Clodia Alvogen 75 mg tablets # 30
Author Ольга Кияница
|Amount in a package||30|
|Manufacturer||Alvogen IPCO (Germany)|
|The main medicament||Claudia|
Clodia (CLODIA) instructions for use
active ingredient: clopidogrel; 1 tablet contains clopidogrel, besylate is equivalent to clopidogrel 75 mg;
auxiliary substances: cellulose microcrystalline mannitol (E 421) hydroxypropyl cellulose; crospovidone; acid citric monohydrate, polyethylene glycol 6000; stearic acid
film membrane Opadrai II Pink 32K14834: hypromellose (E 464) lactose monohydrate, iron oxide red (E172) triacetin (E1518), titanium dioxide (E 171).
Antithrombotic agents. Antiaggregants. The code of automatic telephone exchange В01А С04.
- Prevention of atherothrombosis in adults
- patients who underwent myocardial infarction (the beginning of treatment - in a few days, but no later than 35 days after the onset), ischemic stroke (the beginning of treatment - after 7 days, but no later than 6 months after the onset) or who are diagnosed with peripheral arteries (arterial damage and atherothrombosis of the vessels of the lower extremities);
- patients with acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without Q wave), including patients who had a stent in the course of percutaneous coronary angioplasty, in combination with acetylsalicylic acid;
- patients with acute myocardial infarction with ST segment elevation, in combination with acetylsalicylic acid (patients receiving standard medication and thrombolytic therapy is indicated).
- Prevention of atherothrombotic and thromboembolic events in atrial fibrillation.
- Clopidogrel in combination with acetylsalicylic acid (ASA) is indicated in adult patients with atrial fibrillation who have at least one risk factor for vascular events in which there are contraindications to treatment with vitamin K antagonists (AVCs) and who have a low risk of bleeding for prevention atherothrombotic and thrombotic events, including stroke.
For more information, see the section "Pharmacological properties".
Hypersensitivity to the active ingredient or to any component of the drug severe hepatic insufficiency acute bleeding (eg ulcer or intracranial hemorrhage) hereditary galactose intolerance, Lappease lactase deficiency or malabsorption of glucose-galactose.
Dosing and Administration
Adults, incl. patients of advanced age. The drug is prescribed 75 mg once a day, regardless of food intake.
Patients with acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without Q-wave on the ECG) should be treated with a single loading dose of 300 mg and then continued at a dose of 75 mg once daily (with acetylsalicylic acid (ASA) in a dose of 75-325 mg per day). Since the use of higher doses of ASA increases the risk of bleeding, it is recommended not to exceed the dose of acetylsalicylic acid 100 mg. The optimal duration of treatment is not formally established. Usually treatment is long. The term of treatment is determined by the doctor depending on the therapeutic effect and the tolerability of the drug.
For patients with acute myocardial infarction with ST-segment elevation, clopidogrel is prescribed 75 mg once a day, starting with a single loading dose of 300 mg in combination with ASA, with or without thrombolysis. Treatment of patients older than 75 years begins without a loading dose of clopidogrel. Combination therapy should be started as soon as possible after the onset of symptoms and continue for at least four weeks. The benefit of using a combination of clopidogrel with ASA for more than 4 weeks with this disease has not been studied.
Patients with atrial fibrillation use clopidogrel in a single dose of 75 mg.
Together with clopidogrel, you should start and continue the use of ASA (in a dose of 75-100 mg per day) (see Section "Pharmacological properties").
In case of missing the dose:
- if from the moment when it was necessary to take the next dose, it was less than 12:00, the patient should immediately take the missed dose, and the next dose can be taken at the usual time;
- if more than 12:00 has passed, the patient should take the next regular dose at the usual time but do not double the dose in order to compensate for the missed dose.
Children and teenagers. Clopidogrel should not be used in children, because it has no data on the effectiveness of the drug (see Section "Pharmacological").
Renal failure. The therapeutic experience of using the drug for patients with renal insufficiency is limited (see Section "Features of application").
