Брилинта®
Producer: AstraZeneca (Astrazenek) Sweden
Code of automatic telephone exchange: B01BC24
Release form: Firm dosage forms. Tablets.
General characteristics. Structure:
Active agent: ticagrelor of 90 mg
Excipients: Mannitolum of 126 mg, calcium hydrophosphate of 63 mg, carboxymethylstarch of sodium of 9 mg, hypro rod of 9 mg, magnesium stearate of 3 mg;
as a part of a film cover of a tablet: gipromelloza of 2910 5,6 mg, titanium mg E 171 1,7 dioxide, talc of 1,0 mg, macrogoal of 400 0,6 mg, dye ferrous oxide of yellow E 172 0,1 mg.
Description. Round, biconvex tablets, film coated yellow color, with an engraving 90 on one party.
Pharmacological properties:
Action mechanism
The drug Brilinta® contains in the structure ticagrelor, the representative of a chemical class of cyclopentyltriazolopyrimidines who is the selection and reversible antagonist of P2Y12 of a receptor to adenosinediphosphate (ADF) and can prevent ADF-oposredovannuyu activation and aggregation of thrombocytes. Ticagrelor is active at intake and reversibly interacts with P2Y12 the ADF-receptor of thrombocytes. Ticagrelor does not interact with the place of binding of ADF, but its interaction with P2Y12 a receptor of thrombocytes to ADF prevents transduction of signals.
Pharmacodynamics. Beginning of action
At patients with the stable course of the coronary heart disease (CHD) against the background of use of acetylsalicylic acid ticagrelor begins to work quickly that is confirmed by results of definition of average value of the inhibition of aggregation of thrombocytes (IAT): in 0,5 hours after reception of a load dose of 180 mg of ticagrelor the IAT average value makes about 41%, the IAT maximum value of 89% is reached in 2-4 hours after administration of drug and maintained within 2-8 hours. At 90% of patients the IAT final value more than 70% are reached in 2 hours after administration of drug.
End of action
When planning AKSh, the risk of bleedings increases if ticagrelor is stopped less, than in 96 hours prior to the procedure.
Data on transition from one drug on another
Transition from a klopidogrel to ticagrelor leads to increase in an absolute value of IAT by 26,4%, and change of therapy from ticagrelor on klopidogret leads to decrease in an absolute value of IAT by 24,5%. It is possible to change therapy from a klopidogrel for ticagrelor without interruption of antitrombotichesky effect.
Clinical performance
18 624 patients at whom in the last 24 hours symptoms of unstable stenocardia, a myocardial infarction without raising of a segment of ST or a myocardial infarction with raising of a segment of ST developed and which were treated conservatively, or by means of the transdermal coronary intervention (TCI), or aortocoronary shunting (AKSh) participated in the research PLATO (PLATelet Inhibition and Patient Outcomes – Inhibition of thrombocytes and outcomes at patients) (see the section "Indications to Use"). In this research against the background of daily therapy by acetylsalicylic acid ticagrelor of 90 mg twice a day was compared from klopidogrely 75 mg a day concerning efficiency in the prevention of development of the combined final point of cardiovascular death, a myocardial infarction or a stroke due to influence on the frequency of cardiovascular death and myocardial infarctions. The load dose made 300 mg of a klopidogrel (the dose of 600 mg was also allowed when carrying out ChKV) or 180 mg of ticagrelor.
The effect of ticagrelor was shown early (for the 30th day the decrease in absolute risk (DAR) for 0,6% and the decrease in relative risk (DRR) for 12%), with maintenance of a permanent effect of therapy within 12 months that led to the decrease in absolute risk (DAR) for 1,9% and to the decrease in relative risk (DRR) for 16% within a year.
Брилинта® reduces relative risk of the combined final point (set of cardiovascular death, a heart attack and stroke) at patients with unstable stenocardia, a myocardial infarction without raising of a segment of ST and a myocardial infarction with raising of a segment of ST by 16% (the relation of risks (RR) 0,84; 95% confidence interval (CI) 0,77-0,92; p = 0,0003), cardiovascular death for 21% (the SHOUTING 0,79; 95% of DI 0,69-0,91; p=0,0013), a myocardial infarction for 16% (the SHOUTING 0,84; 95% of DI 0,75-0,95; p=0,0045).
Efficiency of the drug Brilinta® is shown at various subgroups of patients, irrespective of the body weight, a floor, existence in the anamnesis of a diabetes mellitus, the tranzitorny ischemic attack or not hemorrhagic stroke, the revascularization accompanying therapy (including heparin, inhibitors of glycoprotein IIb/IIIa of receptors (see the section "Interaction with Other Medicines and Other Types of Medicinal Interaction"), the final diagnosis (a myocardial infarction without raising of a segment of ST, a myocardial infarction with raising of a segment of ST and unstable stenocardia) and the treatment planned at randomization (invasive or conservative).
