Brilinta® (Brilinta®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceTikagrelorTikagrelor
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  • Brilinta®
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    AstraZeneca AB     Sweden
  • Brilinta®
    pills inwards 
    AstraZeneca AB     Sweden
    • Dosage form: & nbspfilm-coated tablets
    Composition:On 1 tablet:

    Active substance: ticagrelor 60 mg;

    Excipients: Mannitol 84 mg, calcium hydrophosphate 42 mg, sodium carboxymethyl starch 6 mg, giprolose 6 mg, magnesium stearate 2 mg; tablet shell: Hypromellose 4.4 mg, titanium dioxide (E 171) 2.2 mg, macrogol 400 0.4 mg, ferric oxide black oxide 0.001 mg, iron oxide dye red 0.01 mg.

    Description:

    Round, biconvex tablets, covered with a film shell of pink color, with engraving 60 on one side.

    Pharmacotherapeutic group:Antiaggregant agent
    ATX: & nbsp

    B.01.A.C   Inhibitors of platelet aggregation (excluding heparin)

    B.01.A.C.24   Tikagrelor

    Pharmacodynamics:

    Mechanism of action

    The preparation of Brilint® contains in its composition ticagrelor, a representative of the chemical class of cyclopentyltriazolopyrimidines, which is an oral, selective and reversible P2Y antagonist12 receptors of direct action and prevents adenosine diphosphate-mediated P2Y12-dependent activation and aggregation of platelets. Tikagrelor does not prevent the binding of adenosine diphosphate (ADP), but its interaction with P2Y12 the platelet receptor prevents ADP-induced signal transduction. Since platelets are involved in the initiation and / or development of thrombotic complications of atherosclerosis, it has been shown that inhibition of platelet function reduces the risk of developing cardiovascular events, such as cardiovascular death, myocardial infarction or stroke.

    Ticagrelor has an additional mechanism of action, increasing local concentrations of endogenous adenosine by inhibiting the endogenous equilibrium nucleoside transporter type 1 (ENT-1).

    Adenosine is formed locally in places of hypoxia and tissue damage by release from adenosine triphosphate and ADP. Since the cleavage of adenosine is essentially limited to intracellular space, inhibition ENT-1 ticagrelor prolongs the half-life of adenosine and, thereby, increases its local extracellular concentration, strengthening the local adenosine response. Tikagrelor has no clinically significant direct effect on adenosine receptors (A1, A2A, A2c, A3) and is not metabolized to adenosine. Adenosine has several effects that include: vasodilation, cardioprotection, inhibition of platelet aggregation, modulation of inflammation and the occurrence of dyspnea, which may affect the clinical profile of ticagrelor.

    It was shown that in healthy volunteers and in patients with acute coronary syndrome (ACS) ticagrelor strengthened the following effects of adenosine: vasodilation (estimated as an increase in coronary blood flow in healthy volunteers and in patients with ACS), inhibition of platelet function (in vitro in the whole human blood) and shortness of breath. Nevertheless, the association of elevated local adenosine concentrations with clinical outcomes (eg morbidity and mortality) has not been proven.

    Pharmacodynamics

    Start of action

    In patients with stable course of ischemic heart disease (CHD) in the presence of acetylsalicylic acid (ASA) ticagrelor begins to act quickly, which is confirmed by the results of determining the mean value of inhibition of platelet aggregation (IAT): 0.5 hours after taking a loading dose of 180 mg of ticagrelor, the average value of IAT is approximately 41%, the maximum value of IB is 89% 2-4 hours after admission drug and is maintained for 2-8 hours.In 90% of patients, the final value of IAT greater than 70% is achieved 2 hours after taking the drug.

    End of action

    When planning CABG, the risk of bleeding increases if ticagrelor is stopped less than 96 hours before the procedure.

    Data on the transition from one drug to another

    Transition from clopidogrel 75 mg once a day to Brilint® 90 mg twice daily leads to an increase in the absolute value of IAT by 26.4%, and the change in therapy from ticagrelor to clopidogrel leads to a decrease in the absolute value of the IAT by 24.5%. You can change the therapy with clopidogrel for ticagrelor without interrupting the antithrombotic effect (see section "Method of administration and dose").

    Clinical efficacy and safety

    The clinical effectiveness of the Brilint® preparation is confirmed by the results of two Phase 3 studies.

    Study PLATO (acute coronary syndrome)

    In the study PLATO (PLATelet Inhibition and Patient Outcomes - Inhibition of platelets and outcomes in patients) involved 18624 patients who developed symptoms of unstable angina, myocardial infarction without segment elevation in the last 24 hours ST or myocardial infarction with segment elevation ST and who have been treated conservatively, either by percutaneous coronary intervention (PCI), or by aortocoronary shunting (CABG).

    In this study, with daily ASA therapy ticagrelor 90 mg twice daily was compared with clopidogrel 75 mg per day for effectiveness in preventing the development of a combined end point of cardiovascular death, myocardial infarction or stroke due to the effect on the incidence of cardiovascular deaths and myocardial infarction. The loading dose was 300 mg of clopidogrel (a dose of 600 mg was also tolerated by PCI) or 180 mg of ticagrelor.

    Study PEGASUS (myocardial infarction in the anamnesis)

    Study PEGASUS TIMI-54 with the participation of 21162 patients was conducted to assess the prevention of atherothrombotic complications with ticagrelor in two doses (90 mg twice daily or 60 mg twice daily) in combination with low-dose ASA (75-150 mg) compared to ASA alone in patients with a history of myocardial infarction and additional risk factors for atherothrombosis.

