Security Overview
The safety profile of the Brilint® preparation has been studied in two major studies on outcome outcomes (PLATO and PEGASUS), in which more than 39,000 patients took part (see the section "Pharmacodynamics").
In the study PLATO patients receiving the Brilint® drug were more likely to discontinue therapy because of adverse events than patients who received clopidogrel (7.4% compared with 5.4%). In the study PEGASUS in patients receiving Brilint®, the frequency of discontinuation of therapy due to adverse events was higher than in patients receiving ACA monotherapy (16.1% in the ticagrelor group 60 mg in combination with ASA and 8.5% in the ASA monotherapy group) . The most common adverse events in patients taking ticagrelor, there was bleeding and shortness of breath.Below are the undesirable reactions noted in these studies.
The list of undesirable reactions
The undesirable reactions noted in the clinical studies of the Brilint® preparation are distributed according to the organ system class and the frequency of development.
The frequency of unwanted reactions is determined using the following categories: 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).
Benign, malignant and unspecified neoplasms (including cysts and polyps): infrequently - bleeding from a tumor2.
From the hemopoietic system and lymphatic system: very often bleeding related to blood disease3.
Metabolism and nutrition disorders: very often - hyperuricemia1; often - gout.
Mental disorders: infrequently - confusion.
From the nervous system: often - dizziness, fainting; infrequently - intracranial hemorrhage.
From the side of the organ of vision: infrequently - a bleeding in the eye4.
From the organ of hearing: often - vertigo; infrequently - a hemorrhage in the ear.
From the cardiovascular system: often - arterial hypotension.
From the respiratory system: very often - shortness of breath; often - bleeding from the respiratory system5.
From the gastrointestinal tract: often - gastrointestinal bleeding6, diarrhea, nausea; infrequently, retroperitoneal bleeding.
From the skin side and subcutaneous tissue: often - subcutaneous or cutaneous hemorrhage7, itchy skin.
From the musculoskeletal system: infrequently - a hemorrhage into the muscles8.
From the side of the urinary system: often bleeding from urinary tract ways9.
From the side of the reproductive system and mammary glands: infrequently - bleeding from the genital tract10.
Laboratory and instrumental data: often - increased concentration creatinine in the blood1.
Trauma, intoxication and complications of manipulation: often - bleeding after manipulation, traumatic bleeding11.
1 - Frequency of abnormalities of laboratory parameters (increased uric acid concentration above the upper limit of the norm from the initial value, which was within the norm or below the lower limit of the norm, increase in the creatinine concentration> 50% of the initial value), rather than the frequency of reports of adverse events.
2 - For example, bleeding from a tumor (cancer) of the bladder, from a tumor (cancer) of the stomach, from a tumor (cancer) of the colon.
3 - For example, the tendency to bruising, spontaneous hematoma, hemorrhagic diathesis.
4 - For example, conjunctival, retinal, intraocular hemorrhage.
5 - For example, epistaxis (nosebleeds), hemoptysis.
6 - For example, bleeding from the gums, rectal bleeding, bleeding from a stomach ulcer.
7 - For example, ecchymosis, cutaneous hemorrhage, petechia.
8 - For example, hemarthrosis, a hemorrhage in the muscle.
9 - For example, hematuria, hemorrhagic cystitis.
10 - For example, vaginal bleeding, hematospermia, postmenopausal bleeding.
11 - For example, a bruise, 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 hypovolemic shock or severe hypotension,Bleeding and requiring the use of vasoconstrictors / inotropic drugs or surgical intervention, or clinically apparent bleeding, accompanied by a decrease in hemoglobin concentration by more than 50 g / l, or by transfusion of 4 or more red blood cells.
- Large bleeding by definition PLATO: causing significant patient incapacity, or clinically apparent bleeding, accompanied by a decrease in the level of hemoglobin by 30-50 g / l, or requiring transfusion of 2-3 units of whole blood or erythrocytes.
- 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 concentration 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 level 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 the patient's death within 7 days.
Data on bleeding cases in PLATO studies (Kaplan-Meier score (%) 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, sex, body weight, race, 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 not related to the criteria PLATO. No groups with an increased risk of bleeding were identified.