The additional analysis allowed to assume existence of possible communication with a dose of acetylsalicylic acid which was expressed that the lowered efficiency was observed at administration of drug of Brilinta® in a combination with the raised doses of acetylsalicylic acid. The recommended dose of acetylsalicylic acid for constant reception in combination with the drug Brilinta® - 75-150 mg (see the sections "Route of Administration and Doses" and "Special Instructions").
Брилинта® showed statistically significant LITTER by cumulative criterion: death from the cardiovascular reasons, a myocardial infarction and a stroke - at patients with an acute coronary syndrome which planned invasive intervention (LITTER of 16%, SAR of 1,7%, p=0,0025). In the search analysis Brilinta® also showed LITTER on primary final point at patients with an acute coronary syndrome which appointed conservative therapy (LITTER of 15%, SAR of 2,3%, nominal p=0,0444). At patients is after stenting
at use of ticagrelor decrease in frequency of thrombosis of stents (LITTER of 32%, SAR of 0,6%, nominal p=0,0123) was noted.
Брилинта® caused statistically significant LITTER for 16% (SAR of 2,1%) by such cumulative criterion as death from all reasons, a myocardial infarction and a stroke.
LITTER of death from all reasons on administration of drug of Brilinta® 22% at nominal level of significance р made =0,0003 and SAR - 1,4%.
Cumulative criterion of the integrated efficiency and safety
The cumulative criterion of the integrated efficiency and safety (death from the cardiovascular reasons, a myocardial infarction, a stroke or big bleeding by definition of the research PLATO) confirms that within 12 months after an acute coronary syndrome the positive effect of ticagrelor is not neutralized by cases of big bleedings (LITTER of 8%, SAR of 1,4%, OP 0,92; p=0,0257).
Pharmacokinetics. Ticagrelor shows linear pharmacokinetics, and exposure of ticagrelor and an active metabolite (AR-C124910XX) is approximately proportional to a dose up to 1260 mg.
Absorption
Ticagrelor is quickly absorbed from average tmax about 1,5 hours. Formation of the main metabolite of AR-C124910XX circulating in blood (also active) of ticagrelor happens quickly to average tmax about 2,5 hours. After reception on an empty stomach of ticagrelor in a dose of 90 mg of Cmax makes 529 ng/ml and AUC - 3451 ¡ú*þ/ml.
Average absolute bioavailability of ticagrelor makes 36%. Reception of greasy food does not influence Cmax of ticagrelor or AUC of an active metabolite, but leads to increase for 21% of AUC ticagrelor and to decrease by 22% of Cmax of an active metabolite. These little changes have the minimum clinical importance; therefore it is possible to appoint ticagrelor regardless of meal.
Distribution
The volume of distribution of ticagrelor in an equilibrium state makes 87,5 l. Ticagrelor and an active metabolite actively contact proteins of a blood plasma (> 99%).
Metabolism
CYP3A4 is the main isoenzyme which is responsible for metabolism of ticagrelor and formation of an active metabolite, and their interactions with other CYP3A substrates vary from activation to inhibition. Ticagrelor and an active metabolite are weak inhibitors of the R-glycoprotein.
The main metabolite of ticagrelor is AR-C124910XX which is also active that is confirmed by results of assessment of linkng with P2Y12 a receptor of ADF of thrombocytes of in vitro. System exposure of an active metabolite makes about 30-40% of ticagrelor exposure.
Excretion
The main way of removal of ticagrelor – through hepatic metabolism. At introduction marked ticagrelor isotope on average about 57,8% of radioactivity allocates with excrements, 26,5% with urine. Removal of ticagrelor and an active metabolite with urine makes less than 1% of a dose. Generally active metabolite is removed with bile. The average elimination half-life of ticagrelor and an active metabolite made 7 and 8,5 hours, respectively.
Special populations of patients
Elderly patients
At elderly patients (aged from 75 years is also more senior) higher exposure of ticagrelor (Cmax and AUC about 25% higher) and an active metabolite in comparison with young patients is noted. These distinctions are not considered clinically significant (see the section "Route of Administration and Doses").
Children
There are no data on use of ticagrelor for children.
Floor
At women higher exposure of ticagrelor and an active metabolite in comparison with men is noted. These distinctions are not considered as clinically significant.
