Brilinta® [Ticagrelor]

Pharmacological properties

mechanism of action. The brillinta contains ticagrelor, which belongs to the chemical class of cyclopentyltriazolopyrimidines (cptp) and is a selective and reversibly binding antagonist of p2y12 receptors of direct action adf, which prevents ad-mediated p2y12-dependent activation and platelet aggregation. ticagrelor does not prevent adf binding but, by binding to p2y12 receptors, inhibits ad-induced signaling. since platelets are involved in the initiation and / or development of thrombotic complications of atherosclerosis, inhibition of platelet function has been shown to reduce the risk of cardiovascular events such as death, myocardial infarction (s) or stroke.

Ticagrelor also increases local levels of endogenous adenosine by inhibiting the activity of the balancing nucleoside subtype 1 transporter (ENT-1).

Ticagrelor enhances the following adenosine-induced effects in healthy individuals and in patients with acute coronary syndrome (ACS): vasodilation (measured by increasing blood flow in coronary vessels in healthy volunteers and patients with ACS, headache), inhibition of platelet function (whole human blood in in vitro) and shortness of breath. However, the relationship between the observed increase in adenosine levels and clinical outcomes (e.g. morbidity / mortality) has not been clearly established.

Pharmacodynamic effects

The beginning of the action. In patients with stable coronary artery disease who receive acetylsalicylic acid (ASA), the pharmacological effect of ticagrelor appears quickly, as evidenced by the average platelet aggregation inhibition (PAT) by ticagrelor 0.5 hours after applying a loading dose of 180 mg at about 41% with a maximum the effect of PAT at the level of 89% after 2–4 hours after application of the dose, which remained for 2–8 hours. In 90% of patients, the final indicator of PAT after 2 hours after application of the dose was 70%.

The end of the action. If a coronary artery bypass grafting (CABG) procedure is planned, the risk of bleeding in patients using ticagrelor is increased compared with those using clopidogrel if therapy is stopped less than 96 hours before the procedure.

Transition from one drug to another. The transition from clopidogrel at a dose of 75 mg to ticagrelor at a dose of 90 mg 2 times a day leads to an absolute increase in PAT by 26.4%, and the transition from ticagrelor to clopidogrel leads to an absolute decrease in PAT by 24.5%. Patients can be transferred from clopidogrel to ticagrelor without interrupting the antiplatelet effect (see APPLICATION).

Clinical efficacy and safety. Clinical evidence for the efficacy and safety of ticagrelor was obtained in two trials of the third phase:

The PLATO study [PLATelet Inhibition and Patient Outcomes - Platelet Inhibition and Patient Implications], which compared ticagrelor and clopidogrel when used in combination with ASA and other standard therapy.

PEGASUS TIMI-54 study [PrEvention with TicaGrelor of SecondAry Thrombotic Events in High-RiSk AcUte Coronary Syndrome Patients - Prevention of secondary thrombotic events in patients with high-risk acute coronary syndrome using ticagrelor], which compared ticagrelor in combination with ASA and treatment only ASK.

The study of PLATO (acute coronary syndrome). The PLATO study involved 18 624 patients who had symptoms of unstable angina pectoris, myocardial infarction without ST segment elevation or myocardial infarction with ST segment elevation in the last 24 hours, and who were first treated with medication or with percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG).

Clinical efficacy. Against the background of daily intake of ASA (acetylsalicylic acid), the use of 90 mg ticagrelor 2 times a day was more effective than clopidogrel 75 mg / day in preventing the primary combined endpoint, which included cardiovascular death, myocardial infarction (MI) or stroke due to the difference in cardiovascular death and MI. Patients received a loading dose of 300 mg of clopidogrel (in the case of PCI, possibly 600 mg) or 180 mg of ticagrelor.