    The study included patients aged 50 years and older with a history of myocardial infarction (1-3 years before randomization), and with at least one of the following risk factors for atherothrombosis: age ≥ 65 years,diabetes requiring medication, a second previous myocardial infarction, confirmed multivessel coronary artery disease, or a chronic renal impairment of the non-terminal stage.

    Preparation Brilinta® 60 mg twice daily and 90 mg twice a day in combination with ASA was effective in preventing atherothrombotic complications (combined endpoint of cardiovascular death, myocardial infarction and stroke), maintaining a constant treatment effect over the entire period studies, which led to a decrease in the relative risk (GRA) 16% to absolute risk reduction (ATS) to 1.27% with 60 mg ticagrelor COP and a decrease by 15% and ATS 1.19% with ticagrelor 90 mg.

    With a comparable efficacy of ticagrelor 90 mg and 60 mg, the best tolerability and safety profile for the risk of bleeding and dyspnea ticagrelor 60 mg. In this connection, in order to prevent atherothrombotic events (cardiovascular death, myocardial infarction and stroke) in patients with previous myocardial infarction (heart attack moved one year or more ago), and high risk of atherothrombotic complications recommended drug Brilinta® 60 mg twice per day in combination with ASA.

    Brilint® 60 mg twice daily significantly reduced the primary combined end point of cardiovascular death, myocardial infarction and stroke, with a decrease in each component: cardiovascular deaths by 17%, myocardial infarction by 16% 25%.

    Ticagrelor 60 mg in combination with ASA reduced the number of deaths from cardiovascular causes and deaths from all causes, although no statistical significance was achieved. The COP of the combined endpoint from 1 to 360 days (GF 17%) and from 361 days onwards (COP 16%) was comparable, with the maintenance of the effect of therapy during a study lasting up to 48 months (median 33 months), thereby showing that therapy with ticagrelor can continue as long as the patient has a high risk of developing atherothrombotic complications (see the section "Dosing and Administration").

    The effectiveness of Brilint® 60 mg twice daily was demonstrated in different subgroups of patients, regardless of body weight, gender, anamnesis, region, and does not depend on the use of other cardiovascular agents, including lipid-lowering drugs, beta-blockers,angiotensin-converting enzyme (ACE inhibitors), angiotensin II receptor antagonists, calcium channel blockers, nitrates and proton pump inhibitors (see "Interactions with Other Drugs and Other Drug Interactions").

    Pharmacokinetics:

    Ticagrelor demonstrates linear pharmacokinetics, and the exposure of ticagrelor and active metabolite (AR-C124910XX) is approximately proportional to the dose up to 1260 mg.

    Absorption

    Tikagrelor is rapidly absorbed with the median Tmah about 1.5 hours. Formation of the main circulating metabolite in the blood AR-C124910XX (also active) from ticagrelor occurs rapidly with the median TmOh approximately 2.5 hours. After taking an empty stomach ticagrelor at a dose of 90 mg CmOh is 529 ng / ml and AUC - 3451 ng * h / ml. The relation CmOh and AUC metabolite to ticagrelor is 0.28 and 0.42, respectively.

    The average absolute bioavailability of ticagrelor is 36%. Admission of fatty foods leads to an increase of 21% AUC tikagrelor and a decrease of 22% CmOh active metabolite, but does not affect CmOh ticagrelor or AUC active metabolite. These small changes have minimal clinical significance; so ticagrelor can be administered regardless of the meal.

    Ticagrelor in the form of a suspension of ground tablets in drinking water ingested or inserted into the stomach through a nasogastric tube is bioequivalent to a ticagrelor taken internally in the form of tablets of the Brilint® preparationAUC and CmOh ticagrelor and active metabolite in the range of 80-125%). In the case of the suspension, the initial exposure (0.5 and 1 hour after administration) was higher than with ticagrelor in the form of Brilint® tablets, but later (from 2 to 48 hours), the concentration profile was almost the same.

    Distribution

    The volume of distribution of the ticagrelor in the equilibrium state is 87.5 liters. Tikagrelor and active metabolite actively bind to blood plasma proteins (> 99.0%).

    Biotransformation

    CYP3A4 is the main isoenzyme responsible for the metabolism of ticagrelor and the formation of an active metabolite, and their interactions with other substrates CYP3A vary from activation to inhibition. Tikagrelor and active metabolite are weak inhibitors of glycoprotein P (P-gp).

    The main metabolite of ticagrelor is AR-C124910XX, which is also active, as evidenced by the results of binding evaluation with P2Y12 receptor for ADP platelets in vitro. The systemic exposure of the active metabolite is approximately 30-40% of the exposure of the ticagrelor.

    Excretion

    The main way of deducing ticagrelor is through hepatic metabolism. When an isotope-labeled ticagrelor is administered an average of about 84% of radioactivity is released (57.8% with feces, 26.5% in urine). The excretion of ticagrelor and active metabolite with urine is less than 1% of the dose. Basically, the active metabolite is excreted with bile. The mean half-life of ticagrelor and active metabolite was 7 and 8.5 hours, respectively.

    Special populations of patients

    Elderly patients

    In elderly patients (aged 75 years and older) with ACS, a higher exposure of ticagrelor (FROMmOh and AUC approximately 25% higher) and an active metabolite compared to younger patients. These differences are not considered clinically relevant (see section "Method of administration and dose").

    Children

    There was no evaluation of ticagrelor in children (see section "Contraindications").

    Floor

    Women have a higher exposure to ticagrelor and an active metabolite compared to men. These differences are not considered clinically significant.

