Lopyrel - instructions for use, dose, side effects, contraindications

Excipients: lactose 78.13 mg, microcrystalline cellulose 68.75 mg, crospovidone (type A) 13.75 mg, glyceride dibehenate 8.25 mg, talc 8.25 mg, Opadrai II 85G34669 Pink about 8.25 mg (polyvinyl alcohol 3.63 mg, talc 1.65 mg, titanium dioxide (E171) 1.63 mg, macrogol 3350 1.02 mg, lecithin (E322) 0.29 mg, iron oxide dye red (E172) 0.03 mg).

Description:

Round, biconcave, film-coated, pink tablets with engraved "I" on one side.

Pharmacotherapeutic group:Antiaggregant agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

Pharmacodynamics:

Mechanism of action

Clopidogrel is a prodrug, one of its metabolites is active and inhibits the aggregation of platelets. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to P2Y_I2platelet receptor and subsequent ADP-mediated activation of the glycoprotein complex IIb/IIIa, leading to suppression of platelet aggregation. Due to irreversible binding, platelets remain immune to stimulation of ADP for the rest of their life (about 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal.

Aggregation of platelets caused by agonists other than ADP is also inhibited by blockade of enhanced platelet activation by the released ADP.Since the formation of the active metabolite occurs with the isoenzymes of the P450 system, some of which may differ in polymorphism or may be inhibited by other drugs, not all patients may adequately inhibit platelet aggregation.

Pharmacodynamic properties

With a daily intake of clopidogrel at a dose of 75 mg, a significant inhibition of ADP-induced platelet aggregation is noted from the first day of administration, which gradually increases for 3-7 days and then reaches a constant level (when the equilibrium state is reached). In the equilibrium state, when taking a dose of 75 mg / day, platelet aggregation is inhibited by an average of 40-60%. After stopping the use of clopidogrel, platelet aggregation and bleeding time gradually return to the baseline level on average for 5 days.

Clinical efficacy and safety

Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular, in the lesions of cerebral, coronary or peripheral arteries.

Clinical study ACTIVE-A showed that in patients with atrial fibrillation who had at least one risk factor for vascular complications, but were able to take indirect anticoagulants, clopidogrel in combination with acetylsalicylic acid (compared to taking only acetylsalicylic acid alone) reduced the incidence of combined stroke, myocardial infarction, systemic thromboembolism outside the central nervous system (CNS), or vascular mortality, to a greater extent by reducing the risk of stroke. The effectiveness of taking clopidogrel in combination with acetylsalicylic acid was detected early and lasted up to 5 years. Reduction of the risk of major vascular complications in the group of patients taking clopidogrel in combination with acetylsalicylic acid, was mainly due to a greater reduction in the frequency of strokes. The risk of stroke of any severity with the use of clopidogrel in combination with acetylsalicylic acid was reduced, and there was a tendency to decrease the incidence of myocardial infarction in the group treated with clopidogrel in combination with acetylsalicylic acid, but there was no difference in the frequency of thromboembolism outside the CNS or vascular death.In addition, the use of clopidogrel in combination with acetylsalicylic acid reduced the total number of days of hospitalization for cardiovascular reasons.

Pharmacokinetics:

Suction

After a single dose and with oral administration at a dose of 75 mg / day clopidogrel quickly absorbed. The mean values of the maximum concentration in blood plasma (C_mOh) of unchanged clopidogrel are about 2.2-2.5 ng / ml and are reached approximately 45 minutes after administration. According to the data on excretion of metabolites of clopidogrel with kidneys, its absorption is at least 50%.

Distribution

In vitro Clopidogrel and its main circulating non-active metabolite in the blood reversibly bind to plasma proteins by 98% and 94%, respectively. In vitro this bond is unsaturated in a wide range of concentrations.

Metabolism

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo Clopidogrel is metabolized in two ways: first - through esterases and subsequent hydrolysis with the formation of an inactive derivative of carboxylic acid (85%) from

circulating in the systemic circulation of metabolites, and the second way through the cytochrome P450 system.Originally clopidogrel is metabolized to 2-oxoklopidogrel, which is an intermediate metabolite. Subsequent metabolism of oxoxlopidogrel leads to the formation of an active metabolite of clopidogrel-thiol clopidogrel derivative. In vitro this way of metabolism occurs with the participation of isoenzymes CYP3A4, CYP2C19, CYP1A2 and CYP2B6. Active thiol metabolite of clopidogrel, which was isolated in studies in vitro, quickly and irreversibly binds to platelet receptors, thus inhibiting their aggregation.