Ethnic groups
Average bioavailability of drug at Asian patients is 39% higher, than at Caucasians. Bioavailability of the drug Brilinta® is 18% lower at patients of negroid race in comparison with patients of Caucasian race.
Renal failure
Exposure of ticagrelor and active metabolite is about 20% lower at patients with a heavy renal failure (clearance of creatinine <30 ml/min.) in comparison with patients with normal function of kidneys (see the section "Route of Administration and Doses").
Liver failure
Cmax and AUC ticagrelor were for 12% and 23% above at patients with a liver failure of easy degree in comparison with healthy volunteers. Ticagrelor researches at patients with a moderate or heavy liver failure were not conducted, and its use at these patients is contraindicated (see the sections "Route of Administration and Doses" and "Contraindications").
Indications to use:
Брилинта®, applied along with acetylsalicylic acid, it is shown for prevention of aterotrombotichesky events at patients with an acute coronary syndrome (unstable stenocardia, a myocardial infarction without raising of a segment of ST or a myocardial infarction with raising of a ST [STEMI] segment), including the patients receiving medicinal therapy and the patients subjected to the transdermal coronary intervention (TCI) or aortocoronary shunting (AKSh)).
Route of administration and doses:
For intake. The drug Brilinta® can be accepted regardless of meal.
Use of the drug Brilinta® it is necessary to begin with a single load dose 180 mg (two tablets on 90 mg) and then to continue reception on 90 mg two times a day.
The patients accepting the drug Brilinta® have to accept daily acetylsalicylic acid (from 75 mg to 150 mg at constant reception) (see the section "Pharmacological Properties") if there are no specific contraindications.
It is necessary to avoid breaks in therapy. The patient who missed administration of drug of Brilinta® has to take only one pill of 90 mg (the following dose) in the planned time.
If necessary the patients accepting klopidogret, can be transferred to administration of drug of Brilinta® (see the section "Pharmacological Properties").
It is recommended to carry out therapy by the drug Brilinta® within 12 months, except cases of clinical need for early drug withdrawal (see the section "Pharmacological Properties"). Data on ticagrelor use are limited more than 12 months. Patients with an acute coronary syndrome have an early cancellation of any antiagregantny therapy, including the drug Brilinta®, can increase risk of cardiovascular death or a myocardial infarction as a result of a basic disease (see the section "Special Instructions"). It is necessary to avoid the premature termination of administration of drug.
Elderly patients
Dose adjustment is not required (see the section "Pharmacological Properties").
Patients with a renal failure
It is not required to adjust a drug dose at patients with a renal failure (see the section "Pharmacological Properties"). There is no information on use of the drug Brilinta® for patients on a hemodialysis therefore its use for these patients is not shown.
Patients with a liver failure
It is not required to adjust a drug dose at patients with a slight liver failure. Drug Brilinta® researches at patients with a moderate or heavy liver failure therefore its use at these patients is contraindicated were not conducted (see the sections "Pharmacological Properties" and "Contraindications").
Children
Safety and efficiency of the drug Brilinta® at children are younger than 18 years according to the indication approved at adults is not established.
Features of use:
Risk of development of bleeding
At the patients with an acute coronary syndrome receiving therapy by the drug Brilinta® and acetylsalicylic acid the increased risk of the big bleedings and bleedings, untied with AKSh, requiring the increased medical attention such as big + small bleedings by PLATO definition, but the risk лелетальных / life-threatening bleedings did not increase was noted (see the section "Side effect").
At purpose of the drug Brilinta® it is necessary to estimate a ratio of advantage of prevention of aterotrombotichesky events and risk at patients with the increased risk of development of bleedings.
In the presence of clinical indications Brilinta® it has to be used with care in the following groups of patients:
Predisposition of patients to development of bleeding (for example, in connection with recently traumatized, recently performed operation, disturbances of coagulability of blood, active or recent gastrointestinal bleeding). Use of the drug Brilinta® is contraindicated at patients with active pathological bleeding, intracraneal hemorrhage in the anamnesis, a moderate or heavy liver failure.
The accompanying use of drugs which can increase risk of development of bleeding (for example, the non-steroidal anti-inflammatory drugs, peroral anticoagulants and/or fibrinolitik accepted within 24 hours before administration of drug of Brilinta®).
There are no data on haemo static efficiency of transfusions of thrombocytes at drug Brilinta® use; Брилинта® can inhibit transfuzirovanny thrombocytes in blood. As at the accompanying use of the drug Brilinta® and desmopressin the standardized bleeding time did not decrease, it is improbable that desmopressin will effectively stop bleeding.