    Impaired renal function

    The exposure of ticagrelor is approximately 20% lower, and its active metabolite is approximately 17% higher in patients with impaired renal function of severe degree (creatinine clearance <30 ml / min) compared to patients with normal renal function (see section "Method of administration and dose ").

    Impaired liver function

    FROMmax and AUC ticagrelor were 12% and 23% higher in patients with mild liver function impairment compared to healthy volunteers, but the effect of Brilint ® on IAT was comparable in both groups. No dose adjustment is required in patients with mild liver function disorder. There have been no studies of ticagrelor in patients with severe hepatic dysfunction, and there is no information on pharmacokinetic parameters in patients with impaired liver function of moderate severity (see "Contraindications", "Dosage and administration" and "Special instructions").

    Ethnic groups

    The average bioavailability of the drug in Asians is 39% higher than in Caucasian patients. The bioavailability of ticagrelor was 18% lower in patients of the Negroid race than in the Caucasoid race, and in the studies of clinical pharmacology, exposure (FROMmOh and AUC) tikagrelor in Japanese was about 40% (20% after correction for body weight) higher than that of Caucasians. Exposure in patients-Spaniards or Hispanics was similar to that of Caucasians.

    Indications:

    Brilint®, used concomitantly with acetylsalicylic acid, is indicated for the prevention of atherothrombotic complications in adult patients with a history of myocardial infarction (myocardial infarction was transferred one year or more ago) and a high risk of atherothrombotic complications.

    Contraindications:

    - Hypersensitivity to ticagrelor or any auxiliary substance of the drug.

    - Active pathological bleeding.

    - Intracranial hemorrhage in the anamnesis.

    - Dysfunction of the liver of a severe degree.

    - Combined use of ticagrelor with potent inhibitors of isoenzyme CYP3A4 (eg, ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir).

    - Children under 18 years of age (due to lack of data on efficacy and safety of use in this group of patients).

    Carefully:

    Predisposition of patients to the development of bleeding (for example, in connection with the recently received trauma,a recent operation, bleeding disorders, poor liver function of moderate severity, active or recent gastrointestinal bleeding).

    Patients with concomitant therapy with drugs that increase the risk of bleeding (ie non-steroidal anti-inflammatory drugs, oral anticoagulants and / or fibrinolytics) within 24 hours prior to taking Brilint®.

    Patients with a history of myocardial infarction with a previous ischemic stroke with a duration of therapy more than one year.

    Patients with impaired liver function of moderate severity.

    Patients with a risk of developing a bradycardia (for example, patients without a pacemaker with sinus node weakness syndrome, atrioventricular blockage of 2nd or 3rd degree, syncope associated with bradycardia) (see section "Special instructions").

    When combined with drugs that can cause bradycardia (see section "Interaction with other drugs and other types drug interaction ").

    Patients with bronchial asthma and / or chronic obstructive pulmonary disease (COPD) in history.

    It is not recommended joint use of ticagrelor and a high maintenance dose of ASA (more than 300 mg).

    With the combined use of ticagrelor with potent inhibitors of glycoprotein P and moderate isoenzyme inhibitors CYP3A4 (e.g., verapamil and quinidine) (see the section "Interaction with other drugs and other types drug interaction ").

    When combined use of selective serotonin reuptake inhibitors (for example, paroxetine, sertraline and citalopram) with ticagrelor (see "Interaction with Other Drugs and Other Drug Interactions").

    When combined use of digoxin and Brilint® is recommended, thorough clinical and laboratory monitoring (heart rate, and in the presence of clinical indications, also ECG and digoxin concentration in the blood).

    With the joint application of Brilint® with preparations that affect hemostasis (see the section "Interaction with other drugs and other types of drug interactions").

    Pregnancy and lactation:

    Women of reproductive age

    Women of reproductive age should use appropriate contraceptive methods to avoid pregnancy during therapy with Brilint®.

    Pregnancy

    Data on the use of ticagrelor in pregnant women are absent or limited.

    In animal studies ticagrelor caused a slight decrease in weight gain in females, a decrease in the viability of the newborn and its body weight, and a slowdown in growth. Brilint® is not recommended during pregnancy.

    Breastfeeding period

    Available pharmacodynamic, toxicological data in animals have shown that ticagrelor and its active metabolites are excreted with milk. The risk to the newborn / infant can not be ruled out. The decision to stop breastfeeding or to abolish therapy with Brilint® should be taken in consideration of the benefits of breastfeeding for the baby and the benefits of therapy for the mother.

    Fertility

    Ticagrelor had no effect on the fertility of males and females.

    Dosing and Administration:

    For ingestion. Brilint® can be taken without regard to food intake.

    For patients with difficulty swallowing, the Brilint® 60 mg tablet should be ground to a fine powder, stirred in half a glass of drinking water and immediately drunk the resulting suspension. Residue mixed with an additional half of a glass of drinking water and drink the resulting suspension. The suspension can also be administered via a nasogastric tube (CH8 or larger). After the introduction of the suspension, it is necessary to rinse the nasogastric tube with water so that the dose of the drug completely enters the patient's stomach.

    Patients with a history of myocardial infarction (myocardial infarction transferred one year or more ago) do not require a loading dose of Brilint®, the recommended dose is 60 mg twice a day.

    Long-term therapy with Brilint® is recommended, except in cases of clinical need for early withdrawal of the drug (see the section "Pharmacodynamics"). The experience of Brilint® 60 mg over 3 years in patients with myocardial infarction in history is absent.