With a single admission of clopidogrel in a loading dose of 300 mg C_mOh active metabolite is 2 times higher than C_mOh upon admission clopidogrel in a maintenance dose of 75 mg for 4 days. FROM_mOh The active metabolite is reached after 30-60 min after taking clopidogrel.

Excretion

Within 120 hours after ingestion by a human ¹⁴C-labeled clopidogrel about 50% of radioactivity is released through the kidneys and approximately 46% of the radioactivity - through the intestine. After a single oral dose of 75 mg half-life (T_1/2) of clopidogrel is about 6 hours. After a single dose and repeated doses of T_1/2The main circulating inactive blood metabolite is 8 hours.

Pharmacogenetics

Using isoenzyme CYP2C19 are formed as an active metabolite, and an intermediate metabolite - 2-oxoklopidogrel. Pharmacokinetics and antiplatelet effect of the active metabolite clopidogrel, in the study of platelet aggregation ex vivo, vary depending on the genotype of the isoenzyme CYP2C19.

Gene allele CYP2C19 * 1 corresponds to fully functional metabolism, whereas gene alleles CYP2C19 * 2 and CYP2C19 * 3 are non-functional. Alleles of genes CYP2C19 * 2 and CYP2C19 * 3 cause a decrease in metabolism in the majority of representatives of the Caucasoid (85%) and Mongoloid races (99%). Other alleles that are associated with a lack or decrease in metabolism are less common and include, but are not limited to, gene alleles CYP2C19 * 4, * 5, * 6, * 7 and * 8. Patients, which are weak metabolizers, should have the two alleles of the gene with loss of function indicated above. Published frequency of occurrence of phenotypes of weak metabolizers CYP2C19 are 2% in Caucasians, 4% in Negroid people and 14% in Chinese.

In a cross-sectional study of 40 volunteers, 10 people in each group with four isoenzyme subtypes CYP2C19 (ultra-metabolisers, extensive metabolisers, intermediate metabolizers, poor metabolisers) evaluated the pharmacokinetics and antiplatelet effect when clopidogrel at a dose of 300 mg followed by its receiving 75 mg / day, and when receiving clopidogrel at a dose of 600 mg followed by its intake at 150 mg / day for 5 days (reaching the equilibrium state). There were no significant differences in exposure of the active metabolite, and average values of inhibition of platelet aggregation (IAT) (ADP-induced) in ultrafast, intensive and intermediate metabolizers been identified. In weak metabolizers, the exposure of the active metabolite was reduced by 63-71% compared to intensive metabolizers. When using the treatment regimen of 300 mg / 75 mg in poor metabolizers antiplatelet effect decreased with average values IAT was 24% (after 24 hours) and 37% (by 5 day treatment), compared with the IAT, constituting 39% (after 24 hours) and 58% (on the 5th day of treatment) in intensive metabolizers and 37% (after 24 hours) and 60% (on the 5th day of treatment) in intermediate metabolizers. If the weak metabolizers received the 600 mg / 150 mg treatment regimen, the exposure of the active metabolite was higher than with the 300 mg / 75 mg treatment regimen.In addition, 32% (24 hours) and 61% (at day 5 of treatment) were 32% greater than that of the weak metabolizers who received the 300 mg / 75 mg treatment regimen and were similar to those in the higher intensity groups CYP2C 19-metabolism, receiving a treatment regimen of 300 mg / 75 mg. However, in studies with clinical outcomes, the dosage regimen of clopidogrel for patients in this group has not yet been established.

According to the results of this study, a meta-analysis of six studies, which included data from 335 volunteers who received clopidogrel and were in the state of reaching the equilibrium concentration, showed that in the case of intermediate metabolizers, the exposure of the active metabolite decreased by 28% and in weak metabolizers by 72%, although the IAB was reduced in comparison with the intensive metabolizers with differences in the IB of 5.9% and 21.4%, respectively.

An evaluation of the influence of the genotype CYP2C19 on clinical outcomes in patients who received clopidogrel, in prospective, randomized, controlled trials. However, to date, there are several retrospective analyzes.The results of genotyping are available in the following clinical studies: CURE (n=2721), CHARISMA (n=2428), CLARITY-TIMI 28 (n=227), TRITON-TIMI 38 (n= 1477) and ACTIVE-A (n= 601), as well as in several published cohort studies.

