Lopirel tabs 75mg #28

Lopirel instruction

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Lopirel is an antiplatelet agent.

Release form and composition

Lopirel is available in the form of film-coated tablets: round, biconvex, pink, with an "I" engraving on one side (7 or 10 tablets in a blister: in a cardboard box 1, 2, 4 or 8 blisters of 7 tablets or 1, 2, 3, 5, 6, 9 or 10 blisters of 10 tablets, in a cardboard box for a hospital 10, 20, 30 or 40 blisters).
1 Lopirel tablet contains:
    active substance: clopidogrel - 75 mg;
    excipients: microcrystalline cellulose, lactose, talc, glyceryl dibegenate, crospovidone (type A);
    sheath: Opadray II 85G34669 Pink [talc, polyvinyl alcohol, macrogol 3350, titanium dioxide (E171), iron dye red oxide (E172), lecithin (E322)].

Pharmacodynamics

Mechanism of action

Clopidogrel belongs to the category of prodrugs. One of its metabolites is an active inhibitor of platelet aggregation: it inhibits the binding of adenosine diphosphate (ADP) and the P2Y12 receptor of platelets, followed by ADP-mediated activation of the glycoprotein IIb / IIIa complex, which inhibits platelet aggregation. An irreversible binding mechanism allows platelets to be immune to ADP stimulation throughout their entire life span (approximately 7–10 days). The normal function of platelets is restored depending on the rate of their renewal.
Also, Lopirel inhibits platelet aggregation caused by agonists other than ADP. The formation of an active metabolite is caused by the action of isoenzymes of the P450 system, and since some of the isoenzymes may differ in polymorphism or be inhibited by other drugs, not every patient has sufficient inhibition of platelet aggregation.

Pharmacodynamic properties

Daily intake of clopidogrel at a dose of 75 mg provides a significant suppression of ADP-induced platelet aggregation from the first day of administration. Gradually, over the course of 3–7 days, the degree of suppression increases, reaching a constant level after reaching an equilibrium state. When taking a daily dose of 75 mg in an equilibrium state, platelet aggregation is suppressed by 40-60%. Within 5 days after stopping the drug intake, bleeding time and platelet aggregation gradually return to the initial level.

Clinical efficacy / safety

Clopidogrel prevents the development of atherothrombosis in any localization of atherosclerotic vascular lesions (for example, with lesions of the coronary, peripheral or cerebral arteries).
In the course of the ACTIVE-A clinical study, it was shown that in the presence of atrial fibrillation in patients who had one or more risk factors for vascular complications, but could take indirect anticoagulants, the combination of clopidogrel and acetylsalicylic acid (compared to monotherapy with acetylsalicylic acid) reduced the frequency together taken myocardial infarction, stroke, systemic thromboembolism outside the central nervous system, or vascular mortality, mainly by reducing the risk of stroke. The effectiveness of the joint administration of clopidogrel and acetylsalicylic acid was manifested early and persisted for 5 years. A decrease in the likelihood of developing major vascular complications in patients taking acetylsalicylic acid and clopidogrel was mainly due to a significant decrease in the incidence of strokes. With therapy with these drugs, the risk of stroke of any severity decreased, and there was also a trend towards a decrease in the incidence of myocardial infarction, but no differences were found in the incidence of thromboembolism outside the central nervous system or vascular death. Along with this, taking clopidogrel and acetylsalicylic acid reduced the total amount of hospitalization time for patients with cardiovascular problems.

Pharmacokinetics

Suction

Both with a single dose and with a course intake of clopidogrel at a dose of 75 mg per day, the substance is rapidly absorbed. On average, the maximum plasma concentration of unchanged clopidogrel is reached approximately 45 minutes after oral administration and ranges from 2.2 to 2.5 ng / ml. The absorption of clopidogrel by the kidneys (according to the excretion of its metabolites) is at least 50%.

Distribution

Clopidogrel and its main inactive metabolite circulating in the blood in vitro reversibly bind to plasma proteins by 98 and 94%, respectively. In vitro, these bonds are unsaturated over a wide concentration range.