    Patients taking Brilint® should take a low maintenance dose of ASA every day (75-150 mg) if there are no specific contraindications.

    Patients can start therapy with Brilint® 60 mg twice daily, one year after myocardial infarction, regardless of the antiplatelet therapy that preceded it and the presence of interruptions in therapy.

    Patients who started taking Brilint ® 90 mg twice a day during an acute period can continue treatment with Brilint® 60 mg twice a day, without breaks, after one year.

    Before starting the Brilint® drug (in combination with ASA), patients should stop the current antiplatelet therapy.

    When transferring patients to the Brilint® preparation, the first dose should be given 24 hours after the last dose of another antiplatelet drug.

    Premature cancellation of any antiplatelet therapy, including Brilint®, may increase the risk of cardiovascular death or myocardial infarction as a result of the underlying disease. It is necessary to avoid premature discontinuation of the drug. Also, avoid interruptions in therapy. A patient who misses a Brilint® preparation should take only one 60 mg tablet (the next dose) at the scheduled time.

    Special patient groups

    Elderly patients

    No dosage adjustment is required (see section "Pharmacokinetics").

    Patients with impaired renal function

    It is not necessary to adjust the dose of the drug in patients with impaired renal function (see section "Pharmacokinetics"). There is no available information on the treatment of patients on hemodialysis, therefore, the Brilint® preparation is not recommended for these patients.

    Patients with impaired hepatic function

    There were no studies of Brilint ® in patients with severe liver dysfunction, the use of the drug in these patients is contraindicated (see the section "Contraindications"). Information on the therapy of patients with impaired liver function of moderate severity is limited. No dose adjustment is required for patients with mild or moderate liver dysfunction (see the sections "Pharmacokinetics", "Special instructions").

    Children

    The safety and efficacy of Brilint ® in children under 18 years of age according to the indications approved in adults are not established (see the section "Contraindications").

    Side effects:

    Security Overview

    The safety profile of the Brilint® preparation was evaluated in two phase 3 studies (PLATO and PEGASUS), which included more than 39000 patients (see Fig.section "Pharmacological properties"). Below are the undesirable reactions noted in these clinical trials.

    In the study PLATO patients receiving the Brilint® drug were more likely to discontinue therapy because of the development of adverse events than patients who received clopidogrel (7.4% compared with 5.4%).

    In the study PEGASUS The frequency of cessation of treatment due to the development of adverse events was higher with Brilint® than with ACA monotherapy (16.1% in the ticagrelor group 60 mg + ASA, compared with 8.5% in the ASA monotherapy group). The most frequently observed undesirable reactions in patients taking ticagrelor, there were bleeding and shortness of breath (see section "Special instructions").

    List of unwanted reactions in the form of a table

    Undesirable reactions from clinical studies of Brilint® are described in the organ system class and frequency of development and are listed in descending order of severity. The frequency of unwanted reactions is determined using the following symbols: very often (≥1 / 10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10000, <1/1000), very rarely (<1/10000), unspecified frequency (can not be estimated from the received data).

    Table 1.Undesirable reactions to the frequency of development and the class of organ system noted in Phase 3 clinical trials PLATO and PEGASUS

    Class of organ systems

    Often

    Often

    Infrequently

    Benign, malignant and unspecified neoplasms (including cysts and polyps)

    Bleeding from a tumora

    Violations of the blood and lymphatic system

    Bleeding due to blood diseasesb

    Immune system disorders

    Hypersensitivity reactions, including angioedemafrom

    Disorders from the metabolism and nutrition

    Hyperuricemiad

    Gout / Gouty Arthritis

    Disorders of the psyche

    Confusion of consciousness

    Disturbances from the nervous system

    Dizziness, fainting, headache

    Intracranial hemorrhage

    Disturbances on the part of the organ of sight

    Hemorrhage in the eyee

    Hearing disorders and labyrinthine disorders

    Vertigo

    Ear bleeding

    Vascular disorders

    Arterial hypotension

    Disturbances from the respiratory system, chest and mediastinal organs

    Dyspnea

    Bleeding from the respiratory systemf

    Infringements from gastrointestinal tract

    Gastrointestinal bleedingg, diarrhea, nausea, indigestion, constipation

    Retroperitoneal bleeding

    Disturbances from the skin and subcutaneous tissues

    Subcutaneous or dermal bleedingh, itchy skin, rash

    Disturbances from musculoskeletal and connective tissue

    Muscular bleedingi

    Disorders from the kidneys and urinary tract

    Bleeding from the urinary tractj

    Violations of the genitals and mammary gland

    Bleeding from the genitalsk

    Laboratory and instrumental data

    Increase in the concentration of creatinine in the bloodd

    Trauma, intoxication and complications of manipulation

    Bleeding after manipulation, traumatic bleedingl

    a For example, bleeding from a tumor of the bladder, from a tumor of the stomach, from a tumor of the large intestine.

    b for example, an increased tendency to bruising, spontaneous hematoma, hemorrhagic diathesis.

    from noted in postmarketing applications.

    d the frequency of laboratory abnormalities is shown (an increase in the concentration of uric acid above the upper limit of the norm from the initial value, which was within the norm or less than the lower limit of the norm.Increasing the creatinine concentration> 50% of the original value), rather than the frequency of reports of adverse events.

    e for example, conjunctival, retinal, intraocular hemorrhage.

    f for example, epistaxis (nosebleeds), hemoptysis.

    g for example, gingival hemorrhage, rectal bleeding, bleeding from a stomach ulcer.

    h for example, ecchymosis, cutaneous hemorrhage, petechia.

    i for example, hemarthrosis, muscle hemorrhage,

    jfor example, hematuria, hemorrhagic cystitis.

    k for example, vaginal bleeding, hematospermia, postmenopausal bleeding.

    l for example, bruising, traumatic hematoma, traumatic bleeding.