In the study TRITON-TIMI 38 and 3 cohort studies (Collet, Sibbing, Giusti), the patients of the combined group with intermediate or weak metabolism had a higher incidence of cardiovascular complications (death, myocardial infarction and stroke) or stent thrombosis compared to those of intensive metabolizers.

In the study CHARISMA and one cohort study (Simon), an increase in the frequency of cardiovascular complications was observed only in weak metabolizers (when compared with intensive metabolizers).

In the study CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk) there was no increase in the incidence of cardiovascular complications as a function of intensity CYP2C19-metabolism.

Clinical studies conducted to date have not had a sufficient sample size to detect differences in clinical outcome in patients with low isoenzyme activity CYP2C19.

Pharmacokinetics in special clinical cases

The pharmacokinetics of the active metabolite of clopidogrel in certain groups of patients has not been studied.

In elderly volunteers (over 75 years) when compared with volunteers of young age, there was no difference in platelet aggregation and bleeding time. No dose adjustment is required in elderly patients.

Pharmacokinetics of clopidogrel in children not studied.

Patients with severe renal disease (creatinine clearance 5-15 ml / min) after repeated use of clopidogrel at a dose of 75 mg / day, the initiation of ADP-induced platelet aggregation was lower (25%) than that of healthy volunteers, but the lengthening of bleeding time was similar to that of in healthy volunteers who received clopidogrel in a dose of 75 mg / day. Clopidogrel well tolerated in all patients.

In patients with severe liver damage after daily administration of clopidogrel at a dose of 75 mg / day for 10 days, inhibition of ADP-induced platelet aggregation was similar to that of healthy volunteers. The mean bleeding time was also comparable in both groups.

Prevalence of alleles of isoenzyme genes CYP2C9, responsible for the intermediate and reduced metabolism, is different in representatives of different racial groups. There are very small literary data among representatives of the Mongoloid race, which does not allow to assess the importance of genotyping isoenzyme CYP2C19 for the development of ischemic complications.

Indications:

Prevention of atherothrombotic complications:

- in adult patients with myocardial infarction (from a few days to 35 days old), ischemic stroke (with a prescription from 7 days to 6 months) or with a diagnosed occlusive disease of peripheral arteries;

- in adults with acute coronary syndrome: without ST segment elevation (unstable angina or myocardial infarction without Q wave), including patients who underwent stenting with percutaneous coronary intervention (in combination with acetylsalicylic acid); with ST segment lift (acute myocardial infarction) with drug treatment and the possibility of carrying out thrombolysis (in combination with acetylsalicylic acid).

Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation (atrial fibrillation)

In patients with atrial fibrillation (atrial fibrillation), which have at least one risk factor for vascular complications, they can not take indirect anticoagulants and have a low risk of bleeding (in combination with acetylsalicylic acid).

Contraindications:

- Hypersensitivity to clopidogrel or any auxiliary substance of the drug;

- severe hepatic impairment;

- acute bleeding, eg bleeding from peptic ulcers or intracranial hemorrhage;

- rare hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome;

- pregnancy and the period of breastfeeding;

- children under 18 years of age (safety and efficacy not established).

Carefully:

- With moderate hepatic insufficiency, which may predispose to bleeding (limited clinical experience of use);

- with renal failure (limited clinical experience of use);

- with injuries, surgical interventions (risk of increased bleeding);

- with diseases,at which there is a predisposition to the development of bleeding (especially gastrointestinal or intraocular);

- with simultaneous administration of serotonin reuptake inhibitors (SSRIs);

- with the simultaneous administration of non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2);

- while concomitant administration of warfarin, heparin, glycoprotein inhibitors IIb/IIIa;

- with a history of allergic and hematologic reactions to other thienopyridine (such as ticlopidine, prasugrel) in connection with the possibility of cross-allergic and hematological reactions (see section "Special instructions");

- in patients with a genetically determined decrease in the isoenzyme function CYP2C19 (in patients who are weak CUR2C19 metabolizers, when clopidogrel is used in recommended doses, less active metabolite of clopidogrel is formed and its antiplatelet effect is less pronounced, weak metabolizers receiving clopidogrel in recommended doses, with acute coronary syndrome or percutaneous coronary intervention,may have a higher incidence of cardiovascular complications than patients with normal isoenzyme function CYP2C19).

Pregnancy and lactation:

Pregnancy

As a precaution contraindicated Lopirel receiving the drug during pregnancy due to lack of clinical data on its acceptance by pregnant women, although studies in animals and clopidogrel did not reveal any direct or indirect adverse effects on pregnancy, fetal development, parturition and postnatal development.