Metabolism

The active substance is extensively metabolized in the liver. Clopidogrel in vivo and in vitro is metabolized in two ways: through esterase followed by hydrolysis, resulting in the formation of an inactive derivative of carboxylic acid (85%) from metabolites that circulate in the systemic circulation; through the cytochrome P450 system.
At the initial stage, clopidogrel is metabolized to an intermediate metabolite - 2-oxoclopidogrel. The subsequent metabolism of oxoclopidogrel causes the appearance of an active metabolite - a thiol derivative of clopidogrel. This in vitro metabolic pathway involves the isoenzymes CYP2C19, CYP3A4, CYP2B6 and CYP1A2. The active thiol metabolite isolated in vitro irreversibly and quickly binds to platelet receptors, inhibiting their aggregation.
In the case of a single dose of clopidogrel at a dose of 300 mg, the maximum concentration of the active metabolite is twice as high as in the case of a maintenance dose of clopidogrel 75 mg for 4 days. The maximum concentration of the active metabolite of clopidogrel was recorded 0.5–1 hour after taking Lopirel.

Withdrawal

In humans, after oral ingestion of 14C-labeled clopidogrel for 120 hours, approximately 46% of the radioactivity is excreted through the intestine and approximately 50% of the radioactivity through the kidneys. After a single dose of clopidogrel at a dose of 75 mg, the half-life is approximately 6 hours. With a single dose and repeated doses, the half-life of the main inactive metabolite circulating in the blood is about 8 hours.

Pharmacogenetics

The active metabolite of clopidogrel and the intermediate metabolite 2-oxoclopidogrel are formed by the isoenzyme CYP2C19. The genotype of the isoenzyme CYP2C19 influences the antiplatelet effect and pharmacokinetics of the active metabolite during ex vivo platelet aggregation studies.
The allele of the CYP2C19 * 1 gene corresponds to a fully functional metabolism, and the alleles of the CYP2C19 * 3 and CYP2C19 * 2 genes are non-functional and cause a decrease in metabolism in most of the Mongoloid (99%) and Caucasoid (85%) races. Other alleles that cause a decrease or absence of metabolism (including, but not limited to, alleles of the CYP2C19 * 4, * 5, * 6, * 7, * 8 genes) are less common. Patients who are poor metabolizers should have the two indicated alleles of the loss-of-function gene. According to the literature, the incidence of phenotypes of weak metabolizers of CYP2C19 in blacks is 4%, in Caucasians - 2%, in Chinese - 14%.
To assess the pharmacokinetics and antiplatelet effect when taking an initial dose of clopidogrel 300 mg and then taking it at 75 mg per day, as well as when taking an initial dose of clopidogrel 600 mg and then taking it at 150 mg per day for 5 days (until an equilibrium state is reached ), a crossover study was conducted with the participation of 40 volunteers in 4 groups of 10 people with 4 subtypes of the isoenzyme CYP2C19 (ultrafast, intense, weak or intermediate metabolizers). As a result, there were no significant differences in the exposure of the active metabolite in intensive, intermediate and ultrafast metabolizers, as well as in the average values ​​of inhibition of platelet aggregation (induced by ADP). The exposure of the active metabolite in weak metabolizers in comparison with intensive metabolizers decreased by 63–71%. In the case of using the 300 mg / 75 mg regimen, the antiplatelet effect in weak metabolizers decreased with the average values ​​of inhibition of platelet aggregation, which were 24% (after 24 hours) and 37% (on the 5th day) in comparison with the average values ​​of inhibition of platelet aggregation in intensive (39% - after 24 hours and 58% - on the 5th day) and intermediate (37% - after 24 hours and 60% - on the 5th day) metabolizers. In the case of using the scheme 600 Allele of the CYP2C19 * 1 gene provides a fully functional metabolism of mg / 150 mg, the exposure of the active metabolite in weak metabolizers was higher than with the 300 mg / 75 mg scheme. The mean inhibition of platelet aggregation was 32% (after 24 hours) and 61% (on the 5th day), which was higher than the same indicator for the 300 mg / 75 mg regimen, but was similar to the groups of patients with increased intensity of CYP2C 19- metabolism, who received treatment on a 300 mg / 75 mg regimen. It should be noted that in the study, taking into account the clinical outcome for patients of this group, the dosage regimen of clopidogrel has not yet been established.
A meta-analysis of six studies, which includes data from 335 volunteers who received clopidogrel and were in a state of equilibrium concentration, showed that the exposure of the active metabolite in weak metabolizers decreased by 72%, and in intermediate ones - by 28%, although the mean value of inhibition of platelet aggregation was reduced in comparison with intensive metabolizers by 21.4 and 5.9%, respectively.
Evaluation of the relationship between the CYP2C19 genotype and clinical outcomes in clopidogrel-treated patients in prospective, controlled, randomized trials has not been carried out, however, several retrospective analyzes are currently available. Published data from several cohort studies, as well as the results of genotyping in clinical trials: CHARISMA (n = 2428), CURE (n = 2721), TRITON-TIMI 38 (n = 1477), CLARITY-TIMI 28 (n = 227), ACTIVE- A (n = 601).
In three cohort studies (Giusti, Collet, Sibbing) and the TRITON-TIMI 38 clinical study in patients of the combined group with weak and intermediate metabolism, a higher incidence of cardiovascular complications (myocardial infarction, stroke, death) or stent thrombosis was recorded in comparison with similar data on intensive metabolizers.
In the Simon cohort study and the CHARISMA study, an increased incidence of cardiovascular complications was recorded only in weak metabolizers (when compared with intensive ones).
In the Trenk cohort study and the CLARITY, CURE, ACTIVE-A studies, no association of cardiovascular complications with the intensity of CYP2C19 metabolism was recorded.
Clinical studies carried out to date have insufficient sample size to detect differences in clinical outcome in patients with low CYP2C19 isoenzyme activity.