Bleeding associated with AKW: In the study PLATO 42% of patients from 1584 (12% of the cohort) who underwent CABG developed large lethal / life-threatening hemorrhages without significant differences 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 CABG according to the PLATO criteria, but with the use of the Brilint® preparation, large bleeding as a whole, as determined by the PLATO study (4.5% compared to 3.8% = 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 the procedure was more frequent with a ticagrelor (2.9%) compared with clopidogrel (1.2%, p <0.001).
Intracranial hemorrhage: In the tikagrelor group, more intracranial bleeding not associated with procedures (n = 27 bleedings in 26 patients, 0.3%) than in the clopidogrel group (n = 14 bleedings, 0.2%), of which 11 bleeding on ticagrelor and 1 on clopidogrel were fatal .However, there were no significant differences in the total number of fatal bleeding.
Data on cases of bleeding in the study PEGASUS (Kaplan-Meier estimate (%) to 36 months)
In the study PEGASUS-TIMI 54 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 increased risk of lethal bleeding; There was only a slight increase in the incidence of intracranial hemorrhages (0.6%) compared with ASA alone (0.5%). Several cases of lethal bleeding were noted: 11 (0.3%) in the Brilint group® 60 mg and 12 (0.3%) in the ASA monotherapy group. Increased risk of major bleeding by definition TIMI when using the Brilint® 60 mg drug was due mainly to a higher frequency of other 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 with 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 therapy 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, nosebleeds, bruises, bruises.
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 observed with similar frequency in use of the drug Brilinta® 60 mg and ASA alone (13 cases, 0.2% in each treatment group). The incidence of intracranial hemorrhage due to trauma or procedure was slightly higher in the Brilint group® 60 mg (15 cases, 0.2%) compared with ASA alone (10 cases, 0.1%).There were 6 lethal intracranial hemorrhages with Brilint ® 60 mg and 5 lethal intracranial hemorrhages with ASC 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 study PLATO undesirable phenomena in the form of dyspnoea (dyspnea, dyspnea at rest, dyspnea with exercise, paroxysmal nocturnal dyspnoea and nocturnal dyspnea) developed in 13.8% of patients receiving Brilint's preparation® 90 mg twice a day, and in 7.8% of patients taking clopidogrel 75 mg once a day. According to the researchers, 2.2% of patients in the ticagrelor group had shortness of breath associated with therapy.
Most of the shortness of breath cases were mild or moderate in intensity and were often resolved without canceling the therapy. Usually, dyspnea developed at the beginning of therapy and 87% of patients developed as 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 with developmental dyspnea were older, often they had shortness of breath, chronic heart failure, COPD, or bronchial asthma prior to initiating ticagrelor therapy.
Research data PLATO suggest that a higher incidence of dyspnea against the background of the Brilint® preparation is not 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 received the Brilint ® 60 mg bid twice a day, and 5.5% of patients receiving ASA monotherapy. As in the study PLATO, in most cases, dyspnea was from mild to moderate severity (see section "Special instructions").
Postmarketing application
Below are the undesirable reactions that were noted in the post-marketing application of the Brilint preparation®. Since messages are received spontaneously from a population of an unidentified size, it is not always possible to reliably estimate the frequency of development.
Immune system disorders: reactions of hypersensitivity, including angioedema (see "Contraindications").
Disturbances from the skin and subcutaneous tissues: skin rash.
Also, when Brilint® was used, the following were noted:
- unwanted reactions, the relationship of which with taking the drug can not be ruled out with taking into account the mechanism of action of ticagrelor: thrombocytopenia, immune thrombocytopenic purpura, thrombocytosis, coagulopathy, thromboembolism of the pulmonary artery;
- undesirable reactions, probably, representing hypersensitivity to the drug: urticaria, dermatitis;
- undesirable reactions, the relationship of which with the reception of the drug is not established: hemoconcentration, hematocrit increase, hemoglobin decrease, anxiety, anxiety, insomnia, headache, ischemic stroke, tremor, aphonia, dysphonia, tachycardia, bradycardia, arterial hypertension, chest pain, rhythm disturbances heart (including atrial fibrillation, ventricular extrasystole), cardiac conduction disorder (including atrioventricular block of degree 2), peripheral edema, cough, asthma, bronchospasm, gastritis (including e erosive), a stomach ulcer,epigastric pain, dyspepsia, pancreatitis, acute renal failure, arthralgia, myalgia, asthenia, malaise, increased bilirubin concentration in the blood.