    Description of some unwanted reactions

    Bleeding

    In studies PLATO and PEGASUS the following definitions of bleeding were used:

    - Large lethal / life-threatening bleeding by definition PLATO: lethal, or any intracranial hemorrhage, or bleeding into the pericardial cavity with cardiac tamponade; or with hypovolemic shock or severe arterial hypotension, requiring the use of vasoconstrictors / inotropic drugs or surgical intervention,or clinically obvious bleeding, accompanied by a decrease in the hemoglobin concentration by more than 50 g / l, or by transfusion of 4 or more red blood cells.

    - Large bleeding by definition PLATO: causing a significant incapacity of the patient, or clinically obvious bleeding, accompanied by a decrease in the concentration of hemoglobin by 30-50 g / l, or by transfusion of 2-3 units of red blood cells.

    - Small bleeding by definition PLATO: requires medical intervention to stop or treat bleeding.

    - Large bleeding by definition TIMI: lethal, or any intracranial hemorrhage, or clinically clear signs of hemorrhage associated with a 50 g / l decrease in hemoglobin concentration or more, or if hemoglobin data are not available, then a 15% decrease in hematocrit.

    - Large bleeding by definition TIMI: not lethal, not intracranial large bleeding by definition TIMI.

    - Small bleeding by definition TIMI: clinically obvious bleeding, accompanied by a decrease in the concentration of hemoglobin by 30-50 g / l.

    - Bleeding, requiring medical intervention, by definition TIMI: requires medical intervention or leads to hospitalization, or emergency examination.

    - Lethal hemorrhage: leads to death of the patient within 7 days.

    Data on cases of bleeding in the study PLATO (estimate by Kaplan-Meier (%) by 12 months)

    Brilint® and clopidogrel did not differ in the frequency of major bleeding as a whole according to the criteria PLATO (11.6% and 11.2%, respectively), lethal / life-threatening bleeding by criteria PLATO (5.8% in both groups). However, the frequency of the aggregate of large and small bleedings according to the criteria PLATO was higher in the ticagrelor group (16.1%) compared with clopidogrel (14.6%, p = 0.0084). Several cases of lethal bleeding were noted: 20 (0.2% of patients) in the ticagrelor group and 23 (0.3% of patients) in the clopidogrel group.

    Age, gender, body weight, ethnicity, geographic region, concomitant diseases, concomitant therapy, history, including a prior stroke and transient ischemic attack, did not affect the incidence of major bleeding in general and unrelated to the procedures by criteria PLATO. No groups with an increased risk of bleeding were identified.

    Bleeding associated with CABG: In the study PLATO 42% of the 1588 (12% of the cohort) patients undergoing CABG developed large lethal / life-threatening hemorrhages without distinction in both treatment groups. Lethal hemorrhage associated with CABG was noted in 6 patients in each treatment group (see section "Special instructions").

    Bleeding, not associated with CABG, and bleeding not associated with procedures: Brilint® and clopidogrel did not differ in the frequency of cases of major lethal / life-threatening bleeding not associated with CAB by criteria PLATO, but with the use of ticagrelor, large bleeding generally developed according to the criteria PLATO (4.5% compared with 3.8%, p = 0.0264). If the cases of development of procedural bleeding were removed, more bleeding occurred in the ticagrelor group (3.1%) than in the clopidogrel group (2.3%, p = 0.0058). The discontinuation of treatment due to bleeding not associated with procedures was more frequent with ticagrelor (2.9%) compared with clopidogrel (1.2%, p <0.001).

    Intracranial hemorrhage: In the ticagrelor group, there were more intracranial hemorrhages that were not associated with procedures (n = 27 hemorrhages in 26 patients, 0.3%) than in the clopidogrel group (n = 14 hemorrhages, 0.2%), of which 11 ticagrelor haemorrhages and 1 on clopidogrel were lethal.However, there were no significant differences in the total number of lethal bleeding. The percentage of intracranial hemorrhages was low in both treatment groups, given the significant concomitant diseases and risk factors for the development of cardiovascular complications in the study population.

    Data on cases of bleeding in the study PEGASUS (Kaplan-Meier estimate (%) for 36 months)

    In the study PEGASUS large bleeding by definition TIMI when using Brilint® 60 mg twice daily, more often (2.3%) than with ACA monotherapy (1.1%). There was no increase in the risk of lethal bleeding, but only a slight increase in the incidence of intracranial hemorrhage (0.6%) compared to ASA alone (0.5%). Several cases of lethal bleeding were noted: 11 (0.3%) in the Brilint® 60 mg group and 12 (0.3%) in the ASA monotherapy group. Increased risk of developing large bleeding by definition TIMI when using the Brilint® 60 mg drug was due mainly to a higher frequency of other large bleeding by definition TIMI due to phenomena from the gastrointestinal tract.

    Against the background of Brilint® 60 mg, an increase in the frequency of large or small bleeding by definition TIMI (3.4% with Brilint® 60 mg compared to 1.4% with ASA monotherapy), large bleeding by definition PLATO (3.5% compared with 1.4%) and large or small bleeding by definition PLATO (15.2% compared to 6.2%). Discontinuation of treatment due to bleeding was more frequent with Brilint® 60 mg than with ASA alone (6.2% and 1.5%, respectively). Most of these bleedings were less severe (classified as bleeding requiring medical intervention, by definition TIMI), for example, epistaxis, bruising, bruising.