Anti-fibrinolitic therapy (aminocapronic acid or traneksamovy acid) and/or recombinant factor of VIIa can strengthen a hemostasis. After establishment of the reason of bleeding and its stopping it is possible to resume therapy by the drug Brilinta®.
Surgeries
Before the planned operation or the beginning of reception of new drugs the patient should inform the doctor that it accepts the drug Brilinta®.
The patients who are exposed to aortocoronary shunting (AKSh), at use of the drug Brilinta® had the same frequency of development of big bleedings, as at use of a klopidogrel in all days after therapy cancellation, except day 1 when the frequency of development of big bleedings was higher at administration of drug of Brilinta® (see the section "Side effect").
If the patient is exposed to planned operation and the antitrombotichesky effect is not desirable, then therapy by the drug Brilinta® should be stopped in 7 days prior to operation.
Patients with risk of development of bradycardia
Due to the identification in earlier conducted clinical trial, generally asymptomatic pauses, patients with the increased risk of development of bradycardia (for example, patients without pacemaker for whom the sick sinus syndrome, an atrioventricular block of heart of the 2nd or 3rd degree is diagnosed; the syncope connected with bradycardia) were not included in the main research for assessment of safety and efficiency of the drug Brilinta®. Therefore in connection with limited clinical experience of use of drug for these patients, such patients are recommended to appoint with care the drug Brilinta® (see the section "Pharmacological Properties").
Additional precaution has to be observed at combined use of the drug Brilinta® with the drugs capable to cause bradycardia. However clinically significant side effects at combined use with one or more drugs which can cause bradycardia (for example, 96% beta adrenoblockers, 33% blockers of calcium channels, including diltiazem and verapamil, and 4% digoxin) were not noted (see the section "Interaction with Other Medicines and Other Types of Medicinal Interaction").
In the course under - researches with use of daily monitoring of an ECG on Holtera in group of ticagrelor in comparison with klopidogrely more than patients in an acute phase of the acute coronary syndrome (ACS) had ventricular pauses> 3 seconds. Increase in number of the ventricular pauses registered by means of daily monitoring on Holtera against the background of reception of ticagrelor was noted more often at patients with chronic heart failure in comparison with the general population in an acute phase of Construction Department, but not on the first month. Pauses at these patients were not followed by the subsequent undesirable clinical effects (faints and installation of a pacemaker).
Asthma
Asthma at drug Brilinta® use usually weak or moderate on the intensity, often passes in process of therapy continuation by drug. Patients with bronchial asthma / HOBL can have the raised absolute
risk of an asthma on administration of drug of Brilinta® (see the section "Side effect"). At patients with bronchial asthma / HOBL ticagrelor has to be used with care. The asthma mechanism on reception of ticagrelor is not found out. If at the patient the new episode of an asthma developed, an asthma remains or amplified during drug Brilinta® use, then it is necessary to conduct full examination, and in case of intolerance, administration of drug should be stopped.
Increase in level of creatinine
On administration of drug of Brilinta® the level of creatinine can increase (see the section "Side effect"). The mechanism of this effect is not known. Assessment of renal function needs to be made in a month from the beginning of administration of drug, and in the subsequent according to routine clinical practice, paying special attention to patients of 75 years and is more senior, patients with a moderate or heavy renal failure and the angiotensin receptors receiving therapy by antagonists.
Increase in level of uric acid
Patients on ticagrelor had higher risk of a hyperuricemia, than accepting klopidogret (see the section "Side effect"). It is necessary to be careful at patients with a hyperuricemia or gouty arthritis in the anamnesis. As a preventive measure it is necessary to avoid use of ticagrelor for patients with a giperurikemichesky nephropathy.
Others
On the basis of observed interaction between a maintenance dose of acetylsalicylic acid and efficiency of ticagrelor in comparison with klopidogrely, combined use of a high maintenance dose of acetylsalicylic acid (more than 300 mg) and the drug Brilinta® is not recommended (see the sections "Pharmacological Properties", "With Care").
Combined use of the drug Brilinta® with powerful CYP3A4 inhibitors (for example, кетоконазол, кларитромицин, нефазодон, ритонавир and атазанавир) is contraindicated (see the section "Contraindications") as it can lead to substantial increase of exposure of the drug Brilinta® (see the section "Interaction with Other Medicines and Other Types of Medicinal Interaction").
Combined use of the drug Brilinta® with the powerful inductors CYP3A4 (for example, rifampicin, dexamethasone, Phenytoinum, carbamazepine and phenobarbital) is not recommended as their joint reception can reduce exposure and efficiency of ticagrelor (see the section "Interaction with Other Medicines and Other Types of Medicinal Interaction").
