on the use of the drug for medical use Klapitaks
Registration number: LP-002 497 on 04.07.2015
International Non-Proprietary Name (INN): clopidogrel
Dosage Form: tablet, film-coated
|Clopidogrel hydrogen sulfate
(in terms of clopidogrel)
|Giproloza (low substituted)
|Colloidal silicon dioxide
|Opadry Pink *
|Opadry white **
* Opadry Pink contains: lactose monohydrate BP - 39.5%, hypromellose BP - 39.25%; BP titanium dioxide (E171) - 10% Triacetin USP - 10% iron oxide red dye BP (E172)) - 1.25%
** Opadry White comprises: lactose monohydrate BP - 40%, hypromellose BP - 40% BP titanium dioxide (E171) - 10% Triacetin USP - 10%
Tablets 75 mg: Round biconvex tablets, film-coated pink
Tablets 150 mg: Round biconvex tablets, film-coated white with Valium on the one hand
Tablets 300 mg: Round biconvex tablets, film-coated white
A cross section (for all doses) is almost white (white with a yellowish tinge) weight with single dark patches
Pharmacological group: antiplatelet agent
ATX code: B01AC04
Clopidogrel is a prodrug and an active metabolite which is an inhibitor of platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of ADP (adenosine diphosphate) with platelet P2Y12 receptor and the subsequent ADP-mediated activation of GPIIb / IIIa complex, resulting in suppression of platelet aggregation. Due to the irreversible binding of platelets remain impervious to ADP stimulation throughout the remainder of the term of his life (approximately 7-10 days) and recovery of normal platelet function occurs at a rate corresponding to the refresh rate of platelets.
Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the activation of enhanced platelet ADP releasable. Because formation of an active metabolite occurs by means of cytochrome P450 isoenzymes, some of which may differ polymorphism, or may be inhibited by other drugs is not possible in all patients adequate platelet inhibition.
With a daily intake of clopidogrel 75 mg on the first day the reception there was a significant inhibition of ADP-induced platelet aggregation, which is gradually increased for 3-7 days and then goes on a constant level (when the equilibrium state). At equilibrium, platelet aggregation is suppressed by an average of 40-60%. After discontinuation of clopidogrel platelet aggregation and bleeding time gradually returned to baseline levels within an average of 5 days.
In the study of clopidogrel of pharmacodynamics indicated minimal inhibition of ADP-induced platelet aggregation in women. In this case there were no differences between men and women in prolonged bleeding.
Clopidogrel is capable of preventing the development of atherothrombosis for any localization of atherosclerotic vascular lesions, particularly in patients with lesions of the cerebral, coronary or peripheral arteries.
In patients with recent myocardial infarction, ischemic stroke, and / or diagnosed occlusive peripheral arterial disease in the clopidogrel dose of 75 mg per day significantly reduces the risk of cardiovascular complications (myocardial infarction, stroke, cardiovascular mortality)
In acute coronary syndrome without ST-segment elevation on the electrocardiogram (unstable angina, myocardial infarction), clopidogrel (loading dose of 300 mg once, then 75 mg / day) in combination with acetylsalicylic acid at a dose of 75-325 mg / day, and other standard therapy significantly and independently from other kinds of treatment reduces the risk of cardiovascular complications.
Myocardial infarction with ST-segment elevation on ECG clopidogrel (loading dose of 300 mg once daily for the first 12 hours of the disease, followed by 75 mg / day) in combination with acetylsalicylic acid (150-325 mg loading dose, followed by 75-162 mg / day), a fibrinolytic therapy and, if indicated, heparin reduces the incidence of occlusion of the infarct-related coronary artery (according to coronary angiography at discharge), reinfarction and death. Patients who are at discharge was not carried out coronary angiography, clopidogrel according to the scheme reduces the incidence of deaths and re-myocardial infarction up to 8 days of illness or until discharge from the hospital.
In general, myocardial infarction, regardless of the ECG changes (segment elevation ST, ST-segment depression or first emerged complete blockade of the left Hiss bundle branch), clopidogrel 75 mg / day in combination with acetylsalicylic acid 162 mg / day leads to a decrease in overall mortality and the total frequency of recurrent myocardial infarction, ischemic stroke and death.
