during pregnancy, the drug is not recommended during pregnancy. Animal studies have not identified direct or indirect adverse effects on pregnancy, development of the embryo/fetus, during birth or postnatal development.
In animal studies it has been proven the penetration of clopidogrel in breast milk. Therefore, if necessary, therapy with clopidogrel is recommended to stop breastfeeding.
Classification of frequency of side effects (who): very often — >often 1/10 — >1/100 to <1/10 uncommon — >1/1000 to <1/100 rare >1/10000 to <1/1000 very rare <1/10000, including individual messages.
With the hematopoietic system: rarely — thrombocytopenia, leukopenia, eosinophilia, elongation of bleeding time rare neutropenia, including severe very rare — thrombotic thrombocytopenic purpura, aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anemia.
From the nervous system: rare — intracranial hemorrhage (there are reports of several cases with fatal outcome), headache, paraesthesia, dizziness very rare — hallucinations, confusion.
By SSS: very rarely — vasculitis, hypotension.
The respiratory system: rarely — bleeding from the respiratory tract (haemoptysis, pulmonary haemorrhage), bronchospasm, interstitial pneumonitis.
From the digestive system: often — diarrhea, abdominal pain, dyspepsia uncommon — gastric and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence very rare gastrointestinal and retroperitoneal bleeding, sometimes with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis, violation of the liver function tests, hepatitis, acute liver failure.
With the skin: rarely — rash, pruritus, skin bleeding (purpura) rare bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), angioedema, rash erythematous, urticaria, eczema, flat lichen very rarely hemorrhage.
From the side of musculoskeletal system: rare — muscular-skeletal bleeding (hemarthrosis), arthritis, arthralgia, myalgia.
With the genitourinary system: rare — hematuria rarely — glomerulonephritis, increased creatinine.
From the sensory organs: rarely, intraocular bleeding (conjunctival, retinal).
Allergic reactions: very rare — serum sickness, anaphylactoid reactions, bleeding from postoperative wounds.
Other: rarely — fever.
Oral anticoagulants: concurrent use of clopidogrel and oral anticoagulants is not recommended (may increase the intensity of bleeding).
Blockers IIb/IIIa receptor: the simultaneous use of clopidogrel and blokatorov IIb/Sha-receptors requires caution in patients with increased risk of bleeding complications (with trauma, surgery or other pathological conditions that require simultaneous administration of inhibitors of glycoprotein IIb/Sha).
Ask: ask no effect on clopidogrel-induced inhibition of platelet aggregation induced by ADP, but clopidogrel potentiates the effect of ASA on kollageninducyruemuyu platelet aggregation. However, simultaneous administration of 500 mg ASA, 2 times a day for one day significantly lengthens bleeding time caused by clopidogrel. Pharmacodynamics interaction between clopidogrel and ASA is possible, and increases the risk of bleeding. Given this, care should be taken while taking these drugs, although clinical studies, the patients received combination therapy with clopidogrel and ASA for one year.
Heparin: in clinical studies in healthy subjects when clopidogrel was not required to change doses of heparin, and did not change the anticoagulant effects of heparin. The combined use of heparin had no effect on inhibition of platelet aggregation with clopidogrel. Possible pharmacodynamic interaction between clopidogrel and heparin, leading to increased risk of bleeding. Therefore, the simultaneous use of these drugs requires caution.
Thrombolytics: the safety of concurrent use of clopidogrel or nonspecific fibrinoliticeski of thrombolytics and heparin was assessed in patients with acute myocardial infarction. The incidence of clinically relevant bleeding were comparable frequency while the use of thrombolytics, heparin with ASA.
NSAIDs: according to a clinical study involving healthy volunteers, the simultaneous use of clopidogrel and naproxen increased hidden gastrointestinal bleeding. However, due to the lack of interaction studies with other NSAIDs it is currently unknown whether increases the risk of gastrointestinal bleeding with all NSAIDs. Therefore, concomitant therapy of NSAIDs, including COX-2 inhibitors and clopidogrel should be undertaken with caution (see “Special instructions”).