Liver failure . The therapeutic experience of using the drug for patients with moderate liver disease and the possibility of hemorrhagic diathesis is limited (see Section "Features of application").
The safety of clopidogrel use has been studied in more than 44,000 patients who took part in clinical trials (of which more than 12,000 people took 1 year or longer treatment). Clinically significant side effects that have been observed in the studies of CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A are described below. In the CAPRIE study, the effect of clopidogrel at a dose of 75 mg per day was generally comparable to the effect of ASA at a dose of 325 mg per day, regardless of age, sex or race of patients.
In addition to these clinical studies, data on adverse reactions during the use of the drug in clinical practice were taken into account.
Bleeding was a common side effect, which was observed in both clinical studies and post-marketing studies, during which it most often occurred in the first month of treatment.
In the CAPRIE study, patients who received clopidogrel or ASA had a total bleeding rate of 9.3%. The incidence of severe cases of bleeding was the same for clopidogrel and ASA.
In the CURE study, there was no increase in the incidence of significant bleeding with a combination of clopidogrel + ASA for 7 days after aorto-coronary bypass surgery in patients who discontinued treatment more than 5 days before surgery. In patients who continued treatment for 5 days before the operation of aorto-coronary bypass surgery, the incidence of this phenomenon was 9.6% in the clopidogrel + ASA group and 6.3% in the placebo + ASA group.
In the CLARITY study, there was a general increase in the incidence of bleeding in the group taking clopidogrel + ASA compared to the placebo + ASA group. The incidence of severe bleeding was similar in both groups. This value was stable in subgroups of patients, which were noted for the initial parameters and type of fibrinolytic or heparin therapy.
In the COMMIT study, the overall incidence of severe non-cerebral or cerebral bleeding was low and similar in both groups.
In the ACTIVE-A study, the incidence of significant bleeding was higher in the clopidogrel + ASA group than in the placebo + ASA group (6.7% vs. 4.3%). In both groups, significant bleeding was predominantly of extracranial origin (5.3% in the clopidogrel + ASA group, 3.5% in the placebo + ASA group), mainly gastrointestinal bleeding (3.5% versus 1.8%). There was an increase in the number of intracranial bleedings in the clopidogrel + ASA group compared with the placebo + ASA group (1.4% vs. 0.8%, respectively). Between these groups, there was no statistically significant difference in the incidence of lethal bleeding (1.1% in the clopidogrel + ASA group and 0.7% in the placebo + ASA group), as well as hemorrhagic stroke (0.8% and 0.6% according).
On the part of the blood system and lymphatic system: thrombocytopenia, leukopenia; eosinophilia; neutropenia, including severe neutropenia; thrombotic thrombocytopenic purpura (TTP) aplastic anemia pancytopenia agranulocytosis severe thrombocytopenia acquired hemophilia A; granulocytopenia; anemia.
On the part of the immune system: serum sickness, anaphylactoid reactions, cross-hypersensitivity between thienopyridines (such as clopidine, prasugrel) (see Section "Application Features").
Mental disorders: hallucinations, confusion.
From the nervous system: intracranial bleeding (in some cases - with a fatal outcome), headache, paresthesia, dizziness, change in taste.
On the part of the organs of vision: bleeding into the eye area (conjunctiva, spectacle, retinal).
From the organs of hearing and the labyrinth: vertigo.
From the cardiovascular system: hematoma, severe hemorrhage, bleeding from the operating wound, vasculitis, arterial hypotension.
On the part of the respiratory system: epistaxis, bleeding of the respiratory tract (hemoptysis, pulmonary hemorrhages), bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.
On the part of the digestive tract: gastrointestinal bleeding, diarrhea, abdominal pain, indigestion, stomach and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence, retroperitoneal hemorrhage, gastrointestinal and retroperitoneal bleeding with fatal outcome, pancreatitis, colitis (in particular ulcerative or lymphocytic), stomatitis.
On the part of the digestive system: acute liver failure, hepatitis, abnormal results of liver function tests.