Patients with atrial fibrillation having at least one risk factor for vascular complications and do not take on any reason indirect anticoagulants, clopidogrel 75 mg / day in combination with acetylsalicylic acid (compared with the reception of only acetylsalicylic acid) reduces the total the incidence of stroke, myocardial infarction, systemic thromboembolism is the central nervous system and cardiovascular mortality, mainly due to the decrease in the risk of non-fatal stroke. This effect of clopidogrel was observed in studies lasting up to 5 years.
In single and course taken orally at a dose of 75 mg per day, clopidogrel is rapidly absorbed. The average maximum concentration (Cmax) unchanged clopidogrel in plasma is very low (approximately 2.2-2.5 ng / ml after oral administration of a single dose of 75 mg) is reached after about 45 minutes after administration. According clopidogrel excretion of metabolites in the urine, its absorption is approximately 50%.
The concentration of unchanged substance in plasma decreases rapidly and within 2 hours after taking the measurement reaches the limit (0.025 mg / l).
In vitro clopidogrel and its main circulating metabolite in the blood inactive reversibly bind to plasma proteins (98% and 94%, respectively) and this association is insatiable in a wide range of concentrations.
As a prodrug, clopidogrel extensively metabolized in the liver. The active metabolite in the blood can not be detected.
In vitro and in vivo, clopidogrel is metabolized in two ways:
- by esterases and subsequent hydrolysis to form an inactive carboxylic acid derivative (85% of circulating metabolites);
- through the cytochrome P450 system. First, clopidogrel is metabolised to a 2-oxo-clopidogrel intermediate metabolite being. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of the active metabolite of clopidogrel - clopidogrel thiol derivative. In vitro metabolism in this way takes place by means of cytochrome P450 isoenzymes - CYP3A4, CYP2C19, CYP1A2 and CYP2B6. Clopidogrel thiol active metabolite, which was isolated in vitro studies, in vivo conditions rapidly and irreversibly binds to receptors on platelets, inhibiting aggregation of blood platelets.
Cmax active metabolite of clopidogrel loading dose after administration of 300 mg 2 times the Cmax after administration of a maintenance dose of 75 mg of clopidogrel for 4 days. When you receive a 300 mg clopidogrel TCmax is approximately 30-60 minutes.
After repeated administration of clopidogrel oral dose of 75 mg daily Cmax primary inactive metabolite is about 3 mg / L, the inactive metabolite TSmax achieved after 1 hour.
Over 120 hours after oral administration of 14C-labeled human clopidogrel about 50% of the radioactivity is excreted in the urine and approximately 46% of the radioactivity in the faeces.
After a single dose and repeated doses receiving half-life (T1 / 2) of the main circulating metabolite in the blood inactive (carboxylic acid derivative) is 8 hours.
Several polymorphic cytochrome P450 isozymes involved in the activation of clopidogrel. CYP2C19 isozyme is involved in the formation as an active metabolite or an intermediate metabolite - 2-oxo-clopidogrel. The pharmacokinetics and antiplatelet effect is the active metabolite of clopidogrel was investigated by ex vivo platelet aggregation, differ depending on the genotype isoenzyme CYP2C19.
Allele CYP2C19 * 1 gene is responsible for the normal functioning metabolism, whereas alleles of genes CYP2C19 * 2 and CYP2C19 * 3 are nonfunctional. These alleles are responsible for the decrease in metabolism of about 85% of Caucasians and 99% of representatives of the Mongoloid race. Other alleles are associated with absence or reduction of metabolism - CYP2C19 * 4, * 5, * 6, * 7, and * 8, but they are rare in the general population. Patients with low activity isoenzyme CYP2C19, should have two aforementioned gene allele loss function.
The published incidence of individual phenotypes with low CYP2C19 isoenzyme activity in individuals Caucasian 2% in those blacks 4% and 14% Chinese.
There are tests to determine the genotype CYP2C19 patient; These tests can be used as an aid in determining the treatment strategy.