Breastfeeding period

Breastfeeding in the case of treatment with Lopirel should be discontinued, as studies in rats have shown that clopidogrel and / or its metabolites are excreted in breast milk. Does it penetrate clopidogrel in human milk is unknown.

Dosing and Administration:

The drug Lopirel is taken orally, regardless of food intake.

Adults and elderly people with normal isoenzyme activity CYP2C19

Myocardial infarction, ischemic stroke and diagnosed peripheral arterial occlusive disease

The drug is taken 75 mg once a day.

Acute coronary syndrome without segment elevation ST (unstable angina, myocardial infarction without a tooth Q)

Treatment with clopidogrel should be started with a single dose of 300 mg, and then continued with a 75 mg dose once a day (in combination with acetylsalicylic acid at doses of 75-325 mg / day). Since the use of higher doses of acetylsalicylic acid is associated with an increased risk of bleeding, the recommended dose of acetylsalicylic acid should not exceed 100 mg. The optimal duration of treatment is not officially defined. Clinical trials support the use of the drug for up to 12 months, and the maximum beneficial effect was observed by the third month of treatment.

Acute coronary syndrome with segment elevation ST (acute myocardial infarction with segment elevation ST)

Clopidogrel should be taken once 75 mg / day with the initial single dose of a loading dose of clopidogrel 300 mg in combination with acetylsalicylic acid in combination with thrombolytic agents or without combination with thrombolytics. In patients older than 75 years, treatment clopidogrel om should begin without taking its loading dose. Combination therapy is started as soon as possible after the onset of symptoms, and continues for at least 4 weeks. The effectiveness of the use of a combination of clopidogrel and acetylsalicylic acid with this indication over 4 weeks has not been studied.

Atrial fibrillation (atrial fibrillation)

Clopidogrel should be taken once a day at a dose of 75 mg. In combination with clopidogrel, you must start and then continue taking acetylsalicylic acid (75-100 mg / day).

Skipping the next dose

1. If less than 12 hours have passed after missing the next dose, the missed dose of the drug should be taken immediately, and then the following doses should be taken at the usual time.

2. If more than 12 hours have passed after missing the next dose, the patient should take the next dose at the usual time (do not take a double dose).

Patients with genetically determined reduced isoenzyme activity CYP2C19

Low isoenzyme activity CYP2C19 is associated with a decrease in the antiplatelet effect of clopidogrel. The mode of application of higher doses (600 mg - loading dose, then - 150 mg once a day daily) in patients with low isoenzyme activity CYP2C19 increases the antiplatelet effect of clopidogrel (see section Pharmacokinetics). However, at the moment, clinical trials that take into account clinical outcomes have not established an optimal dosing regimen for clopidogrel for patients with reduced metabolism due to genetically determined low isoenzyme activity CYP2C19.

Special patient groups

Elderly people

In elderly volunteers (over 75 years old), when compared with young volunteers, there was no difference in platelet aggregation and bleeding time. Do not require dose adjustment for the elderly.

Children

The drug Lopirel should not be used in children, as there is no experience of its use in this group of patients.

Patients with impaired renal function

After repeated use of clopidogrel at a dose of 75 mg / day in patients with severe renal disease (SC from 5 to 15 ml / min), inhibition of ADP-induced platelet aggregation (25%) was lower than that of healthy volunteers, but prolongation of bleeding time was similar to that of healthy volunteers who received clopidogrel in a dose of 75 mg / day.In addition, all patients had good tolerability of the drug.

Patients with impaired hepatic function

After daily administration of clopidogrel at a daily dose of 75 mg for 10 days in patients with severe liver disease, inhibition of ADP-induced platelet aggregation was similar to that of healthy volunteers. The mean bleeding time was also comparable in both groups.

Patients of different ethnicity

Prevalence of alleles of isoenzyme genes CYP2C19, responsible for the intermediate and decreased metabolism of clopidogrel to its active metabolite, varies among representatives of different ethnic groups (see Pharmacogenetics section). There are only limited data for representatives of the Mongoloid race on the impact of the genotype of the isoenzyme CYP2C19 on clinical outcome events.

Female and male patients

In a small study comparing the pharmacodynamic properties of clopidogrel in men and women, women had less inhibition of ADP-induced platelet aggregation, but there was no difference in bleeding time elongation. In a large controlled study CAPRIE (clopidogrel in comparison with acetylsalicylic acid in patients with the risk of developing ischemic complications), the frequency of clinical outcomes, other side effects and deviations from the norm of clinical and laboratory indicators was the same for both men and women.