The effect was achieved quickly and persisted over the entire 12-month treatment period, which ensured a reduction in absolute risk (ATS) of 1.9% per year and a decrease in relative risk (COP) of 16%. Treatment with ticagrelor instead of clopidogrel in 54 patients with ACS prevented one atherothrombotic event; treatment with ticagrelor in 91 patients prevented one cardiovascular death. Higher efficacy of treatment with ticagrelor compared to clopidogrel has been consistently observed in many subgroups, regardless of body weight, gender, history of diabetes mellitus, transient ischemic attack or non-hemorrhagic stroke or revascularization, concomitant drug therapy, including heparin, GpIIb / IIIa inhibitors and proton pump inhibitors (see INTERACTIONS). Efficiency did not depend on the treatment method chosen at the time of randomization (invasive or medication) both in patients with unstable angina pectoris, MI without increasing the ST segment, and in patients with MI with increasing ST segment.

Weakly observed drug interactions in the region, as a result of which the risk ratio (RR) for the primary endpoint is in favor of ticagrelor in other countries of the world, but in favor of clopidogrel in North America, which amounted to about 10% of the entire study population (p - value interactions equal to 0.045). A search analysis indicates a possible interaction with a dose of ASA, since a decrease in the effectiveness of ticagrelor was noted with an increase in the dose of ASA. Doses of ASA for continuous daily use simultaneously with the drug Brilint should be 75-150 mg (see APPLICATION)

So, the Brilinta drug at a dose of 90 mg 2 times a day in combination with low doses of ASA can be prescribed to patients with ACS (unstable angina, MI without ST segment elevation or IM with ST segment elevation), including patients who are treated with medication, with using PCI or CABG.

Genetic study of PLATO. Genotyping of 10,285 patients with CYP 2C19 and ABCB1 in the PLATO study allowed us to establish a relationship between the genotype groups and the results of the PLATO study. The advantages of ticagrelor over clopidogrel in reducing the incidence of serious cardiovascular events are largely independent of the genotype of CYP 2C19 or ABCB1 patients. The overall rate of major bleeding in the PLATO study did not differ between the ticagrelor and clopidogrel groups, regardless of the CYP 2C19 or ABCB1 genotype. The frequency of non-CABG-related major bleeding, as defined by the PLATO study, was increased with ticagrelor compared with clopidogrel in patients with one or more functional CYP 2C19 alleles, but similar with clopidogrel in patients without loss of functional alleles.

A comprehensive component of efficiency and safety. The complex component of efficacy and safety (cardiovascular death, myocardial infarction, stroke, or the total number of major bleeding, as determined by the PLATO study) indicates that the advantages of the effectiveness of ticagrelor compared to clopidogrel are not offset by cases of large bleeding (ATS - 1.4%, COP - 8%, RR - 0.92; p = 0.0257) within 12 months after ACS.

Clinical safety

Holter studies at PLATO. According to Holter monitoring, in a PLATO study, patients who had episodes of ventricular asystole of 3 s in the acute phase of ACS had more in the ticagrelor group than in the clopidogrel group; such episodes were more often observed in patients with chronic heart failure (CHF) compared with the general population; however, no statistically significant difference between the ticagrelor and clopidogrel groups after 1 month was noted.Undesirable clinical consequences (including fainting or the need to install a pacemaker) caused by such a discrepancy were not observed in this patient population.

PEGASUS study (history of MI). The PEGASUS TIMI-54 study was a randomized, double-blind, placebo-controlled, parallel-group, multicenter case-control study of 21,162 patients conducted to evaluate the prevention of atherothrombotic events using ticagrelor in two doses (90 mg 2 times a day) or 60 mg 2 times a day) in combination with low doses of ASA (75–150 mg) compared with ASA therapy alone in patients with a history of MI and the presence of additional risk factors for atherothrombosis.

Patients were eligible to participate in the study if their age was ≥50 years old, they had MI (1-3 years before randomization), and also had at least one of the following risk factors for atherothrombosis: age ≥65 years, diabetes mellitus with the need for medication treatment, the second previously transferred myocardial infarction, signs of coronary heart disease with multiple vascular lesions or chronic renal failure not in the terminal stage.