In the crossover study, involving 40 healthy volunteers (10 volunteers with a very fast, extensive, intermediate and delayed metabolism) were studied pharmacokinetics and clopidogrel antiplatelet effect when applied in two schemes:
- 300 mg dose followed by administration of 75 mg per day for 5 days
- 600 mg dose followed by administration of 150 mg daily for 5 days (to reach equilibrium)
We not identified significant differences in exposure to the active metabolite and the average level of inhibition of platelet aggregation (IAT) between groups of volunteers with very rapid, extensive and intermediate metabolism. The volunteers with a reduced rate of metabolism of the active metabolite was effects on 63-71% lower compared to volunteers extensively metabolized clopidogrel.
In applying the drug scheme 300 mg once / day to 75 mg, platelet response (stimulation with ADP 5 microns) in volunteers sustained metabolism of clopidogrel was lowered: IAT was 24% (after 24 hours) and 37% (Day 5). For comparison, the volunteers with extensive metabolism IAT was 39% (after 24 hours) and 60% (Day 5).
When clopidogrel scheme 600 mg once / 150 mg per day in volunteers with a reduced rate of metabolism of clopidogrel drug effect was more pronounced than when the drug in doses of 300 mg once / 75mg per day: IAT was 32% (after 24 hours) and 61% (Day 5), which is comparable to IAT volunteers in groups at a different rate of metabolism of clopidogrel treated preparation scheme of 300 mg / 75 mg. A suitable dosing regime for a patient population with decreased metabolic rate of clopidogrel has not been set in clinical studies.
Likewise, a meta-analysis of six studies in which the data included 335 healthy volunteers receiving clopidogrel and were in a state of achieving equilibrium concentration, showed that the intermediate metbolizatorov active metabolite exposure was decreased by 28%, and poor metabolizers - 72%. Compared with extensive metabolizers, platelet aggregation inhibition in the intermediate and poor metabolizers was reduced respectively by 5.9% and 21.4%.
Assessing the impact of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been evaluated in a prospective randomized controlled study. Existing data retrospective analyzes of clinical trials, which are the results of genotyping patients who did not have sufficient power to assess differences in clinical outcomes in poor metabolizers of clopidogrel compared with the extensive and intermediate metabolisers.
Certain groups of patients
In elderly volunteers (aged 75 years) compared to young volunteers was not obtained in terms of differences in platelet aggregation, and bleeding time. Dose adjustment of clopidogrel in the elderly is not required
Age younger than 18 years
The pharmacokinetics of clopidogrel has not been studied in children.
Impaired Renal Function
After repeated receptions of clopidogrel 75 mg / day in patients with severe renal failure (creatinine clearance (CC) of 5-15 ml / min), inhibition of ADP-induced platelet aggregation were 25% lower than in healthy volunteers but the elongation bleeding time was noted.
Abnormal liver function
Upon receiving clopidogrel at a dose of 75 mg per day for 10 days in patients with severe liver inhibition of ADP-induced platelet aggregation did not differ from that in healthy volunteers. The mean bleeding time in patients with severe liver disease and in healthy volunteers was similar.
The prevalence of CYP2C19 alleles isoenzyme, responsible for intermediate or decreased metabolism, is different from the representatives of different racial groups. Available published data are insufficient to estimate the value of genotyping of CYP2C19 isoenzyme for the prediction of ischemic complications.
Prevention of atherothrombotic events in adult patients with
- myocardial infarction (with a prescription from a few days to 35 days)
- ischemic stroke (from 7 days prescription of up to 6 months)
- diagnosed with peripheral arterial occlusive disease
- acute coronary syndrome:
- segment elevation ST (unstable angina, myocardial infarction without the Q wave), including patients who underwent stenting during percutaneous coronary intervention (in combination with acetylsalicylic acid);
- segment elevation ST (acute myocardial infarction) for medical treatment and the possibility of thrombolysis (in combination with acetylsalicylic acid).
Prevention of atherothrombotic and thromboembolic events (including stroke) in atrial fibrillation (atrial fibrillation) in adult patients in the presence of at least one risk factor for vascular complications, contraindications to anticoagulants and low risk of bleeding (in combination with acetylsalicylic acid).
- Hypersensitivity to clopidogrel or any ancillary components of the formulation.
- Severe hepatic insufficiency.
- Active bleeding, such as bleeding peptic ulcer or intracranial hemorrhage.
- Hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.