Side effects:

The safety of clopidogrel was investigated in more than 44,000 patients, including more than 12,000 patients who received treatment for a year or longer. The overall tolerability of clopidogrel was similar to the tolerability of acetylsalicylic acid, regardless of the age, gender and race of the patients. The following are clinically significant adverse effects observed in clinical trials: CAPRIE, CURE, CLARITY, COMMIT and ACTIVE A. Transferability of clopidogrel at a dose of 75 mg / day in the trial CAPRIE corresponded to the tolerability of acetylsalicylic acid at a dose of 325 mg / day. Including reported adverse reactions in spontaneous reports.

Most often in clinical trials, as well as during post-marketing use of clopidogrel, the development of bleeding was reported, most of which developed in the first month of treatment.

In a clinical study CAPRIE total bleeding in patients who received clopidogrel or acetylsalicylic acid, was 9.3%. The frequency of severe bleeding with clopidogrel was similar to that of acetylsalicylic acid.

In a clinical study CURE there was no increase in the incidence of severe bleeding with clopidogrel with acetylsalicylic acid for seven days after the operation of coronary artery bypass grafting in patients who had stopped therapy more than 5 days before surgery. In patients who continued therapy for five days before the start of coronary artery bypass surgery, the frequency of this event was 9.6% for the combination clopidogrel with acetylsalicylic acid and 6.3% for placebo in combination with acetylsalicylic acid.

In a clinical study CLARITY observed a general increase in the frequency of bleeding in the group clopidogrel + acetylsalicylic acid compared with the placebo + acetylsalicylic acid. The frequency of major bleeding was similar in both groups and was virtually independent of the initial characteristics of patients and the type of fibrinolytic or heparin therapy.

In a clinical study COMMIT the overall incidence of non-cerebral large bleeding or cerebral hemorrhage was low and did not differ significantly in both groups.

In a clinical study ACTIVE-A frequency of major bleeding in the group clopidogrel acetylsalicylic acid was higher than in the placebo +acetylsalicylic acid (6.7% against 4.3%). Large bleeding was mainly extracranial in both groups (5.3% vs. 3.5%), mainly gastrointestinal bleeding (3.5% vs. 1.8%). In a group clopidogrel acetylsalicylic acid intracranial hemorrhage was greater in comparison with the placebo group + acetylsalicylic acid (1.4% vs. 0.8%, respectively). There were no statistically significant differences between these treatment groups in the frequency of fatal bleeding (1.1% vs. 0.7%) and hemorrhagic stroke (0.8% vs. 0.6%).

Further, unwanted reactions are observed that have been observed in clinical studies or have been reported as spontaneous reports. The reaction frequency is presented according to the following classification: very often (≥1/10); often (≥1/100, <1/10); infrequently (≥1/1000, <1/100); rarely (≥1/10 000, <1/1000); very rarely (<1/10 000), the frequency is unknown (can not be determined from available data). In each of the subgroups on the classification of organ organs and organ systems, adverse reactions are presented in order of severity.

From the lymphatic and circulatory system: infrequently - thrombocytopenia, leukopenia, eosinophilia; rarely - neutropenia, including severe neutropenia; very rarely thrombotic thrombocytopenic purpura (TTP) (see Special instructions), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired hemophilia type A, granulocytopenia, anemia.

From the immune system: very rarely - serum sickness, anaphylactoid reactions; frequency is unknown - cross-reactive hypersensitivity reactions with thienopyridines (such as ticlopidine, prasugrel) (see section Special instructions).

Disorders of the psyche: very rarely - hallucinations, confusion.

From the nervous system: infrequently - intracranial hemorrhage (some cases were fatal), headache, paresthesia, dizziness; very rarely - a taste disorder.

From the side of the organ of vision: infrequently - eye hemorrhage (in conjunctiva, in the tissue of the eye, retina).

From the side of the hearing organ and labyrinthine disorders: rarely - vertigo.

From the side of the vessels: often - hematomas, very rarely - heavy bleeding, bleeding from operating wounds, vasculitis, lowering blood pressure.

From the respiratory and thoracic and mediastinal organs: often - epistaxis; very rarely - bleeding from the respiratory system (hemoptysis, pulmonary hemorrhage), bronchospasm, intestinal pneumonitis, eosinophilic pneumonia.