Patients were not eligible to participate in the study if they planned to use a P2Y receptor antagonist₁₂, dipyridamole, cilostazol or anticoagulant therapy during the study period; if they had a clotting disorder or ischemic stroke or a history of intracranial hemorrhage, a central nervous system tumor, or an intracranial vascular anomaly; if they have gastrointestinal bleeding within the previous 6 months or if they have undergone major surgery in the previous 30 days.

Clinical efficacy. Dosage regimens for the administration of ticagrelor in doses of 60 mg 2 times a day and 90 mg 2 times a day in combination with ASA were more effective for the prevention of atherothrombotic events compared with the use of ASA alone (complex endpoint: cardiovascular death, MI and stroke) with a stable treatment effect during the entire study period, which predetermined a COP of 16% and ATS of 1.27% when using ticagrelor at a dose of 60 mg and 15% and 1.19%, respectively, when using ticagrelor at a dose of 90 mg .

Despite the similarity between the efficacy profiles of 90 and 60 mg doses, there is evidence that a lower dose is better tolerated and has a better safety profile regarding the risk of bleeding and shortness of breath. Therefore, only Brilinta at a dose of 60 mg 2 times a day with the simultaneous use of ASA is recommended for the prevention of atherothrombotic events (cardiovascular death, MI and stroke) in patients with a history of MI and a high risk of atherothrombotic events.

Relatively only ASA ticagrelor at a dose of 60 mg 2 times a day caused a significant decrease in the frequency of the primary complex endpoint, including cardiovascular death, MI and stroke. The decrease in the frequency of the primary complex endpoint was due to a decrease in the frequency of each of the components (COP of cardiovascular death by 17%, COP of them by 16% and COP of stroke by 25%).

The COP of the complex endpoint from day 1 to day 360 (COP by 17%) and from day 361 onwards (COP by 16%) was almost the same. Data on the efficacy and safety of ticagrelor if treatment is continued for more than 3 years is limited.

There was no evidence of an advantage (no reduction in the frequency of the primary complex endpoint, including cardiovascular death, MI and stroke, but an increase in the frequency of major bleeding) of ticagrelor at a dose of 60 mg 2 times a day in clinically stable patients more than 2 years after MI or more than 1 year after the cessation of previous treatment with an ADP receptor inhibitor (see APPLICATION).

Clinical safety.The rate of premature discontinuation of ticagrelor at a dose of 60 mg due to bleeding and shortness of breath was higher in patients aged 75 years (42%) compared with younger patients (range 23–31%) with a difference compared with placebo of more than 10% (42% versus 29%) in patients aged 75 years.

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

Absorption. Ticagrelor is absorbed rapidly, median t_max is ≈1.5 hours. The formation of the main circulating active metabolite by healthy volunteers AR-C124910XX occurs quickly, the median t_max is ≈2.5 hours. After oral administration of a single dose of 90 mg of fasting ticagrelor C_max was 529 ng / ml, and AUC 3451 ng · h / ml. The ratio of metabolite to starting compound is 0.28 for C_max and 0.42 for AUC.

The pharmacokinetics of ticagrelor and AR-C124910XX in patients with myocardial infarction were generally similar to those observed in the patient population with ACS. According to the results of a population pharmacokinetic analysis of the PEGASUS study, median C_max ticagrelor was 391 ng / ml, and AUC 3801 ng · h / ml in equilibrium when applied at a dose of 60 mg. For ticagrelor at a dose of 90 mg C_max amounted to 627 ng / ml, and AUC - 6255 ng · h / ml in equilibrium.

The average absolute bioavailability of ticagrelor was calculated to be 36%. Eating fat-rich foods leads to an increase in AUC of ticagrelor by 21% and a decrease in C_max active metabolite by 22%, but does not affect C_max ticagrelor or on an AUC of the active metabolite. It is believed that these minor changes have minimal clinical value, so ticagrelor can be used regardless of food intake. Ticagrelor, like its active metabolite, are substrates of P-glycoprotein.