Special clinical cases

The pharmacokinetics of the active metabolite of clopidogrel for individual groups has not been studied.
In studies involving elderly volunteers (over 75 years) in comparison with the data of young volunteers, no differences in bleeding time and platelet aggregation indicators were obtained. For the treatment of elderly patients, dose adjustment of Lopirel is not required.
The pharmacokinetics of clopidogrel in patients under the age of 18 has not been studied.
In severe kidney damage (with creatinine clearance of 5 to 15 ml / min), as a result of repeated use of clopidogrel at a dose of 75 mg per day, the degree of initiation of ADP-induced platelet aggregation was 25% lower than that in healthy volunteers, however, the lengthening of bleeding time remained a similar indicator for healthy volunteers who received a daily dose of clopidogrel 75 mg. Lopirel was well tolerated by all patients.
In severe liver damage as a result of taking clopidogrel at a dose of 75 mg per day for 10 days, the degree of inhibition of ADP-induced platelet aggregation was similar to that for healthy volunteers. Both groups were also comparable in mean bleeding time.
The prevalence of alleles of the genes of the isoenzyme CYP2C9, which are responsible for reduced and intermediate metabolism, is different in representatives of different racial groups. For representatives of the Mongoloid race, there is a small amount of literature data, which does not allow assessing the value of genotyping of the CYP2C19 isoenzyme in relation to the development of ischemic complications.

Indications for use

Lopirel is used to prevent the following conditions / diseases:
    atherothrombotic complications in adult patients with myocardial infarction (from several days to 35 days), ischemic stroke (from 7 days to 6 months), or diagnosed occlusive peripheral arterial disease;
    atherothrombotic complications in adult patients with acute coronary syndrome: with ST segment elevation (acute myocardial infarction) during drug treatment and the possibility of thrombolysis (together with acetylsalicylic acid); without ST segment elevation (unstable angina pectoris or myocardial infarction without Q wave), including in patients after stenting by percutaneous coronary intervention (together with acetylsalicylic acid);
    thromboembolic and atherothrombotic complications in atrial fibrillation (atrial fibrillation) in patients with atrial fibrillation (atrial fibrillation) who have one or more risk factors for vascular complications, a low likelihood of bleeding and cannot use indirect anticoagulants (in combination with acetylsalicylic acid).