From the gastrointestinal tract: often - bleeding of the gastrointestinal tract, diarrhea, abdominal pain, indigestion; infrequently - ulcers of the stomach and duodenum, gastritis, vomiting, nausea, constipation, flatulence; rarely - retroperitoneal bleeding; very rarely - gastrointestinal and retroperitoneal hemorrhages with a fatal outcome, pancreatitis, colitis (including ulcer or lymphocytic), stomatitis.

From the liver and urinary tract: very rarely - acute liver failure, hepatitis, abnormalities in laboratory tests of the functional state of the liver.

From the skin and subcutaneous tissues: often - bruising; infrequent - rash, itchy skin, purpura (small-spotted capillary hemorrhages into the skin, under the skin or in mucous membranes); very rarely - bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), angioedema, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), erythematous or exfoliative rash, urticaria, eczema, lichen .

From the side of musculoskeletal and connective tissue: very rarely - hemorrhages in the musculoskeletal system (hemarthrosis), arthritis, arthralgia, myalgia.

From the side of the kidneys and urinary tract: infrequently - hematuria; very rarely - glomerulonephritis, an increase in the concentration of creatinine in the blood.

General disorders and disorders at the site of administration: often - bleeding from the puncture site; very rarely - a fever.

Laboratory and instrumental data: infrequent - prolongation of bleeding time, a decrease in the number of neutrophils, a decrease in the number of platelets.

Overdose:

Symptoms: an overdose of clopidogrel may lead to an increase in bleeding time with subsequent complications in the form of development of bleeding.

Treatment: when bleeding occurs, appropriate treatment is required. If rapid correction of prolonged bleeding time is necessary, transfusion of platelet mass is recommended. The antidote of clopidogrel is not established.

Interaction:

Indirect anticoagulants: simultaneous use of clopidogrel and indirect anticoagulants is not recommended in connection with a possible increase in the intensity of bleeding (see section Special instructions). Although administration of clopidogrel at a dose of 75 mg / day did not affect the pharmacokinetics of S-warfarin or an international normalized ratio in patients receiving prolonged therapy with warfarin, concurrent administration of clopidogrel with warfarin increases the risk of bleeding due to independent effects on hemostasis.

Blockers IIb/IIIa-receptors: the appointment of IIb / IIIa receptor blockers together with clopidogrel requires caution (see section Special instructions).

Acetylsalicylic acid: does not alter the effect of clopidogrel, which inhibits ADP-induced platelet aggregation, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation.However, simultaneous with clopidogrel, acetylsalicylic acid at a dose of 500 mg twice a day for 1 day did not cause a significant increase in bleeding time caused by the use of clopidogrel. Between clopidogrel and acetylsalicylic acid, pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, when using them at the same time, care should be taken (see section Special instructions), although in clinical trials patients received combined therapy with clopidogrel and acetylsalicylic acid for up to one year.

Heparin: according to the clinical trial conducted with the participation of healthy individuals, when taking clopidogrel did not require a change in the dose of heparin and did not change its anticoagulant effect. The simultaneous use of heparin did not alter the antiplatelet effect of clopidogrel. Between clopidogrel and heparin, pharmacodynamic interaction is possible, which can increase the risk of bleeding, so the simultaneous use of these drugs requires caution (see section Special instructions).

Thrombolytics: the safety of the combined use of clopidogrel, fibrin-specific or fibrin-specific thrombolytic agents, and heparin was investigated in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the joint use of thrombolytic agents and heparin with acetylsalicylic acid (see Side effect).

NSAIDs: in a clinical study conducted with the participation of healthy volunteers, the combined use of clopidogrel and naproxen increased latent blood loss through the gastrointestinal tract. However, due to the lack of research on the interaction of clopidogrel with other NSAIDs, it is currently unknown whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel along with other NSAIDs. Therefore, the appointment of NSAIDs, including COX-2 inhibitors, in combination with clopidogrel should be performed with caution (see section Special instructions).

Selective serotonin reuptake inhibitors (SSRIs): as SSRIs affect platelet activation and increase the risk of bleeding, simultaneous administration with clopidogrel requires caution.

Other combination therapy

As clopidogrel metabolized to the formation of its active metabolite partially by means of the system CYP2C19, the use of drugs that inhibit this system can lead to a decrease in the concentration of the active metabolite of clopidogrel in the blood plasma and a decrease in its clinical efficacy. The clinical significance of this interaction is unknown. As a precaution, simultaneous intake of strong and moderate isoenzyme inhibitors CYP2C19 should be avoided (see section special instructions and Pharmacokinetics).