    Profile of large bleeding by definition TIMI, large or small bleeding by definition TIMI and large bleeding by definition PLATO Brilinta® from preparation 60 mg was comparable to multiple predefined subgroups (e.g., depending on the age, sex, weight, race, geographic region, concomitant diseases, concomitant therapies and medical history).

    Intracranial hemorrhage: spontaneous intracranial hemorrhage was noted with a similar frequency with Brilint® 60 mg and ASA monotherapy (n= 13 hemorrhages, 0.2% in both treatment groups). The incidence of intracranial hemorrhage due to trauma and procedure was slightly higher with Brilent® 60 mg (n = 15 hemorrhages, 0.2%) compared with ACA monotherapy (n = 10 hemorrhages, 0.1%). There were 6 lethal intracranial hemorrhages with Brilint ® 60 mg and 5 - with ASA monotherapy. The incidence of intracranial hemorrhage was low in both treatment groups, given the significant concomitant diseases and risk factors for the development of cardiovascular complications in the study population.

    Dyspnea

    In the PLATO study, undesirable phenomena in the form of dyspnea developed in 13.8% of patients who received ticagrelor 90 mg twice a day, and 7.8% of patients taking clopidogrel 75 mg once a day. Most of the phenomena of dyspnea were from mild to moderate in intensity and were often resolved without canceling the therapy. Usually dyspnea developed at the beginning of therapy and in 87% of patients was a single episode. Shortness of breath in the form of a serious undesirable phenomenon was noted in 0.7% of patients who received ticagrelor, and in 0.4% of patients taking clopidogrel.

    Patients who reported development of dyspnea were older and often initially with shortness of breath, congestive heart failure, COPD, or bronchial asthma. Research data PLATO do not indicate that a higher incidence of dyspnea on the background of Brilint® is associated with the development of a new or worsening of the existing heart or lung disease. The preparation of Brilint® does not affect the parameters of the function of external respiration (see section "Special instructions").

    In the study PEGASUS Dyspnoea was noted in 14.2% of patients who took the Brilint® 60 mg twice daily and in 5.5% of patients on ASA monotherapy. As in the study PLATO, most cases of dyspnea were from mild to moderate in intensity (see section "Special instructions").

    Overdose:

    Ticagrelor is well tolerated in a single dose of the drug up to 900 mg. In a single study with increasing doses, adverse effects on the gastrointestinal tract were dose-limiting. Other clinically relevant adverse reactions that may occur in an overdose include shortness of breath and ventricular pauses (see section "Side effect").In case of overdose, it should be monitored for these potential adverse reactions with possible ECG monitoring.

    It is not expected that ticagrelor is derived during hemodialysis (see section "Special instructions"), the antidote is not known. In case of overdose, symptomatic therapy should be performed in accordance with local standards. In connection with the inhibition of platelets, the increase in the duration of bleeding is the presumed pharmacological effect of an overdose of the Brilint® preparation, therefore, when supporting bleeding, appropriate supportive measures should be taken.

    Interaction:

    Ticagrelor is mainly a substrate for isoenzyme CYP3A4 and a weak isoenzyme inhibitor CYP3A4. Tikagrelor is also a substrate of P-glycoprotein (P-gp) and a weak inhibitor P-gp, and can increase the exposure of substrates P-gp.

    The effect of other drugs on the Brilint® preparation

    Drugs metabolized by the isoenzyme CYP3A4

    Inhibitors CYP3A4

    - Powerful inhibitors CYP3A4: Co-administration of ketoconazole with ticagrelor increases CmOh and AUC tikagrelor in 2.4 and 7.3 times, respectively. FROMmOh and AUC the active metabolite is reduced by 89% and 56%, respectively. Other powerful inhibitors CYP3A4 (clarithromycin, nefazodone, ritonavir and atazanavir) will have the same effects, so the combined use of potent inhibitors CYP3A4 with Brilint® is contraindicated (see section "Contraindications").

    - Moderate inhibitors CYP3A4: the combined use of diltiazem with ticagrelor increases CmOh tikagrelor by 69%, a AUC 2.7 times, and reduces CmOh of the active metabolite by 38%, a AUC does not change. Tikagrelor does not affect the plasma concentrations of diltiazem. Other mild inhibitors CYP3A4 (e.g., amprenavir, aprepitant, erythromycin, fluconazole) will have similar effects, and they can also be administered concomitantly with Brilint®.

    Inductors CYP3A4

    Joint use of rifampicin with ticagrelor reduces CmOh and AUC tikagrelor by 73% and 86%, respectively. The stasis of the active metabolite does not change, a AUC is reduced by 46%. Other inductors CYP3A4 (e.g., phenytoin, carbamazepine and phenobarbital), apparently, will also reduce the exposure of ticagrelor. Joint use of ticagrelor with powerful inducers CYP3A can reduce the exposure and effectiveness of ticagrelor, therefore, they should not be used together with the Brilint® preparation.

    Cyclosporine (inhibitor P-gp and CYP3A)

    The combined use of cyclosporine (600 mg) with ticagrelor increases CmOh and AUC ticagrelor at 2.3 and 2.8 times, respectively. At the same time there is an increase AUC active metabolite by 32% and decrease in CmOh by 15% in the presence of cyclosporin.

    There is no evidence of a co-administration of ticagrelor with other potent inhibitors of glycoprotein P and moderate inhibitors CYP3A4 (e.g., verapamil and quinidine), which can increase the exposure of ticagrelor. If joint use can not be avoided, it must be done with caution.