Ticagrelor in the form of crushed tablets mixed with water, if taken orally or administered through a nasogastric tube into the stomach, has AUC and C bioavailability comparable to whole tablets_max for ticagrelor and active metabolite. The initial exposure (0.5 and 1 hour after dosing) of the ticagrelor tablets shredded and mixed in water was higher than the initial exposure of whole tablets, and, as a rule, with the same concentration profile in the future (after 2–48 hours).

Distribution. The distribution volume in the equilibrium state of ticagrelor is 87.5 liters. Ticagrelor and its active metabolite are largely associated with plasma proteins (99.0%).

Biotransformation. The main enzyme that is responsible for the metabolism of ticagrelor and the formation of an active metabolite is CYP 3A4. Their interaction with other CYP 3A substrates ranges from activation to inhibition.

The main metabolite of ticagrelor is AR-C124910XX, which is also active, as evidenced by in vitro binding to P2Y platelet ADP receptors₁₂. The systemic exposure of the active metabolite is 30–40% of the exposure of ticagrelor.

Breeding. The main way to eliminate ticagrelor is hepatic metabolism. When using isotope-labeled ticagrelor, the average level of the excreted radioactive label is ≈84% (57.8% in feces, 26.5% in urine). The content of ticagrelor and the active metabolite in the urine is 1% of the dose. The main route of excretion of the active metabolite, most likely, is secretion with bile. Average T_½ ticagrelor was ≈7 hours, active metabolite - 8.5 hours

Special Patients

Elderly patients. According to population pharmacokinetic analysis, elderly people (≥75 years) with ACS had higher levels of ticagrelor exposure and (≈25% higher C_max and AUC) of an active metabolite than in patients of a younger age. The difference is not considered clinically significant (see APPLICATION).

Children. The use of ticagrelor in children has not been studied (see APPLICATION and Pharmacodynamics).

Floor.Women had higher exposures to ticagrelor and an active metabolite than men. These differences are not considered clinically significant.

Impaired renal function. The exposure of ticagrelor was approximately 20% lower, and the exposure of the active metabolite was approximately 17% higher in patients with severe impaired renal function (creatinine clearance 30 ml / min) than in patients with normal renal function (see APPLICATION).

Impaired liver function. C_max and AUC of ticagrelor were respectively 12 and 23% higher in patients with mild hepatic insufficiency compared with those in healthy volunteers. However, the effect of PAT ticagrelor was similar for both groups. Dose adjustment in patients with impaired liver function of a mild degree is not needed. The use of ticagrelor in patients with severely impaired liver function has not been studied; there is no information on the pharmacokinetics of patients with mild hepatic impairment. In patients with a moderate or pronounced increase in one or more laboratory parameters of liver function at baseline, the plasma concentrations of ticagrelor were on average the same or slightly higher compared to patients without deviations at baseline. Dose adjustment for patients with moderate liver dysfunction is not required (see APPLICATION and SPECIAL INSTRUCTIONS).

Ethnicity. In patients of Asian origin, the average bioavailability is 39% higher than in those of the Caucasian race. In patients of the Negroid race, the bioavailability of ticagrelor was 18% lower than in patients of the Caucasian race. In a clinical pharmacology study, exposure (C_max and AUC) of ticagrelor in the Japanese was ≈40% (20% after adjusting for body weight) higher than that of the Caucasian race. The exposure of the drug in patients of Spanish or Hispanic origin was similar to that in patients of the Caucasian race.

Indications

60 mg tablets the use of the drug brilinta simultaneously with ASK is indicated for the prevention of atherothrombotic events in adult patients with:

• ACS or
• A history of MI and a high risk of atherothrombotic events (see APPLICATION and Pharmacodynamics).

90 mg tablets The use of the drug Brilinta simultaneously with ASA is indicated for the prevention of atherothrombotic events in adult patients with ACS.

Application

Dosage. patients taking the drug brilint should also take ASK in a maintenance dose of 75-150 mg daily, if there are no special contraindications for this.

ACS. Treatment with Brilint should be started with a single loading dose of 180 mg (2 tablets of 90 mg) and then taken 90 mg 2 times a day. The recommended duration of treatment with Brilint at a dose of 90 mg in patients with ACS is 12 months in the absence of clinical indications for premature termination of treatment (see Pharmacodynamics). In the presence of clinical indications, treatment with Brilinta can last more than 12 months (see a history of myocardial infarction).