Contraindications

    acute bleeding (intracranial hemorrhage, bleeding from a peptic ulcer, etc.);
    severe liver failure;
    hereditary lactose intolerance, glucose-galactose malabsorption syndrome and lactase deficiency;
    children under 18 years of age;
    pregnancy;
    lactation period;
    hypersensitivity to the components of the drug.
Lopirel is prescribed with caution in the following cases:
    renal failure;
    moderate hepatic impairment with a concomitant predisposition to bleeding;
    trauma, surgery;
    diseases in which bleeding may develop (especially intraocular or gastrointestinal);
    concomitant use of serotonin reuptake inhibitors, non-steroidal anti-inflammatory drugs (including selective inhibitors of cyclooxygenase-2), heparin, warfarin, glycoprotein IIb / IIIa inhibitors;
    a history of hematological and allergic reactions to other thienopyridines (prasugrel, ticlopidine);
    a genetically determined decrease in the function of the isoenzyme CYP2C19.

Method of administration and dosage

Lopirel is taken orally with or without food.
Use in adults and elderly patients with normal activity of the isoenzyme CYP2C19
With myocardial infarction, ischemic stroke and diagnosed occlusive peripheral arterial disease, 75 mg of Lopirel is prescribed once a day.
In acute coronary syndrome without ST-segment elevation (myocardial infarction without Q wave, unstable angina pectoris), treatment should begin with a single dose of a loading dose (300 mg), after which 75 mg is prescribed once a day (together with a daily dose of acetylsalicylic acid 75-325 mg ). Since the use of higher amounts of acetylsalicylic acid increases the risk of bleeding, the dose of acetylsalicylic acid recommended for this indication should not exceed 100 mg. The optimal duration of therapy has not been officially determined. According to clinical studies, it is advisable to take the drug for up to 1 year. The maximum beneficial effect is observed by the 3rd month of treatment.
In acute coronary syndrome with ST segment elevation (acute myocardial infarction characterized by ST segment elevation), a loading dose of Lopirel of 300 mg is prescribed once, followed by 75 mg once a day in combination with acetylsalicylic acid (in combination with or without thrombolytics). When treating patients aged 75 years and older, Lopirel therapy should be carried out without taking a loading dose. Combination therapy begins as soon as symptoms appear and continues for 4 weeks. The effectiveness of using a combination of acetylsalicylic acid and clopidogrel for these indications for more than 4 weeks has not been studied.
With atrial fibrillation (atrial fibrillation), 75 mg of Lopirel is prescribed once a day. Together with clopidogrel, you should start and continue the use of acetylsalicylic acid (daily dose 75-100 mg).
If you miss taking the next dose of Lopirel, you should adhere to the following recommendations:
    if less than 12 hours have passed since the missed dose, you should immediately take a dose of Lopirel, and take the next doses of the drug as usual;
    if more than 12 hours have passed since the missed dose, the next dose of Lopirel should be taken as usual (taking a double dose is prohibited).
Use in patients with a genetically determined decreased activity of the isoenzyme CYP2C19
With low activity of the isoenzyme CYP2C19, the antiplatelet effect of clopidogrel decreases. When using higher doses (loading dose 600 mg, and then 150 mg per day daily), the antiplatelet effect of clopidogrel increases. Taking into account the clinical outcomes of the study, it was not possible to establish the optimal dosage regimen of the drug for patients with reduced metabolism due to low activity of the isoenzyme CYP2C19.

Use in patients of different ethnicity

For representatives of different ethnic groups, the prevalence of alleles of the genes of the isoenzyme CYP2C19, which are responsible for the reduced and intermediate metabolism of clopidogrel to the active metabolite, differs. There is only limited information on the representatives of the Mongoloid race in terms of assessing the relationship between the genotype of the isoenzyme CYP2C19 and clinical resultant events.

Application in men and women

A small study comparing the pharmacodynamic properties of Lopirel in both sexes showed less inhibition of ADP-induced platelet aggregation in women, but there were no differences in bleeding time. In the large controlled study CAPRIE (a combination of clopidogrel and acetylsalicylic acid in patients with an increased likelihood of developing ischemic complications) in women and men, the frequency of clinical outcomes, deviations of clinical and laboratory parameters from the norm and other side effects were the same.