From the skin: subcutaneous hemorrhage, rash, itching, intradermal hemorrhage (purpura), bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), angioedema, skin rash, urticaria, drug hypersensitivity syndrome, medical rash with eosinophilia and systemic manifestations (DRESS-syndrome), eczema, flat lichen.
From the musculoskeletal system: musculoskeletal hemorrhage (hemarthrosis), arthritis, arthralgia, myalgia.
On the part of the urinary system: hematuria, glomerulonephritis, increasing the level of creatinine in the blood.
Common disorders: bleeding at the injection site, fever.
Laboratory indicators: increased bleeding time, a decrease in the number of neutrophils and platelets.
Reporting suspected adverse reactions.
Reporting suspected adverse reactions after approval of the drug by licensing authorities is an important procedure.This allows a constant monitoring of the "benefit / risk" ratio of the use of this drug. Medical workers are asked to report on all suspected adverse reactions through national communication systems.
Symptoms. With an overdose of clopidogrel, there may be an increase in bleeding time with subsequent complications.
Treatment. In case of bleeding, symptomatic treatment is recommended.
The antidote of the pharmacological activity of clopidogrel is unknown. If it is necessary to immediately correct the prolonged bleeding time, the action of clopidogrel can be stopped by transfusing the platelet mass.
Use during pregnancy and lactation
Because of the lack of clinical data on the use of clopidogrel during pregnancy, it is undesirable to prescribe to pregnant women (precautionary measures).
Experiments on animals showed no direct or indirect adverse effects on pregnancy, embryo / fetal development, childbirth and postnatal development.
Fertility. During the studies on laboratory animals, there was no negative effect of clopidogrel on fertility.
It is not known, clopidogrel is excreted in breast milk, therefore, during treatment with clopidogrel, breast-feeding should be discontinued.
Clopidogrel should not be used in children (under 18 years of age) because there is concern about the effectiveness of the drug for this category of patients.
Bleeding and hematological disorders
Because of the risk of bleeding and hematological side effects, an extensive blood test and / or other appropriate tests should be performed immediately if symptoms suggest bleeding occur during the use of the drug (see Section "Adverse Reactions"). Like other antiplatelet agents, clopidogrel should be used with caution in patients with an increased risk of bleeding due to trauma, surgery or other pathological conditions, as well as in patients with ASA, heparin, glycoprotein IIb / IIa inhibitors or non-steroidal anti-inflammatory drugs, in particular COX- 2. It is necessary to closely monitor the manifestations of bleeding symptoms in patients, including latent bleeding, especially in the first weeks of treatment and / or after invasive procedures on the heart and surgical interventions. The simultaneous use of clopidogrel with oral anticoagulants is not recommended, since it can increase the intensity of bleeding (see Section "Interaction with other drugs and other interactions").
In case of planned surgical intervention, temporarily does not require the use of antiplatelet agents, treatment with clopidogrel should be stopped 7 days before the operation. Patients should inform the doctor (including the dentist) that they are taking clopidogrel, before prescribing any surgery, or before applying a new medication. Clopidogrel prolongs the duration of bleeding, so it should be used with caution in patients with an increased risk of bleeding (especially the gastrointestinal and intraocular).
Patients should be warned that during bleeding with clopidogrel (alone or in combination with ASA) bleeding may stop later than usual and that they should inform the doctor of every unusual (in place or duration) bleeding.
Thrombotic thrombocytopenic purpura (TTP)
Very rarely there have been cases of thrombotic thrombocytopenic purpura (TTP) after the use of clopidogrel, sometimes even after its short-term use. TTP is manifested by thrombocytopenia and microangiopathic hemolytic anemia with neurological manifestations, renal dysfunction or fever. TTP is a potentially dangerous condition that threatens life and requires immediate treatment, in particular plasmapheresis.
Acquired hemophilia. The cases of development of acquired hemophilia after application of clopidogrel were reported. In cases of confirmed isolated increase in APTT (activated partial thromboplastin time), accompanied or not accompanied by bleeding, the diagnosis of acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be under medical supervision and receive treatment, the use of clopidogrel should be discontinued.
Recently suffered ischemic stroke
Because of the lack of data, it is not recommended to prescribe clopidogrel in the first 7 days after an acute ischemic stroke.