Combined use of the drug Brilinta® and CYP3A4 substrates with a narrow therapeutic index (for example, цизаприд and ergot alkaloids) is not recommended as ticagrelor can increase exposure of these drugs. Combined use of the drug Brilinta® with simvastatiny or lovastatiny in a dose more than 40 mg is not recommended (see the section "Interaction with Other Medicines and Other Types of Medicinal Interaction").
At combined use of digoxin and the drug Brilinta® careful clinical and laboratory monitoring is recommended (heart rate, and in the presence of clinical indications also of an ECG and concentration of digoxin in blood).
There are no data on combined use of ticagrelor with powerful inhibitors of a glycoprotein of P (for example, verapamil, quinidine and cyclosporine) which can increase ticagrelor exposure. If it is impossible to avoid their combined use, it has to be carried out with care (see the sections "With Care", "Interaction with Other Medicines and Other Types of Medicinal Interaction").
INFLUENCE ON ABILITY TO DRIVE THE CAR AND OTHER MECHANISMS
Researches of influence of the drug Brilinta® on ability to driving of motor transport and control of mechanisms were not conducted. Брилинта® does not influence or in insignificant degree influences ability to manage transport and mechanisms. During therapy of an acute coronary syndrome it was reported about dizziness and confusion of consciousness. In case of development of these phenomena patients should be careful when driving and other mechanisms.
Side effects:
According to the research PLATO the most frequent noted undesirable phenomena the patients accepting ticagrelor had a short wind, bruises and nasal bleedings.
Undesirable reactions are classified by the frequency of development and a class of system of bodies. Frequency of development of undesirable reactions decides on use of the following symbols: very often (≥1/10), it is frequent (≥1/100, 1/10), infrequently (≥1/1000, 1/100), is rare (≥1/10000, 1/1000)
Undesirable medicinal reactions on the frequency of development and a class of system of bodies (SOC)
System of bodies Often Infrequently Seldom
Metabolism and food Hyperuricemia
Nervous system Intracranial Paresthesia
krovoizliyaniyeb, Confusion
headache, consciousnesses
dizziness
Hemorrhage organs of sight
(intraocular,
conjunctival,
retinal)
Acoustic organs Hemorrhage in
ear, вертиго
Respiratory Asthma system, Pneumorrhagia
nasal
bleeding
Digestive Gastro Vomiting with Retroperitonialnoye's blood
system intestinal bleedings from bleeding, a lock
krovotecheniyad ZhKTe ulcers, gemor-
roidalny bleedings,
gastritis, bleedings in
oral cavity (including
gingivalny bleedings),
vomiting, diarrhea, abdominal
pain, nausea, dyspepsia
Skin and hypodermic Hypodermic or Rash, itch
fabrics skin gemorragiif
sinyakig
Musculoskeletal Hemarthrosis
system
Urinary Bleeding from
system urinary puteyh
Reproductive Vaginal
system of bleeding
(including metrorrhagias)
Deviations Increase
laboratory concentration
creatinine indicators in blood
Other Bleeding on Bleeding Bleeding from
the venue after the procedure of a wound,
protseduryi traumatic
bleeding
an a hyperuricemia, increase in concentration of uric acid in blood; you watch the section "Deviations in Values of Laboratory Indicators" below.
b hematencephalon, intracraneal hemorrhage, hemorrhagic stroke.
with an asthma, an asthma at loading, an asthma at rest, a night asthma
d gastrointestinal bleeding, rectal bleeding, intestinal bleeding, a melena, the positive analysis on the occult blood
e a GIT helcomenia, a stomach helcomenia, a duodenum helcomenia, bleeding from a round ulcer
f hypodermic hematoma, skin and hypodermic hemorrhages, petechias
g a bruise, a hematoma, an ecchymoma, the raised tendency to bruises, a traumatic hematoma
h a hamaturia, bleeding from urinary tract
i bleeding from the place of a puncture of a vessel, a hematoma in the place of a puncture of a vessel, bleeding from the place of an injection, bleeding from the place of a puncture, bleeding from the place of catheterization
Description of some undesirable reactions
Bleeding
In the research PLATO the following definitions of bleeding were used:
Big lethal/life-threatening bleeding: lethal, either intracraneal hemorrhage, or bleeding in a pericardium cavity with a cardiac tamponade; either the hypovolemic shock or heavy hypotonia caused by bleeding and demanding use of vasoconstrictors or performing surgery, or clinically explicit
the bleeding which is followed by decrease in level of hemoglobin more, than on 50 g/l, or 4 or more units of whole blood demanding a transfusion or erythrocytes.