Side effects

The safety study has been conducted with over 44,000 patients, including over 12,000 patients who have been treated for at least 1 year. The general tolerance of clopidogrel is similar to that of acetylsalicylic acid, regardless of race, gender and age of patients. A number of clinical studies (CURE, CAPRIE, COMMIT, CLARITY, ACTIVE A) have identified clinically significant side effects listed below.
In the CAPRIE trial, the tolerability of clopidogrel (daily dose 75 mg) was similar to that for acetylsalicylic acid (daily dose 325 mg). Spontaneous messages contain information about adverse reactions.
In the course of clinical studies and post-marketing use of clopidogrel, the facts of the development of bleeding were most often recorded (especially in the first month of treatment).
In the clinical study CAPRIE, the cumulative bleeding rate with separate administration of clopidogrel or acetylsalicylic acid was 9.3%. Severe bleeding with clopidogrel was recorded with the same frequency as with acetylsalicylic acid.
In the course of the CURE clinical study, when acetylsalicylic acid and clopidogrel were used for 7 days after coronary artery bypass grafting in those patients who stopped treatment more than 5 days before surgery, an increase in the frequency of severe bleeding was not observed. In patients who continued to take the complex of these drugs for 5 days before the onset of coronary artery bypass grafting, severe bleeding was observed with a frequency of 9.6% (for the combination of acetylsalicylic acid + clopidogrel) and 6.3% (for the combination of acetylsalicylic acid + placebo).
In the CLARITY clinical study, there was an overall increase in bleeding rates for the acetylsalicylic acid + clopidogrel group compared to the acetylsalicylic acid + placebo group. In both groups, the frequency of severe bleeding was similar and almost did not depend on the type of heparin or fibrinolytic therapy and the baseline characteristics of the patients.
In the COMMIT clinical trial, the cumulative incidence of cerebral hemorrhage or major non-cerebral bleeding was low and did not differ for both groups.
In the ACTIVE-A clinical trial, the incidence of major bleeding for the acetylsalicylic acid + clopidogrel group was higher than for the acetylsalicylic acid + placebo group (6.7% and 4.3%, respectively). In general, large bleeding in both groups was extracranial (5.3% and 3.5%, respectively), most often gastrointestinal bleeding developed (3.5% and 1.8%, respectively). In the acetylsalicylic acid + clopidogrel group, intracranial hemorrhages were more common in comparison with the acetylsalicylic acid + placebo group (1.4% and 0.8%, respectively). Also, there were no statistically significant differences for these groups in the incidence of hemorrhagic stroke (0.8% and 0.6%, respectively) and fatal bleeding (1.1% and 0.7%, respectively).
In clinical studies and with spontaneous messages, the following adverse reactions have been recorded:
    lymphatic and circulatory systems: infrequently - eosinophilia, leukopenia, thrombocytopenia; rarely, neutropenia (including severe neutropenia); very rarely - aplastic anemia, thrombotic thrombocytopenic purpura, agranulocytosis, pancytopenia, severe thrombocytopenia, granulocytopenia, acquired hemophilia (type A), anemia;
    immune system: very rarely - anaphylactoid reactions, serum sickness; the frequency is unknown - the development of cross-reactions of hypersensitivity with thienopyridines (for example, with ticlopidine and prasugrel);
    psyche: very rarely - confusion, hallucinations;
    nervous system: infrequently - headache, intracranial hemorrhage (some fatal cases), dizziness, paresthesia; very rarely - taste disturbances;
    vision: infrequently - eye hemorrhages (in the tissue of the eye, conjunctiva, retina);
    hearing: rarely - vertigo;
    vessels: often - hematomas; very rarely - bleeding from an operating wound, severe bleeding, lowering blood pressure, vasculitis;
    respiratory system: often - nosebleeds; very rarely - bronchospasm, bleeding from the respiratory system (pulmonary hemorrhage, hemoptysis), eosinophilic pneumonia, intestinal pneumonitis;
    gastrointestinal tract: often - diarrhea, gastrointestinal bleeding, dyspepsia, abdominal pain; infrequently - gastritis, stomach and duodenal ulcers, nausea, vomiting, flatulence, constipation; rarely - retroperitoneal bleeding; very rarely - lethal retroperitoneal and gastrointestinal bleeding, colitis (including lymphocytic or ulcerative), pancreatitis, stomatitis;
    liver and urinary tract: very rarely - hepatitis, acute liver failure, abnormalities in laboratory studies of the functional state of the liver;
    skin and subcutaneous tissue: often - bruising; infrequently - itchy skin, rash, purpura; very rarely - angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), drug hypersensitivity syndrome, erythematous or exfoliative rash, drug rash with systemic symptoms and eosinophilia, urticaria; lichen planus, eczema
    musculoskeletal and connective tissue: very rarely - arthritis, hemarthrosis (hemorrhage in the musculoskeletal system), myalgia, arthralgia;
    kidneys and urinary tract: infrequently - hematuria; very rarely - an increase in the concentration of creatinine in the blood, glomerulonephritis;
    instrumental and laboratory tests: infrequently - a decrease in the number of neutrophils, an increase in bleeding time, a decrease in the number of platelets;
    violations at the injection site and general disorders: often - bleeding from the puncture site; very rarely - fever.