To drugs inhibiting isoenzyme CYP2C19 refer omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbamazepine and chloramphenicol.

Proton Pump Inhibitors

When taking omeprazole at a dose of 80 mg once a day, together with clopidogrel or when administered together less than 12 hours, the exposure of the active metabolite was reduced by 45% (loading dose) and by 40% when taking a maintenance dose. This change in values was associated with a decrease in inhibition of platelet aggregation by 39% with a loading dose and by 21% with a maintenance dose. Expected that esomeprazole will give a similar effect of interaction with clopidogrel.

In clinical and observational studies it has produced a number of conflicting data about the clinical relevance of these pharmacodynamic and pharmacokinetic interactions with respect to the development of severe cardiovascular complications. In connection with the observance of precautionary measures, it is recommended to avoid simultaneous administration of omeprazole and esomeprazole (see section Special instructions).

A less pronounced decrease in metabolite exposure was observed with the use of pantoprazole or lansoprazole.

The concentration of the active metabolite has been reduced by 20% upon receipt of a loading dose and by 14% when receiving a maintenance dose during simultaneous reception of pantoprazole in the dose of 80 mg 1 time per day. This was also accompanied by a decrease in the mean inhibition of platelet aggregation by 15 and 11%, respectively. These data indicate that clopidogrel can be used simultaneously with pantoprazole.

There is no evidence that other drugs that reduce the acidity of gastric juice, such as H₂-blocks (except for cimetidine, which is an inhibitor of the isoenzyme CYP2C19) or antacids affect the antiaggregant properties of clopidogrel.

Other medications

A number of clinical studies with clopidogrel and other concomitantly prescribed drugs were conducted to study possible pharmacodynamic and pharmacokinetic interactions. There was no clinically significant pharmacodynamic interaction with clopidogrel combined with atenolol, nifedipine or with both drugs at the same time. In addition, the pharmacodynamic activity of clopidogrel was slightly influenced by simultaneous administration phenobarbital or estrogens.

Pharmacokinetic parameters digoxin and theophylline did not change when they were used together with clopidogrel.

Antacid agents did not reduce the absorption of clopidogrel.

Phenytoin and tolbutamide can be safely applied simultaneously with clopidogrel (study CAPRIE), despite the fact that the data obtained from studies with human liver microsomes indicate that the carboxylic metabolite of clopidogrel can inhibit the activity of the 2S9 isoenzyme of the cytochrome P450 family,which can lead to an increase in the plasma concentrations of certain drugs (phenytoin, tolbutamide and some NSAIDs) that are metabolized by the 2S9 isoenzyme of the cytochrome P450 family.

Other clinical studies of the interaction of clopidogrel with drugs often used in patients with atherothrombotic complications were not conducted. In clinical studies, there were no clinically relevant undesirable interactions with andangiotensin-converting enzyme inhibitors, diuretics, beta-adrenoblockers, slow calcium channel blockers, lipid-lowering agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, hormone replacement therapy and blockers IIb/IIIa receptors.

Special instructions:

Bleeding and hematologic disorders

In connection with the risk of bleeding and hematologic adverse effects (see section Side effects) in case of appearance during treatment of clinical symptoms, suspicious for the occurrence of bleeding, it is urgent to do a clinical blood test,determine the activated partial thromboplastin time (APTT), the number of platelets, the indices of the functional activity of platelets and conduct other necessary studies.

Clopidogrel, as well as other antiplatelet drugs, should be used with caution in patients who have an increased risk of bleeding due to trauma, surgery or other pathological conditions, as well as in patients receiving acetylsalicylic acid, other NSAIDs, including COX- 2, heparin, SSRIs or glycoprotein inhibitors IIb/IIIa.

In the treatment of clopidogrel, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgical intervention, careful monitoring of patients should be conducted to exclude signs of bleeding, including latent.

Joint use of clopidogrel with warfarin may increase the intensity of bleeding (see section Interaction with other medicinal products), therefore, with the exception of special rare clinical situations (such as the presence of a floating thrombus in the left ventricle,stenting in patients with atrial fibrillation) the combined use of clopidogrel and warfarin is not recommended.

If the patient will have a planned surgery, and thus there is no need for antiplatelet effect, then 7 days prior to surgery clopidogrel should be discontinued.