    Other

    According to the results of studies of pharmacological interactions, the concomitant use of ticagrelor with heparin, enoxaparin and ASA or desmopressin does not affect the pharmacokinetics of ticagrelor, its active metabolite and ADP-induced platelet aggregation. If there are clinical indications for prescribing drugs that affect hemostasis, they should be used with caution in combination with ticagrelor.

    With the daily use of large volumes of grapefruit juice (200 ml 3 times a day), a 2-fold increase in the exposure of ticagrelor was noted. It is expected that such an increase in ticagrelor exposure is not clinically important for most patients.

    Effect of Brilint® on other drugs

    Drugs metabolized by the isoenzyme CYP3A4

    - Simvastatin: concomitant use of ticagrelor and simvastatin increases CmOh and AUC simvastatin by 81% and 56%, respectively, and increases CmOh and AUC simvastatinic acid by 64% and 52%, respectively, while in some cases these rates are increased by 2-3 times. Joint use of simvastatin in a dose above 40 mg / day. with ticagrelor may lead to the development of side effects of simvastatin, and it is necessary to evaluate the ratio of potential risk and benefit. Simvastatin did not affect the plasma concentration of ticagrelor. A similar influence ticagrelor can exert on lovastatin. It is not recommended joint use of ticagrelor with simvastatin or lovastatin in a dose exceeding 40 mg.

    - Atorvastatin: concomitant use of atorvastatin and ticagrelor increases CmOh and AUC atorvastatinic acid by 23% and 36%, respectively.Such an increase in the values AUC and CmOh is observed for all metabolites of atorvastatin acid. This increase is not clinically significant.

    - Similar effect on other statins metabolized by isoenzyme CYP3A4, can not be ruled out. In the study PLATO patients who received ticagrelor, took various statins in the absence of any concern for safety in 93% of patients taking this group of drugs.

    Ticagrelor is a weak isoenzyme inhibitor CYP3A4. Joint use of ticagrelor and isoenzyme substrates CYP3A4 with a narrow therapeutic index (for example, cisapride or ergot alkaloids) is not recommended, since ticagrelor can increase the exposure of these drugs.

    Substrates P-gp (including digoxin, ciclosporin)

    The concomitant use of ticagrelor with digoxin increased CmOh and AUC digoxin by 75% and 28%, respectively. When co-administered with ticagrelor, the mean value of the minimum digoxin concentration increased by approximately 30%, in some individual cases, by a factor of two. FROMmOh and AUC Ticagrelor and its active metabolite did not change with digoxin.Therefore, it is recommended to carry out appropriate clinical and / or laboratory monitoring (heart rate, and in the presence of clinical indications, also ECG and digoxin concentration in the blood) with simultaneous application of ticagrelor and P-gp-dependent drugs with a narrow therapeutic index, like digoxin.

    No effect of ticagrelor on the concentration of cyclosporine in the blood was noted.

    Drugs metabolized by the isoenzyme CYP2C9

    The concomitant use of ticagrelor and tolbutamide did not change the plasma concentrations of any of these drugs, indicating that ticagrelor is not an inhibitor of isoenzyme CYP2C9, and it is unlikely that it affects CYP2C9-mediated metabolism of drugs like warfarin and tolbutamide.

    Oral contraceptives

    The combined use of ticagrelor, levonorgestrel and ethinylestradiol increases the exposure of ethinyl estradiol by about 20%, but does not affect the pharmacokinetics of levonorgestrel. It is not expected clinically significant effect on the effectiveness of contraception with the simultaneous use of levonorgestrel, ethinyl estradiol and ticagrelor.

    Drugs that can cause bradycardia

    In connection with the identification of mainly asymptomatic ventricular pauses and bradycardia, care should be taken with the preparation of Brilint® concomitantly with drugs that can induce a bradycardia (see section "Special instructions"). However, in the study PLATO no clinically significant adverse events were observed when combined with one or more drugs that could cause bradycardia (for example, 96% of patients concurrently took beta-blockers, 33% had blockers of "slow" calcium channels, diltiazem and verapamil, and 4% - digoxin).

    Other concomitant therapy

    In clinical studies, the drug Brilinta® advantageously administered together with ACK, proton pump inhibitors, statins, beta-blockers, angiotensin converting enzyme inhibitors and angiotensin receptor antagonists under long-term use for the treatment of related diseases, as well as with heparin, low molecular weight heparins, glycoprotein inhibitors IIb/IIIa receptors for intravenous administration as part of short-term therapy.According to the results of these studies, there were no clinically significant undesirable interactions.

    The combined use of Brilint® with heparin, enoxaparin or desmopressin did not affect activated partial thromboplastin time (ACTT), activated clotting time (ABC), and factor Xa, but due to potential pharmacodynamic interaction, caution should be exercised when combined with drugs that affect on hemostasis.

    In connection with reports of subcutaneous hemorrhages against the background of the use of selective serotonin reuptake inhibitors (for example, paroxetine, sertraline and citalopram), caution should be exercised when they are taken together with ticagrelor, since an increased risk of bleeding may occur.

    Special instructions:

    Risk of bleeding

    When Brilint® is prescribed for patients with an increased risk of bleeding, the benefit ratio from prevention of atherothrombotic complications and the risk of bleeding development should be assessed.

    In the presence of clinical indications, Brilint® should be used with caution in the following situations:

    Patient predisposition to bleeding (eg due to recent trauma, recent surgery, bleeding disorders, poor liver function, moderate or active gastrointestinal hemorrhage). The use of Brilint® is contraindicated in patients with active pathological bleeding, intracranial hemorrhage in the anamnesis, impaired hepatic function of a serious degree (see section "Contraindications").