Overdose

In case of an overdose of Lopirel, the bleeding time may increase with the development of subsequent complications in the form of bleeding.
In the event of the occurrence of the described phenomena, it is necessary to carry out appropriate therapeutic measures. For quick correction of prolonged bleeding time, platelet transfusion is recommended. There is no antidote for clopidogrel.

Special instructions

Bleeding, hematological disorders

When clinical symptoms appear, indicating the occurrence of bleeding and the risk of developing undesirable effects, it is necessary to provide an urgent clinical blood test, determination of activated partial thromboplastin time, platelet count, indicators of platelet functional activity, as well as other necessary studies.
Lopirel should be used with caution in patients with an increased risk of bleeding associated with surgery, trauma, other pathological conditions, and in patients receiving non-steroidal anti-inflammatory drugs (in particular, acetylsalicylic acid, heparin, COX-2 inhibitors, glycoprotein IIb inhibitors / IIIa or selective serotonin reuptake inhibitors).
During the first weeks of therapy with Lopirel and / or after an invasive cardiological procedure or surgical intervention, careful monitoring of the presence of signs of bleeding, including latent, should be carried out.
Due to the possible increase in the intensity of bleeding, the combined use of Lopirel and warfarin is not recommended. The exception is rare clinical situations: the presence of a floating thrombus in the left ventricle, stenting in patients with atrial fibrillation, etc.
In the case of an upcoming planned surgical operation and in the absence of the need to ensure an antiplatelet effect, Lopirel should be discontinued 7 days before the intervention.
Before starting any new medications and before the upcoming surgery, the patient must inform the doctor (including the dentist) about taking Lopirel.
The drug lengthens the bleeding time, therefore it should be used with caution in patients with diseases that predispose to bleeding (especially intraocular and gastrointestinal).
The patient must be warned that in the case of taking Lopirel (in monotherapy or in combination with acetylsalicylic acid), stopping bleeding takes more time. If you experience unusual bleeding (in duration or location), you should seek the advice of your doctor.

Thrombotic thrombocytopenic purpura (TTP)

Even after a short intake of clopidogrel, cases of thrombotic thrombocytopenic purpura, which were characterized by thrombocytopenia, microangiopathic hemolytic anemia, accompanied by impaired renal function, fever, and neurological disorders, were very rare. TTP is considered a potentially life-threatening event requiring immediate treatment, including plasmapheresis.

Acquired hemophilia

During the treatment with clopidogrel, cases of acquired hemophilia have been recorded. When confirming the prolongation of the activated partial thromboplastin time without the development of bleeding or with it, the likelihood of acquired hemophilia should be considered, and if an appropriate diagnosis is established, stop taking Lopirel and initiate adequate treatment.

Recent ischemic stroke

Lopirel is not recommended to be prescribed when acute ischemic stroke is up to 7 days old due to the lack of data on its use in this condition. Combination therapy with acetylsalicylic acid and clopidogrel in patients with a recent transient ischemic attack or ischemic stroke and a high probability of recurrent atherothrombotic events is not more effective than clopidogrel monotherapy, but has a greater risk of extensive bleeding.