- Pregnancy and lactation (see. "Pregnancy and breastfeeding").
- Children under 18 years of age (safety and efficacy not established).
Clopidogrel should be used with caution:
- moderate hepatic insufficiency (7-9 points on a scale Child-Pugh), in which the possible predisposition to bleeding (limited clinical experience);
- chronic renal failure mild to moderate (creatinine clearance 60-30 ml / min) (limited clinical experience);
- trauma, surgical interventions (see "Special Instructions".);
- diseases in which there is a predisposition to bleeding (especially gastrointestinal or intraocular);
- the simultaneous administration of nonsteroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2);
- concomitant use of oral anticoagulants, heparin, glycoprotein IIb / IIIa, selective inhibitors of serotonin reuptake (SSRIs) and thrombolytic agents;
- when genetically determined reduction function isoenzyme CYP2C19.
There are published data indicating that patients with a genetically determined reduction isoenzyme CYP2C19 function exposed at systemic exposure active metabolite of clopidogrel and has a less pronounced antiplatelet effect of the drug, except that they may be a more frequent occurrence of cardiovascular complications after myocardial infarction compared to patients with normal function isoenzyme CYP2C19;
- with a history of allergic or hematological reactions to other thienopyridines (such as ticlopidine, prasugrel) for the opportunity to cross-allergic reactions, or hematologic (see. "Special Instructions" section).
Pregnancy and breast-feeding
As a precaution, it is not recommended clopidogrel during pregnancy due to lack of clinical data on its acceptance by pregnant women, although studies in animals have revealed adverse effects on pregnancy, fetal development, childbirth and postnatal development. Breast-feeding in case of clopidogrel treatment should be discontinued, since studies in rats have shown that clopidogrel and / or its metabolites excreted into breast milk. Gets or not clopidogrel in human breast milk is not known.
Dosing and Administration
Clopidogrel should be taken orally with or without food
Adults and the elderly with normal activity isoenzyme CYP2C19
Myocardial infarction, ischemic stroke and diagnosed occlusive peripheral arterial disease.
The drug is taken at 75 mg once daily
In patients with myocardial infarction, treatment can begin from the first days up to 35 days after myocardial infarction and in patients with ischemic stroke - in the period from 7 days to 6 months. Due to lack of data, clopidogrel is not recommended during the first 7 days after acute ischemic stroke.
Acute coronary syndrome without ST elevation ST (unstable angina, myocardial infarction without tooth Q).
clopidogrel treatment should be initiated with a single oral loading dose of 300 mg, and then continue taking a dose of 75 mg once daily (in combination with aspirin at doses of 75-325 mg per day). Because the use of higher doses of aspirin is associated with increased risk of bleeding, this indication at the recommended dose of acetylsalicylic acid should not exceed 100 mg. The maximum beneficial effect is observed for the third month of treatment. The course of treatment - up to 1 year. The optimal duration of treatment has not been established. Results from clinical studies support the use of the drug milking 12 months after the onset of acute coronary syndrome without ST elevation ST /
Acute coronary syndrome segment elevation ST (acute myocardial infarction with ST-segment elevation)
Clopidogrel is assigned a single dose of 75 mg once a day with an initial loading dose of a single dose (300 mg) in combination with acetylsalicylic acid, thrombolytics (or without thrombolysis). In patients older than 75 years treated with clopidogrel should start without receiving a loading dose. Combination therapy is started as soon as possible after the onset of symptoms, and continued for at least four weeks. Efficacy of the combination of clopidogrel and aspirin in this indication over 4 weeks was not studied.
Clopidogrel is to be taken once daily at a dose of 75 mg in combination with aspirin (75-100 mg / day).
In case of skipping the next dose, provided that at least 12 hours have passed, you should immediately take the missed dose, the next dose should be taken at the usual time; if more than 12 hours, the patient should take the next dose at the usual time (do not double the dose)
Special patient groups
Patients with genetically caused by decreased activity of isoenzyme CYP2C19.
The weakening of the metabolism via CYP2C19 isozyme may lead to a reduction in antiplatelet effect of clopidogrel. mode of application of higher doses (600 mg - loading dose, followed by 150 mg once a day daily) in patients with low activity increases the CYP2C19 isozyme antiplatelet effect of clopidogrel. However, the optimal dosage regimen for patients with impaired metabolism via CYP2C19 isozyme is not established yet.