A history of myocardial infarction. The recommended dose of the Brilint drug for patients with a history of myocardial infarction transferred at least 1 year ago and a high risk of developing atherothrombotic events if long-term treatment is necessary is 60 mg 2 times a day (see Pharmacodynamics). For patients with ACS with a high risk of atherothrombotic events, treatment can be started without interruption - as a continuation of therapy after initial treatment with 90 mg Brilint drug or another ADP receptor inhibitor, which lasted 1 year. Treatment can be started up to 2 years after myocardial infarction or within 1 year after the end of the previous course of treatment with an ADP receptor inhibitor. Data on the effectiveness and safety of the Brilint drug with continued treatment for more than 3 years is limited.

If it is necessary to switch from another drug to the Brilint drug, the first dose of the Brilint drug should be taken 24 hours after taking the last dose of another antiplatelet drug.

Skip dose. Skipping medication should also be avoided. If the patient missed a dose of Brilint, he only needs to take 1 tablet (the next dose) at the appointed time.

Special patient groups

Elderly patients. Dose adjustment in elderly patients is not required (see Pharmacodynamics).

Impaired renal function. Dose adjustment is not required for patients with impaired renal function (see Pharmacodynamics). There is no information on the use of the drug in patients on hemodialysis, therefore ticagrelor is not recommended for use in such patients.

Impaired liver function. The use of ticagrelor in patients with severe hepatic impairment has not been investigated, therefore, the appointment of the drug in such patients is contraindicated (see CONTRAINDICATIONS). Information on the use of the drug in patients with moderate liver dysfunction is limited. Dose adjustment is not recommended, but ticagrelor should be used with caution (see ADVERSE EFFECTS and Pharmacokinetics). Dose adjustment in patients with impaired liver function of a mild degree is not required (see Pharmacodynamics).

Mode of application. For oral use.

The drug Brilinta can be used regardless of food intake.

For patients who cannot swallow the tablet whole, the tablet can be pulverized, mixed with half a glass of water and immediately drunk. The glass must be washed, using another half glass of water, and drink the contents of the glass. The mixture can be administered via a nasogastric tube (CH8 or greater). It is important to rinse the nasogastric tube with water after administration of the mixture.

Contraindications

Hypersensitivity to the active substance or any of the excipients (see side effects).

Active pathological bleeding.

History of intracranial hemorrhage (see ADVERSE EFFECTS).

Impaired liver function of moderate to severe degree (see APPLICATION, Special warnings and special precautions when used and Pharmacokinetic properties).

The simultaneous use of ticagrelor with potent CYP 3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir) is contraindicated, since their simultaneous use can lead to a significant increase in the exposure of ticagrelor (see INTERACTIONS).

During pregnancy and breastfeeding.

Childhood.

Side effects

The safety profile of ticagrelor was evaluated in two large-scale clinical trials of the 3rd phase, which were conducted to study the results of the treatment (plato and pegasus study), in which more than 39,000 patients participated (see Pharmacodynamics).

In the PLATO study in patients receiving ticagrelor, the incidence of premature treatment discontinuation due to side effects was higher than in patients receiving clopidogrel (7.4% versus 5.4%). In the PEGASUS study, the incidence of premature treatment discontinuation due to adverse events was higher among patients receiving ticagrelor compared to patients receiving only ASA (16.1% when using ticagrelor at a dose of 60 mg with ASA versus 8.5% when using only ASA ) The most common adverse reactions in patients treated with ticagrelor were bleeding and shortness of breath (see SPECIAL INSTRUCTIONS).

The following adverse reactions were identified during clinical trials or reported during post-marketing use of ticagrelor (table).

Adverse reactions are given by class of organ systems of the Medical Dictionary of Regulatory Activities (MedDRA). Within each class of organ system, adverse reactions are classified into groups by frequency.Frequency groups are determined according to the following criteria: very often (≥1 / 10), often (≥1 / 100 to 1/10); infrequently (from ≥1 / 1000 to 1/100); rarely (from ≥1 / 10,000 to 1/1000); very rarely (1/10 000); frequency is unknown (cannot be calculated from the available data).