Cross-reactions with thienopyridines

During therapy with thienopyridines, cross-hypersensitivity reactions were recorded, therefore, before starting treatment, it is necessary to clarify the presence of hypersensitivity reactions to thienopyridines (clopidogrel, ticlopidine, prasugrel) in the patient's history.
Taking thienopyridines can lead to allergic reactions of varying severity, such as angioedema, rash, or hematological cross-reactions (neutropenia and thrombocytopenia). Patients with hematological and / or allergic reactions during previous treatment with thienopyridines may increase the likelihood of developing similar or other reactions in the case of therapy with another thienopyridine. It is recommended to control the symptoms of hypersensitivity when treating patients with a history of allergic reactions to thienopyridines.

Cytochrome P450 isoenzyme CYP2C19

In patients with a slow metabolism of the isoenzyme CYP2C19, in the case of taking the recommended doses of clopidogrel, its active metabolite is formed in a smaller amount, and a weaker effect on platelet aggregation was also recorded.
The metabolism of clopidogrel to active metabolites with the partial participation of the isoenzyme CYP2C19 causes a decrease in the content of the active metabolite of clopidogrel when using drugs that inhibit the activity of this enzyme. The clinical significance of this interaction is unknown. The simultaneous administration of moderate and strong inhibitors of the isoenzyme CYP2C19 is not recommended.

Application during pregnancy and lactation

Studies carried out on animals did not reveal a direct and indirect adverse effect of clopidogrel on embryonic development, pregnancy, childbirth, postnatal development, but due to the lack of relevant clinical data, the appointment of Lopirel to pregnant patients is contraindicated.
In the course of studies on rats, it was found that clopidogrel and its metabolites pass into breast milk, therefore, in the case of treatment with Lopirel, breastfeeding should be discontinued. There are no data on the excretion of clopidogrel in human breast milk.

Childhood use

According to the instructions, Lopirel is prohibited for use in children under 18 years of age.

With impaired renal function

Since there are limited data on the use of clopidogrel in patients with impaired renal function, Lopirel should be used with caution when treating patients in this category.

For violations of liver function

Since there are limited data on the use of clopidogrel in patients with moderate liver dysfunction with a high probability of developing hemorrhagic diathesis, Lopirel should be used with caution in the treatment of patients in this category.

Use in the elderly

No dose adjustment of Lopirel is required when treating elderly patients.