In elderly volunteers (aged 75let) when compared to young volunteers was not obtained in terms of differences in platelet aggregation, and bleeding time. For elderly patients dose adjustment of clopidogrel is not required
Experience in the use of the drug in children is not
Patients with impaired renal function
Experience in the use of clopidogrel in patients with chronic renal insufficiency is limited. After repeated receptions of clopidogrel at a dose of 75 mg per day in patients with severe renal (creatinine clearance of 5 to 15 ml / min) inhibition of ADP-induced platelet aggregation were 25% lower compared to that in healthy volunteers but the prolongation of bleeding time It did not differ from that in healthy volunteers who received clopidogrel 75 mg per day.
Patients with hepatic impairment
Experience in the use of clopidogrel in patients with hepatic impairment is limited. After daily administration of clopidogrel at a dose of 75 mg per day for 10 days in patients with severe liver inhibition of ADP-induced platelet aggregation was similar to that of healthy volunteers. The mean bleeding time in both groups were also comparable.
Patients of different ethnicity
The prevalence of CYP2C19 alleles isoenzyme, responsible for intermediate and reduced metabolism of clopidogrel to its active metabolite, different in different ethnic groups (see. "Pharmacogenetics" section). Limited data are available for the representatives of the Mongoloid race to assess the impact of CYP2C19 genotype on clinical isoenzyme resulting events.
Patients, male and female
In a small study comparing the pharmacodynamic properties of clopidogrel in both men and women, women had less inhibition of ADP-induced platelet aggregation, but differences in the elongation of bleeding time was not. In a controlled clinical study CAPRIE (Clopidogrel versus acetylsalicylic acid) in patients at risk of ischemic events), the frequency of clinical outcomes, adverse events and abnormalities of clinical and laboratory parameters of the rules were the same for men and women. Dose adjustment is not required.
The frequency of side effects is defined, according to the WHO classification:
- often> 1/10 (10%)
- often from ≥ 1/100 to <1/10
- rarely of ≥ 1/1000 to <1/100
- rarely of ≥ 1/10000 to <1/1000
- very rare <1/10000
- Frequency unknown (to determine adverse reaction frequency of occurrence of the available data it is impossible).
Violations of the blood and lymphatic system
Uncommon: thrombocytopenia, leukopenia, eosinophilia.
Rare: neutropenia including severe.
Very rare: thrombotic thrombocytopenic purpura (see "Special Instructions".), Aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anemia. the frequency is unknown - acquired hemophilia.
Violations by the immune system
Very rare: anaphylactoid reactions, serum sickness, and allergic cross-reaction with other hematologic thienopyridines (such as ticlopidine, prasugrel).
Very rare: hallucinations, confusion.
Disorders of the nervous system
Uncommon: intracranial bleeding (including fatal), headache, paresthesia, dizziness.
Very rare: disturbances of taste perception.
Violations of the organ of vision
Uncommon: eye haemorrhage (conjunctival, in the tissue and the retina of the eye).
Violations of the organ of hearing and labyrinth disorders
Very rare: serious bleeding from the surgical wound, vasculitis, decreased blood pressure.
Disorders of the respiratory system, organs, thoracic and mediastinal disorders
Very rare: bronchospasm, interstitial pneumonitis, pulmonary hemorrhage, hemoptysis, eosinophilic pneumonia.
Disorders of the digestive system
Very common: gastro-intestinal bleeding, diarrhea, abdominal pain, dyspepsia.
Uncommon: Gastric ulcer and 12 duodenal ulcer, vomiting, nausea, constipation, flatulence.
Rare: retroperitoneal hemorrhage.
Very rare: gastrointestinal bleeding and retroperitoneal haemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative colitis or lymphocytic colitis), stomatitis.
Disorders of the liver and biliary tract
Very rare: Acute liver failure, hepatitis, abnormal liver function tests.
Disorders of the skin and subcutaneous tissue
Often the "bruising" (local subcutaneous hemorrhage).
Uncommon: rash, pruritus, purpura (melkopyatnistye capillary hemorrhages in the skin, under the skin or mucous membranes).