Cytochrome P450 2 C19 (CYP2C19)
In patients with a genetically reduced function of CYP2C19, a lower concentration of the active metabolite of clopidogrel in the blood plasma and a less pronounced antiplatelet effect are observed. Now there are tests to identify the genotype of CYP2C19 in a patient.
Since clopidogrel is converted into its active metabolite partly by CYP2C19, the use of drugs that reduce the activity of this enzyme is likely to lead to a decrease in the concentration of the active metabolite of clopidogrel in the blood plasma. To prevent the above, simultaneous use of strong and moderate inhibitors of CYP2C19 should be avoided (the list of inhibitors of CYP2C19 is given in the section "Pharmacokinetics").
Cross reactivity between thienopyridines. Patients should be checked for a history of hypersensitivity to other thienopyridines (such as ticlopidine, prasugrel), since there have been reports of cross reactivity between the thienopyridine (see "Adverse Reactions" section). The use of thienopyridines can lead to the emergence of mild to severe allergic reactions, such as rash, Quincke's edema, or hematologic reactions such as thrombocytopenia and neutropenia. Patients who had a history of allergic reactions and / or hematologic reactions to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for cross reactivity is recommended.
Impaired renal function
The therapeutic experience of clopidogrel in patients with renal failure is limited, and the drug to such patients should be used with caution (see. Section "Dosage and Administration").
Abnormal liver function
The experience of the drug in patients with liver disease of moderate severity, which may cause a hemorrhagic diathesis limited, however clopidogrel such patients should be used with caution (see. Section "Dosage and Administration").
The preparation contains lactose. Patients with rare hereditary diseases like galactose intolerance, Lapp lactase deficiency or violation of malabsorption of glucose-galactose can not use this drug.
The ability to influence the reaction rate when driving vehicles or other mechanisms
Clopidogrel has no effect or has little effect on the ability to drive vehicles or other mechanisms.
Interaction with other drugs and other interactions
Oral anticoagulants. The simultaneous use of clopidogrel with oral anticoagulants is not recommended because such a combination may increase the intensity of bleeding. Although the use of clopidogrel at a dose of 75 mg per day does not alter pharmacokinetic profile of S-warfarin or prothrombin ratio (INR) in patients who have for a long time being treated with warfarin, the simultaneous use of clopidogrel and warfarin increases the risk of bleeding due to the existence of an independent effect on hemostasis .
Inhibitors of glycoprotein receptor IIb, / IIIa. Clopidogrel should be used with caution in patients who receive inhibitors of glycoprotein receptor IIb, / IIIa (see. Section "Properties application").
Acetylsalicylic acid (ASA). Acetylsalicylic acid does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, clopidogrel, but enhances the effect of ASA on platelet aggregation induced by collagen. However, the simultaneous use of ASA 500 mg 2 times a day for one day did not cause a significant increase in bleeding time, owing to the elongated clopidogrel. Since it is possible pharmacodynamic interaction between clopidogrel and acetylsalicylic acid with increased bleeding risk, the simultaneous use of these drugs requires caution (see. Section "Properties application"). The efficacy of clopidogrel is not dependent on the dose of ASA 75-325 mg 1 time per day
Heparin. Clopidogrel does not require a dose adjustment of heparin and does not alter the effect of heparin on coagulation. The simultaneous use of heparin does not affect the inhibition of platelet aggregation induced by clopidogrel. Since it is possible pharmacodynamic interaction between heparin and clopidogrel with increased bleeding risk, the simultaneous use of these drugs requires caution.
Thrombolytic agents. Safety of simultaneous administration of clopidogrel, fibrinospetsifichnih fibrinonespetsifichnih or thrombolytic agents and heparin was studied in patients with acute myocardial infarction. The incidence of clinically relevant bleeding was similar to that observed in the simultaneous use of thrombolytic agents and heparin with ASA (see. Section "Adverse reactions").