^aFor example, bleeding from a malignant tumor of the bladder, stomach, colon.

^bFor example, an increased tendency to bruise, spontaneous hematoma, hemorrhagic diathesis.

^cIdentified in the post-registration period.

^dThe frequency was established on the basis of laboratory data (increase in uric acid level above the upper limit of the norm from the initial level, which was below the normal range or corresponded to it, an increase in creatinine level is 50% of the initial level) and does not reflect the frequency of reports of adverse events.

^eFor example, conjunctival hemorrhage, retina, intraocular hemorrhage.

^fFor example nosebleeds, hemoptysis.

^gFor example, bleeding from the gums, rectal bleeding, bleeding from a stomach ulcer.

^hFor example, ecchymoses, hemorrhage in the skin, petechiae.

ⁱFor example, hemarthrosis, muscle hemorrhage.

^jFor example, hematuria, hemorrhagic cystitis.

^kFor example, vaginal bleeding, hematospermia, postmenopausal bleeding.

^lFor example, a bruise, traumatic hematoma, traumatic bleeding.

Description of selected adverse reactions

Bleeding

Cases of bleeding in the PLATO study. Ticagrelor and clopidogrel did not differ according to PLATO criteria in the frequency of large fatal / life-threatening bleeding, the total number of large bleeding, the frequency of large bleeding according to the TIMI criteria or the frequency of small bleeding according to the TIMI criteria. However, the frequency of combined PLATO major and minor bleeding was higher in the ticagrelor group compared with the clopidogrel group. Fatal bleeding occurred in several patients in the PLATO study: 20 (0.2%) in the ticagrelor group and 23 (0.3%) in the clopidogrel group (see SPECIAL INSTRUCTIONS).

Age, gender, body weight, race, geographic region, concomitant conditions, concomitant treatment and medical history, including a stroke or transient ischemic attack, were not predictive factors for the total bleeding frequency or the frequency of major bleeding in the PLATO study, not related with the procedures. So, no group was identified as a group at increased risk of bleeding of a particular type.

Bleeding associated with CABG. The frequency of large fatal / life-threatening bleeding according to the PLATO criteria in patients who underwent CABG was similar in the treatment groups with ticagrelor and clopidogrel.

Hemorrhages not related to CABG and bleeding not related to procedures. Ticagrelor and clopidogrel did not differ in the frequency of non-CAB-related fatal / life-threatening major bleeding according to the PLATO criteria, but the total frequency of large bleeding according to the PLATO criteria, the frequency of large bleeding according to the TIMI criteria and the total frequency of large and small bleeding according to the TIMI criteria were higher in the group treatment with ticagrelor. Similarly, if we exclude all bleeding associated with the procedures, their frequency was higher in the ticagrelor group compared to the clopidogrel group.

Intracranial hemorrhage. When using ticagrelor, there was more intracranial hemorrhage that was not associated with the procedures (0.3%) than when using clopidogrel (0.2%). There was no difference in the overall frequency of fatal bleeding.

Cases of bleeding in the PEGASUS study. In the PEGASUS study, large bleeding (TIMI) was more often observed in the ticagrelor treatment group at a dose of 60 mg 2 times a day than in the ASA treatment group. No increased risk of fatal bleeding; in addition, only a slight increase in the frequency of intracranial hemorrhages was revealed compared with treatment with ASA alone. Several cases of fatal bleeding were noted in the study: 11 (0.3%) when using ticagrelor at a dose of 60 mg and 12 (0.3%) when using only ASA. The observed increase in the risk of major bleeding (TIMI) when using ticagrelor at a dose of 60 mg was mainly due to the high frequency of other major bleeding (TIMI), among which cases related to gastrointestinal disorders predominated.

A tendency to increase bleeding frequency, similar to that for large bleeding according to TIMI criteria, was also observed for large or small blood