Unknown frequency: maculo-papular or erythematous rash, urticaria, pruritus, angioedema, bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), drug hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS-syndrome) eczema, lichen planus.
Violations of the musculoskeletal and connective tissue
Very rarely, bleeding into muscles and joints (haemarthrosis), arthritis, arthralgia, myalgia.
Violations of the kidney and urinary tract
Very rare: glomerulonephritis.
General disorders and administration site in
Common: bleeding from the vascular puncture place.
Very rare: fever.
Laboratory and instrumental data
Uncommon: prolonged bleeding time, decreased neutrophil count, decreased number of platelets in the peripheral blood, violation of liver function tests, increase in serum creatinine concentration in the blood plasma
Clopidogrel overdose may lead to a lengthening of bleeding time and subsequent bleeding complications.
Symptomatic. Antidote clopidogrel is not installed. If necessary, the rapid correction lengthen bleeding time, platelet transfusion is recommended.
Interaction with other drugs
Simultaneous administration of clopidogrel with oral anticoagulants may increase the intensity of bleeding, and therefore the use of this combination is not recommended. Clopidogrel 75 mg daily did not affect the pharmacokinetics of warfarin, and does not change the value of international normalized ratio (INR) in patients receiving long-term warfarin. However, the concomitant use of clopidogrel with warfarin may increase the risk of bleeding due to the independent influence of these drugs on hemostasis (see. "Special Instructions").
Inhibitors of glycoprotein IIb / IIIa
Appointment of inhibitors of glycoprotein IIb / IIIa in conjunction with clopidogrel requires caution in patients who have an increased risk of bleeding (for injuries and surgery or other pathological conditions) (see. "Special Instructions" section).
Aspirin does not modify the effect of clopidogrel, which inhibits ADP-induced platelet aggregation, but clopidogrel potentiated the effect of aspirin on collagen-induced platelet aggregation. However, the simultaneous reception of clopidogrel with aspirin 500 mg two times a day does not cause a significant increase in bleeding time over one day reception called clopidogrel. Between clopidogrel and acetylsalicylic acid is possible pharmacodynamic interaction, which leads to increased risk of bleeding. Therefore, although the clinical studies, patients received combination therapy with clopidogrel and acetylsalicylic acid up to one year, should be careful in their simultaneous application.
According to a clinical study conducted in healthy volunteers, while taking clopidogrel did not need to change the dose of heparin and did not change its anticoagulant effect. The simultaneous use of heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation. Between clopidogrel and heparin is possible pharmacodynamic interaction, which may increase the risk of bleeding, so the simultaneous use of these drugs requires caution.
Safety of combined use of clopidogrel, fibrinspetsificheskih fibrinnespetsificheskih or thrombolytic agents and heparin has been studied in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed in the case of joint use of thrombolytic agents and heparin with acetylsalicylic acid.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
With simultaneous use of clopidogrel with NSAIDs may increase the risk of bleeding. In a clinical study conducted in healthy volunteers, concomitant use of clopidogrel and naproxen increased occult blood loss from the gastrointestinal tract. However, due to the lack of research on the interaction of clopidogrel with other NSAIDs, so far it remains unknown whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel with other NSAIDs. Therefore, the use of NSAIDs, including COX-2, in combination with clopidogrel should be done with caution (cm. "Special instructions") inhibitors.
Selective serotonin reuptake inhibitors (SSRIs)
Since SSRIs disrupt platelet activation and increase the risk of bleeding, the simultaneous use of SSRIs with clopidogrel should be used with caution.
inhibitors of CYP2C19
Since Clopidogrel is metabolized to form its active metabolite partially by CYP2C19, use of drugs that inhibit this system may result in lower levels of the active metabolite of clopidogrel and reduce its clinical efficacy. The clinical significance of this interaction is unknown, but as a precaution it is recommended to avoid simultaneous reception of clopidogrel with drugs that inhibit CYP2C19 (omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol).