Before any future operation and before starting any new drug, patients should inform the doctor (including the dentist) about taking clopidogrel.

Clopidogrel prolongs bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (especially gastrointestinal and intraocular).

Patients should be warned that when taking clopidogrel (alone or in combination with acetylsalicylic acid), it may take longer to stop bleeding, and that if they have unusual bleeding (localization or duration), they should be informed about this to your doctor.

Thrombotic thrombocytopenic purpura

Very rarely after the use of clopidogrel (sometimes even a short one), there have been cases of TTP development,which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever. TTP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

Acquired hemophilia

With the use of clopidogrel, the acquired hemophilia was reported. In case of confirmation of the prolongation of APTT with the development of bleeding or without it, the presence of acquired hemophilia should be questioned. If a diagnosis of acquired hemophilia is established, appropriate treatment should be started and the use of clopidogrel should be discontinued.

Recently suffered ischemic stroke

Taking Lopirel is not recommended for acute ischemic stroke less than 7 days old (as there is no data on its use in this condition).

In patients with recent ischemic stroke or transient ischemic attack and a high risk of recurrent atherothrombotic events, combined therapy with clopidogrel and acetylsalicylic acid did not demonstrate a higher efficacy compared with clopidogrel monotherapy,but may increase the risk of major bleeding.

Isozyme CYP2C19 cytochrome P450

Pharmacogenetics: In patients with slow metabolism of isoenzyme CYP2C19 when taking clopidogrel in the recommended doses, the active metabolite of clopidogrel is formed in smaller amounts and a weaker effect on platelet aggregation is observed. The tests for determining the genotype of the isoenzyme are available CYP2C19 in patients.

Because the clopidogrel metabolized to active metabolites in part with the participation of isoenzyme CYP2C19 The use of drugs that inhibit the activity of this enzyme will lead to a decrease in the concentration of the active metabolite of clopidogrel. The clinical significance of this interaction is unknown. As precautionary measures, simultaneous intake of strong and moderate isoenzyme inhibitors CYP2C19 (see section Interaction with other medicinal products for clarification of medicines and section Pharmacokinetics).

Cross reactions with thienopyridines

Since during the treatment with thienopyridines, cross-reactivity of hypersensitivity was reported,before the start of treatment, it is necessary to clarify in the patient the presence of hypersensitivity reactions to thienopyridine in the medical history (clopidogrel, ticlopidine, prasugrel) (see section Side effect).

Tienopyridines can cause allergic reactions of varying severity, such as rash, angioedema, or haematological cross-reactions (thrombocytopenia and neutropenia). In patients who have experienced allergic reactions and / or hematologic reactions in the previous treatment with one of the thienopyridine, the risk of developing similar reactions or reactions of another kind with the administration of another thienopyridine may be increased. It is recommended to control the symptoms of hypersensitivity in patients with allergic reactions to thienopyridines in the anamnesis.

Impaired renal function

The experience with clopidogrel in patients with impaired renal function is limited, so it should be used with caution in this group of patients (see section Method of administration and dose).

Impaired liver function

The experience of using in patients with moderate violations of the liver, who have a risk of hemorrhagic diathesis, is limited.Lopirel should be used with caution in this group of patients (see section Method of administration and dose).

The content of lactose in the preparation

Lopirel should not be taken to patients with rare hereditary intolerance to galactose, lactase deficiency, and glucose-galactose malabsorption syndrome (see section Contraindications).

Effect on the ability to drive transp. cf. and fur:

Clopidogrel does not significantly affect the abilities necessary for driving or working with machinery.

Form release / dosage:

Tablets coated with a film coating, 75 mg.

Packaging:

For 7 or 10 tablets per blister (strip) aluminum foil / aluminum foil.

1, 2, 4, 8 (7 tablets) or 1, 2, 3, 5, 6, 9, 10 (10 tablets) of blisters (strips) together with instructions for use in a cardboard box.

For 10, 20, 40, 60 blisters (strips), along with instructions for use in a cardboard box (for hospitals).

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-007008/08

Date of registration:02.09.2008 / 18.02.2016

Expiration Date:Unlimited

The owner of the registration certificate:AKTAVIS GROUP, AO AKTAVIS GROUP, AO Iceland

Manufacturer: & nbsp

ACTAVIS, Ltd. Iceland

Representation: & nbspAktavis, Open Company Aktavis, Open Company

Information update date: & nbsp01.04.2018

Illustrated instructions

Instructions

Lopyrel (Lopirel)