Nonsteroidal anti-inflammatory drugs (NSAIDs). Concomitant use of clopidogrel and naproxen increased number of hidden gastrointestinal bleeding. It is still not found, the risk of gastrointestinal bleeding when used with all other NSAIDs. Therefore, caution is required while the use of NSAIDs, particularly COX-2 inhibitors, clopidogrel (see. Section "Properties application").
The simultaneous use of other drugs.
Since clopidogrel is converted to its active metabolite partly under the action of an enzyme of the cytochrome P450 CYP2C19, the use of drugs that reduce the activity of this enzyme is likely to lead to a decrease in concentration of the active metabolite of clopidogrel, and also to a decrease of clinical efficacy. Therefore, as a preventive measure to avoid simultaneous use of drugs that inhibit CYP2C19 activity (see. Sections "Features of application" and "Pharmacokinetics").
For drugs that suppress the activity of CYP2C19, are omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.
Proton pump inhibitors (PPIs). Omeprazole 80 mg 1 time per day while the use of clopidogrel in the range 12:00 or between doses of these drugs reduced the exposure of the active metabolite by 45% (loading dose) and 40% (maintenance dose). This reduction was accompanied by a decrease in the inhibition of platelet aggregation by 39% (loading dose) and 21% (maintenance dose). It is expected that a similar interaction with clopidogrel and esomeprazole to enter.
According to the results of both (observational and clinical) trials with conflicting data on the clinical implications of this pharmacokinetic (PK) and pharmacodynamic (PD) interaction in terms of major cardiovascular events. As a preventive measure not to be used simultaneously with clopidogrel omeprazole or esomeprazole (see. Section "Properties application").
Less pronounced decrease in metabolite concentration in blood is observed when using pantoprazole or lansoprazole.
With simultaneous use of pantoprazole in the dose of 80 mg 1 time per day in the plasma concentration of the active metabolite decreased by 20% (loading dose) and 14% (maintenance dose). This reduction was accompanied by a decrease in average inhibition of platelet aggregation by 15% and 11% respectively. The results indicate the possibility of simultaneous use of clopidogrel and pantoprazole.
There is no evidence that other drugs that reduce acid production in the stomach, such as, for example, H 2 blockers or antacids affect the antiplatelet activity of clopidogrel.
Combination with other drugs. A series of clinical trials with clopidogrel and other drugs for the study of potential pharmacodynamic and pharmacokinetic interactions. Clinically significant pharmacodynamic interaction with clopidogrel has not been detected simultaneously with atenolol, nifedipine, or both drugs. Moreover, the pharmacodynamic activity of clopidogrel is practically unchanged while the use of phenobarbital, cimetidine and estrogen.
The pharmacokinetic properties of digoxin or theophylline were not changed while the use of clopidogrel. Antacids do not affect the level of absorption of clopidogrel.
Phenytoin and tolbutamide, which are metabolized with the participation of CYP2C9, can be safely used in conjunction with clopidogrel.
Except for information about the interaction with specific drugs of the above, studies of the interaction of clopidogrel with drugs that are commonly prescribed to patients atherothrombosis not conducted. However, patients applied simultaneously other medications, including diuretics, beta-blockers, ACE inhibitors, calcium antagonists, agents that reduce cholesterol levels, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, hormone replacement therapy and antagonists of GPIIb / IIIa without evidence of clinically significant side effects.
Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) receptor on the platelet surface and subsequent activation of GPIIb / IIIa complex under the action of ADP and thus inhibits platelet aggregation. For the formation of the active inhibition of platelet aggregation requires biotransformation of clopidogrel. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the activity of increasing platelet ADP released. Clopidogrel irreversibly modifies platelet ADP receptors. Thus, platelets have entered into interaction with clopidogrel vary until the end of their life cycle. Normal platelet function is restored at a rate corresponding platelet refresh rate.
With the first application of the day in repeated daily doses of 75 mg is substantial deceleration of ADP-induced platelet aggregation. This action progressively increases and reaches a constant level of between 3 and 7 days. At steady state average level of inhibition of aggregation by the action of 75 mg daily dose is from 40% to 60%. Platelet aggregation and bleeding time are returned to the initial level on average 5 days after cessation of treatment.