Proton pump inhibitors
Omeprazole 80 mg once daily, taken simultaneously with clopidogrel, or at intervals of 12 hours after administration of clopidogrel reduces the effects of the active metabolite by 45% after administration of the loading dose and 40% after administration of the maintenance dose. This reduction results in a reduction of inhibition of platelet aggregation respectively 39% and 21%. It is assumed that esomeprazole has a similar effect on the activity of clopidogrel. Observational and controlled clinical trials were received conflicting data regarding the clinical significance of this interaction (estimated at greater risk for cardiovascular complications). As a precaution, not recommended for use in conjunction with clopidogrel and omeprazole ezomeprozolom.
If there is a need to appoint a proton pump inhibitor simultaneously with clopidogrel, should use the drug with the least inhibition of CYP2C19 (pantaprazol or lansoprazole). In an application with patoprazolom at a dose of 80 mg 1 time per day the concentration of the active metabolite of clopidogrel in plasma is reduced by 20% after administration of the loading dose and 14% after receiving a maintenance dose of clopidogrel. Thus inhibition of platelet aggregation is reduced by 20% after administration of the loading dose and 14% after administration of a maintenance dose of clopidogrel. Thus inhibition of platelet aggregation is reduced by 15% and 11%
Another combination therapy
Since Clopidogrel is metabolized to form its active metabolite partially by CYP2C19 system, the use of drugs that inhibit this system (e.g., omeprazole) can lead to decreased levels of the active metabolite of clopidogrel and reduce its clinical efficacy. The simultaneous administration of drugs that inhibit CYP2C19 system is not recommended. If the proton pump inhibitors should be taken in conjunction with clopidogrel should be used proton pump inhibitor with the least inhibition of CYP2C19 isoenzyme, such as pantoprazole.
a number of clinical studies have been conducted with clopidogrel and other drugs at the same time appointed to examine possible pharmacokinetic and pharmacodynamic interactions, which showed that:
- when used in conjunction with clopidogrel atenolol, nifedepinom or both drugs simultaneously clinically significant pharmacodynamic interactions were observed;
- while taking phenobarbital, cimetidine or estrogen significant effect on the pharmacodynamics of clopidogrel were found;
- pharmacokinetic parameters of digoxin or theophylline were not changed in their joint application with clopidogrel;
- Antacids did not reduce the absorption of clopidogrel;
- according to research results CAPRIE, phenytoin, tolbutamide, and can be safely used simultaneously with clopidogrel, despite the fact that the data obtained in studies with human liver microsomes, suggest that carboxylic metabolite of clopidogrel can inhibit isozyme CYP2C9.
It is unlikely that clopidogrel may affect the metabolism of other drugs, such as phenytoin and tolbutamide and NSAIDs are metabolized involving isoenzyme CYP2C9.
- Angiotensin-converting enzyme (ACE) inhibitors, diuretics, beta-blockers, blockers "slow" calcium channel blockers, lipid-lowering drugs, hypoglycemic agents (including insulin), coronary vasodilators, antiepileptics, drugs hormone replacement therapy and inhibitors of glycoprotein IIb / IIIa - in clinical studies there was no evidence of clinically significant adverse interactions.
In the treatment of clopidogrel, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgery, it is necessary to conduct a thorough monitoring of patients in order to exclude signs of bleeding, including hidden.
Because of the risk of bleeding and haematological undesirable effects (see. "Side effects") in case of occurrence in the course of treatment of clinical symptoms suspicious for the occurrence of bleeding, should urgently make a complete blood count to determine the activated partial thromboplastin time (aPTT), platelet count , indicators of platelet functional activity and conduct other necessary investigations. Clopidogrel, as well as other antiplatelet drugs should be used with caution in patients who have an increased risk of bleeding associated with trauma, surgery or other pathological conditions and in patients receiving aspirin, NSAIDs, including COX -2, heparin, inhibitors of glycoprotein IIb / IIIa, SSRIs or thrombolytic drugs.
The combined use of clopidogrel with warfarin increases the risk of bleeding (see. Section "Interaction with other medicinal products"), so be careful when they are used together.
In the case of the upcoming scheduled surgery, and without the need for antiplatelet effect for 5-7 days before surgery clopidogrel should be discontinued. Upon termination of therapy for more than 5 days prior to CABG major bleeding rate in patients treated with clopidogrel and placebo was comparable (it was 4.4% in patients treated with clopidogrel and acetylsalicylic acid, and 5.3% in patients receiving aspirin and placebo).