    - Concomitant use of drugs that may increase the risk of bleeding (eg, non-steroidal anti-inflammatory drugs, oral anticoagulants and / or fibrinolytics taken within 24 hours before taking Brilint®).

    There is no evidence of hemostatic efficacy of platelet transfusions when ticagrelor is used in patients; circulating ticagrelor can inhibit transfused platelets in the blood. Since the concomitant use of Brilint® and desmopressin did not reduce the standardized bleeding time, it is unlikely that desmopressin will effectively stop clinically significant bleeding (see the section "Interaction with other drugs and other types of drug interactions"). Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and / or recombinant therapy Vila can enhance hemostasis. After establishing the cause of bleeding and its relief, you can resume therapy with ticagrelor.

    Surgical interventions

    Before the planned operation or the start of taking new drugs, the patient should inform the doctor that he is taking the Brilint® preparation.

    In the study PLATO in patients undergoing CABG, when using the Brilint® drug, there was more bleeding than clopidogrel at discontinuation of therapy one day before surgery, but the incidence of major bleeding after discontinuing therapy 2 or more days before surgery was similar in comparison to clopidogrel (see section "Side effect"). If the patient is undergoing routine surgery and the antithrombotic effect is not desired,then therapy with Brilint® should be stopped 7 days before surgery (see section "Pharmacodynamics").

    Patients with a previous ischemic stroke

    Patients with ACS with a previous ischemic stroke can take the Brilint® preparation for up to 12 months (study PLATO).

    In the study PEGASUS patients with a history of myocardial infarction with a previous ischemic stroke were not included. Therefore, in the absence of data, care should be taken with therapy lasting more than 1 year.

    Patients with impaired liver function of moderate severity

    The experience of using the Brilint® preparation in patients with impaired liver function of moderate severity is limited, so care should be taken. The use of Brilint® is contraindicated in patients with severe hepatic dysfunction (see the section "Dosing and Administration", "Contraindications" and "Pharmacokinetics").

    Patients at risk of developing bradycardia

    In connection with the identification in a previous clinical study, mainly asymptomatic ventricular pauses, patients with an increased risk of bradycardia (for example, patients without a pacemaker,in whom syndrome of sinus node weakness is diagnosed, atrioventricular heart block of the 2nd or 3rd degree; syncope associated with bradycardia) were not included in the basic studies to assess the safety and efficacy of ticagrelor. Therefore, due to the limited clinical experience of the use of the drug in these patients, it is advisable to prescribe with caution ticagrelor such patients (see the section "Pharmacodynamics").

    Additional precautions should be observed when the drug Brilint® is used together with drugs that can cause bradycardia. However, there were no clinically significant side effects when combined with one or more drugs that could cause bradycardia (for example, 96% of patients concurrently took beta-blockers, 33% had blockers of "slow" calcium channels, diltiazem and verapamil, and 4% - digoxin) (see the section "Interaction with other drugs and other types of drug interactions").

    In the course of the sub-investigation PLATO using daily monitoring of the ECG by Holter in the ticagrelor group compared to clopidogrel, more patients in the acute phase of ACS had ventricular pauses> 3 seconds.An increase in the number of ventricular pauses recorded with day-to-day Holter monitoring with ticagrelor was noted more often in patients with chronic heart failure than in the general population in the acute phase of ACS, but not in the first month or compared with clopidogrel. Pauses in these patients were not accompanied by subsequent adverse clinical consequences (including fainting and pacemaker placement).

    Dyspnea

    It was reported on the development of dyspnea in patients who took the drug Brilinta. Dyspnoea usually from mild to moderate in intensity often passes without discontinuing therapy. In patients with bronchial asthma / COPD, the absolute risk of dyspnea on taking Brilint® can be increased (see section "Side effect"). Tikagrelor should be taken with caution in patients with bronchial asthma and / or COPD in anamnesis. The mechanism of dyspnea on admission tikagrelor is not clear. If the patient develops a new episode of dyspnea, dyspnoea persists or worsens during the use of Brilint®, then a complete examination should be performed, and in case of intolerance, the drug should be discontinued.

    Other

    Based on the observed in the study PLATO the relationship between the maintenance dose of ASA and the relative efficacy of ticagrelor compared to clopidogrel, the simultaneous use of ticagrelor and a high maintenance dose of ASA (> 300 mg) is not recommended (see "With caution").

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

    There have been no studies of the influence of Brilint® on the ability to drive vehicles and control mechanisms. It is assumed that the Brilint® preparation does not influence or negatively affects the ability to drive vehicles and mechanisms. During the treatment with Brilint®, dizziness and confusion were reported. In the event of the development of these phenomena, patients should be careful with the management of vehicles and other mechanisms.

    Form release / dosage:

    The tablets covered with a film membrane, 60 mg.

    Packaging:

    For 14 tablets in a blister of Al / PVC / PVDC.

    4 or 12 blisters with instructions for medical use in a cardboard box with the control of the first autopsy.

    Storage conditions:

    At a temperature of no higher than 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003779
    Date of registration:12.08.2016
    Expiration Date:12.08.2021
    The owner of the registration certificate:AstraZeneca ABAstraZeneca AB Sweden
    Manufacturer: & nbsp
    Representation: & nbspAstraZeneca Pharmaceuticals Ltd.AstraZeneca Pharmaceuticals Ltd.
    Information update date: & nbsp23.02.2017
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