After oral administration of single and multiple doses of 75 mg per day of clopidogrel is rapidly absorbed. Maximum concentration in the blood plasma of unchanged clopidogrel (approximately 2.2-2.5 ng / ml after a single dose of 75 mg orally) were reached approximately 45 minutes after application of the dose. The absorption is at least 50%, as the excretion with the urine metabolite of clopidogrel.
Clopidogrel and the main (inactive) metabolite circulating in the blood, in vitro reversibly bind to plasma proteins (98% and 94% respectively). This relationship remains insatiable in vitro over a wide concentration range.
Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, there are two basic ways of its metabolism: one occurs with the esterases and leads to hydrolysis to form an inactive carboxylic acid derivative (representing 85% of all metabolites circulating in blood plasma), and other involved system enzymes cytochrome P450. First, clopidogrel is converted into an intermediate metabolite of 2-oxo-clopidogrel. The further metabolism of 2-oxo-clopidogrel thiol derivative is formed - an active metabolite thereof. In vitro, this metabolic pathway is mediated by enzymes CYP3A4, CYP2C19, CYP1A2 and CYP2B6.
The active metabolite of clopidogrel (thiol derivative), which was isolated in vitro, rapidly and irreversibly binds to receptors on platelets, thereby inhibiting platelet aggregation. This metabolite in plasma is not detected
After 120 hours after ingestion of 14 C-labeled clopidogrel about 50% excreted in urine and about 46% - in the feces. After oral administration of a single dose of 75 mg clopidogrel half-life is around 6:00. The half life of the main (inactive) metabolites circulating in blood is 8:00 after single and repeated use of the drug.
CYP2C19 is involved in the formation of active metabolite or an intermediate metabolite of 2-oxo-clopidogrel. The pharmacokinetics of the active metabolite of clopidogrel and antiplatelet effects, as determined by platelet aggregation ex vivo, depend on the genotype CYP2C19.
CYP2C19 * 1 allele corresponds fully functioning metabolism, whereas alleles CYP2C19 * 2 and CYP2C19 * 3 correspond to the non-operation metabolism. Alleles CYP2C19 * 2 and CYP2C19 * 3 allele responsible for most, attenuating function in patients with reduced metabolism Caucasian (85%) and Mongoloid (99%) races. Other alleles associated with absent or impaired metabolism, are much rarer. These include CYP2C19 * 4, * 5, * 6, * 7, and * 8 A patient with reduced metabolism has two non-functional alleles as described above. According to published data, the genotypes of CYP2C19, which correspond to the reduced metabolism to occur in 2% of patients Caucasians, 4% of patients blacks and 14% of patients Hoa. there are tests now,which allow us to determine the genotype CYP2C19.
Specific categories of patients
The pharmacokinetics of the active metabolite of clopidogrel has not been studied in the following categories of patients.
After regular application of 75 mg of clopidogrel per day in patients with severe renal failure (creatinine clearance 5-15 ml / min) inhibition of ADP-induced platelet aggregation was less pronounced (25%) compared to the same effect in healthy volunteers, and the time bleeding was extended almost the same as in healthy volunteers receiving 75 mg of clopidogrel per day. The clinical tolerance was good in all patients.
After regular application of 75 mg of clopidogrel per day for 10 days in patients with severe liver failure inhibition of ADP-induced platelet aggregation were the same as in healthy volunteers. The mean increase in bleeding time was also similar in both groups.
The prevalence of CYP2C19 alleles, which produce intermediate and weak metabolic activity of CYP2C19, differs depending on race / ethnicity (see. Section "pharmacogenetics"). There are limited data on patients Mongoloid race, which allow to evaluate the clinical importance of genotyping of this CYP in terms of clinical outcomes.
Basic physical and chemical properties
tablets of round shape with biconvex surface, covered with a film membrane of pink color.
Does not require special storage conditions. Keep out of the reach of children.
10 tablets in a blister with a polyvinyl chloride film and aluminum foil with a marking in Ukrainian. For 3 blisters in a pack of cardboard with marking in Ukrainian.
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