Big other bleeding: causing essential incapacity of the patient (for example, intraocular hemorrhage with irreversible loss of sight), or clinically explicit bleeding which is followed by decrease in level of hemoglobin by 30 - 50 g/l, or demanding a transfusion of 2-3 units of whole blood or erythrocytes.
Small bleeding: demands medical intervention for a stop or treatment of bleeding (for example, the nasal bleeding demanding visit of hospital for a nose tamponade).
Брилинта® also klopidogret did not differ on the frequency of big bleedings in general by criteria of PLATO (11,6%/year and 11,2%/year, respectively), lethal/life-threatening bleedings by criteria of PLATO (5,8%/year in both groups). However the frequency of set of big and small bleedings by criteria of PLATO was higher in group of ticagrelor (16,1%) in comparison with klopidogrely (14,6%, р =0,0084).
Age, sex, body weight, race, the geographical region, associated diseases, the accompanying therapy, the anamnesis, including the previous stroke and the tranzitorny ischemic attack, did not influence the frequency of big bleedings in general and untied with procedures for criteria of PLATO. Groups with the increased risk of bleedings were not revealed.
The bleeding connected with AKSh: In the research PLATO at 42% of the patients from 1584 (12% from a cohort) subjected to AKSh developed big lethal / life-threatening sick bleeding without significant distinctions in both groups of treatment. The lethal bleeding connected with AKSh was noted at 6 patients in each group of treatment.
The bleeding which is not connected with AKSh, and the bleeding which is not connected with procedures: Брилинта® also klopidogret did not differ on the frequency of cases of the big lethal / life-threatening bleeding which is not connected with AKSh by criteria of PLATO, but at drug Brilinta® use big bleedings in general by definition of the research PLATO developed more often (4,5%/year in comparison with 3,8%/year; Ó =))))))). If to remove cases of development of the bleedings connected with AKSh in group of ticagrelor more bleedings (3,1%/year), than in group of a klopidogrel were noted (2,3%/year; Ó =))))))). Treatment termination
owing to bleedings, untied with the procedure, was more frequent against the background of ticagrelor (2,9%) in comparison with klopidogrely (1,2%, p <0,001).
Intracraneal hemorrhage: In group of ticagrelor more intracranial bleedings, untied with procedures (n=27 of bleedings at 26 patients, 0,3%), than in group of a klopidogrel (n=14 of bleedings, 0,2%) developed from which 11 bleedings on ticagrelor and 1 on the klopidogrel were fatal. However there were no significant distinctions on total number of fatal bleedings.
Asthma
The undesirable phenomena in the form of an asthma (an asthma, an asthma at rest, an asthma at an exercise stress, a paroxysmal night asthma and a night asthma) developed in combinations at 13,8% of the patients receiving the drug Brilinta® and at 7,8% of the patients accepting klopidogret. Researchers considered that at 2,2% of patients from group of ticagrelor an asthma was connected with therapy. The majority of cases of an asthma were weak or moderate on the intensity and represented single episodes right after the beginning of therapy.
About 30% of all cases of an asthma were resolved within 7 days. More often an asthma developed at elderly patients, at patients with congestive heart failure, HOBL or bronchial asthma at the beginning of the research. 0,9% of patients stopped administration of drug of Brilinta® because of an asthma. An asthma was not connected with development new or deterioration in the available heart disease or lungs (see the section "Special Instructions").
The drug Brilinta® does not influence indicators of function of external respiration.
Deviations in values of laboratory indicators
Serumal concentration of creatinine increased more, than by 30% at 25,5% of patients and more, than for 50% at 8,3% of the patients receiving the drug Brilinta®. Increase in creatinine more, than for 50%, met at patients more often 75 years, at patients with a heavy renal failure are more senior at inclusion in a research and at the patients receiving therapy by antagonists of receptors to angiotensin. Total number of the renal undesirable phenomena made 4,9% at patients on ticagrelor, however researchers connected them with administration of drug in 0,6% of cases.
Serumal concentration of uric acid increased above the upper bound of norm at 22% of the patients receiving the drug Brilinta®. The undesirable phenomena connected with a hyperuricemia were noted in 0,5% of cases on ticagrelor, from them researchers connected with ticagrelor reception
0,05% of cases. Gouty arthritis was observed at 0,2% of patients on ticagrelor, any of these cases was not regarded by the researcher as connected with administration of drug.