Clopidogrel prolongs bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (particularly gastrointestinal and intraocular).
Patients should be warned that while taking clopidogrel (alone or in combination with acetylsalicylic acid) to stop the bleeding may take more time, and that in case they have an unusual (for location or duration), they should inform the bleeding tell your doctor. Before any upcoming surgery (including dental procedures) and before taking any new drug, patients should tell your doctor about taking clopidogrel.
Very rarely, after the application of clopidogrel (sometimes short), there have been cases of thrombotic thrombocytopenic purpura (TTP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, renal dysfunction, and fever. TTP is a potentially life-threatening condition that requires immediate treatment including plasmapheresis.
Reported cases of acquired haemophilia when taking clopidogrel. Upon confirmation of an isolated increase in activated partial thromboplastin time (aPTT), accompanied or not by the development of bleeding, you should suspect the possibility of acquired hemophilia. Patients with a confirmed diagnosis of acquired haemophilia should be observed and treated by specialists in this disease. Clopidogrel should be discontinued.
It should specify a history of allergic patients and / or other hematological reactions thienopyridine derivatives (such as ticlopidine and prasugrel) since described cases of cross-allergic and / or hematological reactions among thienopyridines. Thienopyridines may cause mild or severe allergic reactions (rash, angioedema) or hematologic reactions (anemia, neutropenia). Patients who have previously observed allergic and / or hematologic response to one of the drugs - derivatives of thienopyridine, may have an increased risk of such reactions while taking another drug from the group of thienopyridines. These patients require close monitoring during the treatment period for signs of hypersensitivity to clopidogrel.
In the period of treatment is necessary to control the functional activity of the liver. In severe liver damage should be aware of the risk of hemorrhagic diathesis.
Clopidogrel is not recommended for acute stroke with the prescription of less than 7 days (since there are no data on its use in this condition).
In patients with recent ischemic stroke or transient ischemic attack and high risk of recurrent atherothrombotic events combining therapy with clopidogrel and aspirin did not demonstrate a higher efficiency compared to clopidogrel monotherapy, but may increase the risk of major bleeding.
It is necessary to clarify the presence of a history of hypersensitivity to other patients thienopyridine derivative (tiklopedil, prasugrel) since described cases of cross-allergies between thienopyridine. Patients who have previously observed hypersensitivity to other thienopyridines, require careful monitoring throughout the treatment period for signs of hypersensitivity to clopidogrel.
Experience in the use of clopidogrel in patients with chronic renal insufficiency is limited, therefore the clopidogrel in these patients should be used with caution
In severe hepatic dysfunction clopidogrel is contraindicated due to the high risk of hemorrhagic diathesis. The experience of the drug in patients with moderate hepatic impairment is limited, therefore these patients clopidogrel should be used with caution.
Clopidogrel should not be taken in patients with rare hereditary galactose intolerance, lactase deficiency and malabsorption syndrome glucose-galactose (see. "Composition")
The effect on the ability of trucks and other mechanical control means
Clopidogrel has no significant effect on the ability to drive vehicles and other mechanisms.
Tablets, film-coated, 75 mg: 7 or 14 tablets in an aluminum strip; 1, 2, or 4 strips together with instructions for use in paper cartons;
Tablets, film-coated, 150 mg: 7 or 10 tablets in an aluminum strip; 2 strips together with instructions for use in paper cartons;
Tablets, film-coated, 300 mg: 10 tablets in aluminum strip; 1 the Strip, together with instructions for use in paper cartons;
Composite packaging 1 tablet, film-coated, 28 + 300 mg film-coated tablets 75 mg: 7 or 14 to 75 mg tablets in an aluminum strip; 1 tablet of 300 mg in an aluminum strip; 2 or 4 strips with tablets 75 mg and 1 plates with 300 mg tablet with instructions for use in paper cartons
Store in a dry dark place at a temperature not higher than 250C. Keep out of the reach of children
3 years. Do not use after the expiry date stated on the package!
Conditions of supply of pharmacies
The owner of the registration certificate: ESCO PHARMA LTD (Russia)
Produced by: NOVALEK PHARMACEITICAL, Pvt. Ltd. (India)