Another combination therapy: there have been several clinical trials with clopidogrel and the other concurrently used drugs to study the possible pharmacodynamic and pharmacokinetic interactions:
– with simultaneous use of clopidogrel with atenolol and/or nifedipine clinically significant pharmacodynamic interactions have been identified
– the pharmacodynamic activity of clopidogrel was not significantly changed when used together with phenobarbital, cimetidine or estrogen
the pharmacokinetics of digoxin or theophylline were not changed
– antacids means do not affect the extent of absorption of clopidogrel
– phenytoin and tolbutamide safely combined with clopidogrel, however, the inhibition of the activity of cytochrome P450 with 2C9 isoenzyme carboxyl metabolite of clopidogrel. This could potentially lead to increased plasma concentrations of drugs such as phenytoin and tolbutamide and the NSAIDs, which are metabolized by cytochrome P450 2C9
– in addition to the specific interactions with drugs described above, other studies have not been conducted. However, for patients participating in clinical studies with clopidogrel and at the same time taking diuretics, beta-blockers, ACE inhibitors, calcium antagonists, hypolipidemic funds, coronary vasodilators, hypoglycemic drugs (including insulin), antiepileptic funds and antagonists of GPIIb/IIIa, was not identified clinically significant interactions.
Method of application and dose:
Inside, regardless of meals.
Myocardial infarction (MI), stroke, diagnosed with occlusive peripheral arterial disease: drug Salt it is recommended to take 1 table. (75 mg) 1 times a day. Patients with it treatment can begin from the first day up to 35 day after mi, and in patients with ischemic stroke — from 7 days to 6 months.
Acute coronary syndrome without ST-segment elevation (unstable angina or without formation of the Q wave): treatment with clopidogrel should be initiated with a single oral loading dose (300 mg), and then continue to the dose 75 mg 1 times per day (in combination with ASA in doses of 75-325 mg/day). Since the use of higher doses of ASA are associated with a greater risk of bleeding, the recommended dose of ASA should not exceed 100mg. the Maximum favorable effect was observed by the 3rd month of treatment. The course of treatment — up to 1 year.
AMI with ST-segment elevation (acute myocardial formation prong ST): clopidogrel is appointed once a day in a dose of 75 mg (1 table.) 1 time per day with an initial loading dose in combination with ASA in combination or without thrombolytics. For patients older than 75 years, treatment with clopidogrel should be undertaken without the use of a loading dose. Combination therapy is started as early as possible after the onset of symptoms and continued for at least four weeks.
Symptoms: overdose of clopidogrel may lead to prolonged bleeding time and subsequent complications such as development of bleeding.
Treatment: correction of prolonged bleeding time is required platelet transfusion. There’s no antidote.
Clopidogrel prolongs bleeding time. It should be administered with caution to patients with an increased risk of bleeding after injury, surgery or other pathological conditions, as well as patients with a tendency to bleeding (particularly gastrointestinal and intraocular bleeding).
In the case of surgery if antiplatelet effect is undesirable, the treatment should be discontinued 7 days before surgery. Patients should be warned that, since the stop occurs on a background of the drug bleeding requires more time, they should inform the doctor about each case, unusual bleeding. Patients should also inform the doctor about the drug if they have surgery (including dental surgery) or the doctor prescribes a new patient drugs.
During treatment necessary to monitor the performance of the system homeostasis (ACTV, the number of platelets, tests of functional activity of platelets) regularly examine the functional activity of the liver.
In severe liver dysfunction should be aware of the risk of developing a hemorrhagic diathesis.
It is not recommended to appoint patients with ischemic stroke of less than 7 days old.
May cause dyspepsia and diarrhea (contains hydrogenated castor oil).
Very rarely on the background of clopidogrel developed thrombotic thrombocytopenic purpura, sometimes after short-term use. The condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia associated with neurological disorders, kidney damage and fever. Thrombotic thrombocytopenic purpura is a potentially life-threatening condition that requires immediate treatment, including plasmapheresis.
Effects on ability to drive vehicles and work with technical devices. Drug Zyllt not have a significant impact on the ability to drive vehicles and work with technical devices that require high concentration and psychomotor speed reactions.
|The purpose of the medication||Anti-aggregants|