Interaction with other medicines:
Impact of other medicines on the drug Brilinta®
Medicines, metaboliziruyemy CYP3A4 isoenzyme
CYP3A4 inhibitors
Powerful CYP3A4 inhibitors: combined use of a ketokonazol with ticagrelor increases Cmax and AUC ticagrelor in 2,4 and 7,3 times, respectively. Cmax and AUC of an active metabolite goes down for 89% and 56%, respectively. Other powerful CYP3A4 inhibitors (кларитромицин, нефазодон, ритонавир and атазанавир) will render the same effects therefore their combined use with the drug Brilinta® is contraindicated (see sections of "Contraindication", "Special Instructions").
Moderate CYP3A4 inhibitors: combined use of diltiazem with ticagrelor increases ticagrelor Cmax by 69%, and AUC by 2,7 times, and lowers Cmax of an active metabolite by 38%, and AUC does not change. Ticagrelor
does not influence plasma concentration of diltiazem. It is possible to appoint other moderate CYP3A4 inhibitors (for example, ампренавир, an aprepitant, erythromycin, флуконазол) along with the drug Brilinta®.
Inductors CYP3A4
Combined use of rifampicin with ticagrelor lowers Cmax and AUC ticagrelor by 73% and 86%, respectively. Cmax of an active metabolite does not change, and AUC goes down for 46%. Other inductors CYP3A4 (for example, dexamethasone, Phenytoinum, carbamazepine and phenobarbital), apparently, will reduce drug Brilinta® exposure. The powerful inductors CYP3A4 can reduce exposure and efficiency of the drug Brilinta®.
Others
By results of pharmacological researches of interaction the accompanying use of ticagrelor with heparin, enoksapariny and acetylsalicylic acid or desmopressin does not influence pharmacokinetics of ticagrelor, its active metabolite and ADF-zavisimuyu aggregation of thrombocytes. In case of existence of clinical indications to purpose of the drugs influencing a hemostasis they have to be used with care in a combination with the drug Brilinta® (see the section "With Care").
There are no data on combined use of the drug Brilinta® with powerful inhibitors of a glycoprotein of P (for example, verapamil, quinidine and cyclosporine) which can increase ticagrelor exposure. If it is impossible to avoid their combined use, it has to be carried out with care (see the sections "With Care", "Special Instructions").
Influence of the drug Brilinta® on other medicines
Medicines, metaboliziruyemy CYP3A4 isoenzyme
Simvastatin: the accompanying use of ticagrelor and a simvastatin raises Cmax and AUC of a simvastatin for 81% and 56%, respectively, and increases Cmax and AUC of simvastatinovy acid by 64% and 52%, respectively, at the same time, in certain cases these indicators raise by 2-3 times. Combined use of a simvastatin in a dose can lead higher than 40 mg/days with ticagrelor to development of side effects of a simvastatin, and it is necessary to estimate a ratio of potential risk and advantage. Combined use of the drug Brilinta® with simvastatiny and lovastatiny in a dose over 40 mg is not recommended. Atorvastatin: the accompanying use of an atorvastatin and ticagrelor raises Cmax and
AUC of metabolites of atorvastatinovy acid for 23% and 36%, respectively. Similar increase in Cmax and AUC values is observed for all metabolites of atorvastatinovy acid. These changes are recognized clinically not as significant.
Similar effects with the statines which are metabolized CYP3A4 cannot be excluded. In the research PLATO the patients receiving ticagrelor accepted various statines in the absence of any fears concerning safety at 93% of the patients accepting this group of drugs.
Ticagrelor – moderate CYP3A4 inhibitor. Combined use of the drug Brilinta® and CYP3A4 substrates with a narrow therapeutic index (for example, цизаприд or ergot alkaloids) is not recommended as ticagrelor can increase exposure of these drugs.
Medicines, metaboliziruyemy CYP2C9 isoenzyme
The accompanying use of ticagrelor and Tolbutamidum did not change plasma concentration of any of these drugs that says that ticagrelor is not CYP2C9 isoenzyme inhibitor, and, it is improbable that it influences CYP2C9 - the mediated metabolism of drugs, similar to warfarin and Tolbutamidum.
Oral contraceptives
Combined use of ticagrelor, levonorgestrel and ethinylestradiol increases ethinylestradiol exposure approximately by 20%, but does not influence levonorgestrel pharmacokinetics. Clinically significant impact on efficiency of contraception at simultaneous use of levonorgestrel, ethinylestradiol and the drug Brilinta® is not expected.
Substrate of a glycoprotein of P (P-gp) (including digoxin and cyclosporine)
The accompanying use of digoxin with ticagrelor raises Cmax and AUC digoxin for 75% and 28%, respectively. At joint reception with ticagrelor on average the lowest level of digoxin increased by 30%, in some individual cases twice. Cmax and AUC ticagrelor at use of digoxin did not change. Therefore it is recommended to carry out the corresponding clinical and/or laboratory monitoring at simultaneous use of the drug Brilinta® and P-gp-dependent of drugs with a narrow therapeutic index, like digoxin and cyclosporine.