Drug interactions

Due to the risk of increased bleeding intensity, the simultaneous administration of clopidogrel with indirect anticoagulants is not recommended, although taking a daily dose of clopidogrel 75 mg did not change the international normalized ratio or the pharmacokinetics of S-warfarin in patients who received long-term treatment with warfarin. The combined use of warfarin and clopidogrel increases the risk of bleeding due to an independent effect on hemostasis.
Acetylsalicylic acid does not affect the effectiveness of clopidogrel, however, the latter potentiates the effect of ASA on platelet aggregation. At the same time, the simultaneous administration of clopidogrel and ASA (500 mg 2 times a day) did not lead to a significant increase in bleeding time. A pharmacodynamic interaction is possible between ASA and clopidogrel, which increases the risk of bleeding, so caution should be exercised when using them together, although in clinical trials, patients were prescribed combination therapy with clopidogrel and ASA for up to 1 year.
The simultaneous administration of clopidogrel and IIb / IIIa receptor blockers requires caution.
According to a clinical study involving healthy individuals, in the case of taking clopidogrel, a change in the dose of heparin was not required, the anticoagulant effect of which did not change. The simultaneous administration of heparin did not affect the antiplatelet effect of clopidogrel. A pharmacodynamic interaction is possible between heparin and clopidogrel, which can cause the development of bleeding, therefore, these drugs must be used with caution at the same time.
The safety of the combined use of fibrin-specific or fibrin-nonspecific thrombolytic drugs, heparin and clopidogrel was studied in patients after acute myocardial infarction. Clinically significant bleeding occurred with a frequency similar to this indicator in the case of the combined use of thrombolytic drugs, heparin and acetylsalicylic acid.
In a clinical study involving healthy volunteers, it was found that the combined use of naproxen and clopidogrel led to an increase in latent blood loss through the gastrointestinal tract. Since there are no studies on the interaction of clopidogrel and other nonsteroidal anti-inflammatory drugs, it is not known whether there is an increased risk of gastrointestinal bleeding when taking this combination. Therefore, the co-administration of clopidogrel and non-steroidal anti-inflammatory drugs, including COX-2 inhibitors, must be carried out with caution.
Since there is evidence of the effect of selective serotonin reuptake inhibitors on platelet activation with an increased risk of bleeding, these drugs should be prescribed with caution simultaneously with clopidogrel.
The formation of the active metabolite of clopidogrel partially occurs with the help of the CYP2C19 system, therefore, the use of agents that inhibit this system can lead to a decrease in the content of the active metabolite in the blood plasma with a decrease in the clinical efficacy of clopidogrel. The clinical significance of this interaction is unknown. For reasons of precaution, it is necessary to avoid the simultaneous use of moderate and strong inhibitors of the isoenzyme CYP2C19.
Drugs that inhibit the CYP2C19 isoenzyme include esomeprazole, omeprazole, fluoxetine, fluvoxamine, voriconazole, moclobemide, ticlopidine, fluconazole, cimetidine, ciprofloxacin, oxcarbamazepine, chloramphenicol, carbamazepine.
Taking clopidogrel with omeprazole at a dose of 80 mg per day or taking them together for less than 12 hours led to a 45% decrease in the exposure of the active metabolite at a loading dose and by 40% at a maintenance dose. This change in values ​​is associated with a 39% decrease in inhibition of platelet aggregation at a loading dose and by 21% in the case of a maintenance dose. A similar effect is expected with the interaction of clopidogrel and esomeprazole.
In the course of observational and clinical studies, conflicting information was obtained about the clinical significance of the effect of these pharmacokinetic and pharmacodynamic interactions on severe cardiovascular complications. Concomitant use of omeprazole or esomeprazole with clopidogrel is not recommended for safety reasons.
With the use of lansoprazole or pantoprazole, a less pronounced decrease in the exposure of the metabolite was observed.
With the simultaneous use of pantoprazole (single daily dose - 80 mg) and clopidogrel, the concentration of the active metabolite decreased by 20% with a loading dose and by 14% with a maintenance dose. This therapy led to a decrease in the average inhibition of platelet aggregation by 15 and 11%, respectively. These data indicate that clopidogrel and pantoprazole can be used simultaneously.
There is no evidence that other drugs that lower the acidity of gastric juice (antacids or H2 blockers, excluding cimetidine, an inhibitor of the CYP2C19 isoenzyme), change the antiplatelet properties of clopidogrel.
In the course of a number of clinical studies on the intake of clopidogrel and other simultaneously prescribed drugs, data were obtained on a slight change in the pharmacodynamic activity of clopidogrel while taking estrogens or phenobarbital. No clinically significant pharmacodynamic interaction of clopidogrel with nifedipine, atenolol or their combination has been recorded.
Pharmacokinetic parameters of theophylline and digoxin when used together with clopidogrel did not change.
Antacids do not reduce the absorption of clopidogrel.
According to the CAPRIE study, tolbutamide and phenytoin can be co-administered with clopidogrel, although the carboxyl metabolite of clopidogrel inhibits the activity of cytochrome P450 2C9 isoenzyme (data from human liver microsomes). This phenomenon, in turn, can lead to an increase in plasma concentrations of some drugs metabolized by the isoenzyme 2C9 of cytochrome P450 (tolbutamide, phenytoin, some non-steroidal anti-inflammatory drugs).
Clinical studies have not revealed clinically significant undesirable interactions between clopidogrel and angiotensin-converting enzyme inhibitors, beta-blockers, diuretics, slow calcium channel blockers, coronary vasodilators, hypolipidemic drugs, hypoglycemic agents (including insulin), hormone replacement therapy II / III / ...

Terms and conditions of storage

Keep out of reach of children, at temperatures up to 30 ° C.
Shelf life is 3 years.

Reviews about Lopirel

Reviews about Lopirel indicate the effectiveness of this drug and the relatively rare development of side effects during the period of its administration. Some users consider the main disadvantage of Lopirel its relatively high cost.

Terms of sell

You can buy Lopirel without a prescription.