Other accompanying therapy
At combined use of the drug Brilinta® with the drugs capable to cause bradycardia, it has to be careful. However in the research PLATO clinically significant undesirable phenomena at combined use with one or more drugs capable to cause bradycardia (for example, 96% beta adrenoblockers, 33% antagonists of calcium, including diltiazem and verapamil, and 4% - digoxin) were not observed.
In the research PLATO Brilinta® it was preferential appointed together with acetylsalicylic acid, inhibitors of a proton pomp, statines, beta adrenoblockers, inhibitors of an angiotensin-converting enzyme and antagonists of receptors of angiotensin within long reception, and also with heparin, low-molecular heparins, inhibitors of glycoprotein IIb/IIIa of receptors for intravenous administration within short-term therapy. By results of these researches clinically significant undesirable interactions are not revealed.
Combined use of the drug Brilinta® with heparin, enoksapariny or desmopressin did not exert impact on the activated partial tromboplastinovy time (APTT), the activated coagulation time (ACT) and a research of a factor Xa, however owing to potential pharmakodinamichesky interaction, it is required to be careful at combined use with the drugs influencing a hemostasis.
In connection with the messages on hypodermic hemorrhages against the background of selective serotonin reuptake inhibitors (for example, пароксетин, sertraline and to tsitalopra), it is recommended to be careful at their joint reception with the drug Brilinta®.
Contraindications:
Hypersensitivity to ticagrelor or any of drug components
Active pathological bleeding
Intracraneal hemorrhage in the anamnesis
Moderate or heavy liver failure
Combined use of ticagrelor with powerful CYP3A4 inhibitors (for example, ketokonazoly, klaritromitsiny, nefazodony, ritonaviry and atazanaviry)
Children's age up to 18 years (due to the lack of data on efficiency and safety of use for this group of patients)
WITH CARE
Predisposition of patients to development of bleeding (for example, in connection with recently traumatized, recently performed operation, disturbances of coagulability of blood, active or recent gastrointestinal bleeding) (see the section "Special Instructions").
Patients with the accompanying therapy by the drugs increasing risk of bleedings (i.e. non-steroidal anti-inflammatory drugs, peroral anticoagulants and/or fibrinolitik) within 24 hours before administration of drug of Brilinta®.
Patients with the increased risk of development of bradycardia (for example, patients with a sick sinus syndrome without pacemaker, with an atrioventricular block of the 2nd or 3rd degree; the faint connected with bradycardia) in connection with insufficient experience of a clinical use of the drug Brilinta® (see the section "Special Instructions"). At combined use with the drugs causing bradycardia.
Ticagrelor has to be used with care at patients with bronchial asthma and the chronic obstructive pulmonary disease (COPD). If the patient reports about emergence of a new episode of an asthma, about a long asthma or deterioration in an asthma, it is necessary to conduct examination, and in case of intolerance, treatment by ticagrelor has to be stopped.
Against the background of administration of drug of Brilinta® the level of creatinine can increase (see the sections "Side Effect", "Special Instructions") in this connection it is necessary to make assessment of renal function according to routine clinical practice, paying special attention to patients of 75 years and is more senior, patients with a moderate or heavy renal failure, than the patients receiving therapy by antagonists of receptors to angiotensin.
It is necessary to be careful at patients with a hyperuricemia or gouty arthritis in the anamnesis. As a preventive measure it is necessary to avoid use of ticagrelor for patients with a giperurikemichesky nephropathy.
Combined use of ticagrelor and high maintenance dose of acetylsalicylic acid (more than 300 mg) is not recommended.
At combined use of digoxin and the drug Brilinta® careful clinical and laboratory monitoring is recommended (frequencies of cordial
reductions, and in the presence of clinical indications also an ECG and concentration of digoxin in blood).
There are no data on combined use of ticagrelor with powerful inhibitors of a glycoprotein of P (for example, verapamil, quinidine and cyclosporine) in this connection their combined use has to be carried out with care (see the section "Interaction with Other Medicines and Other Types of Medicinal Interaction").
PREGNANCY AND PERIOD OF THE LACTATION
Data on use of the drug Brilinta® for pregnant women are absent or are limited.
In researches on animals ticagrelor caused insignificant decrease in an increase of body weight in mother, decrease in viability of the newborn and his body weight, growth delay. Брилинта® it is not recommended during pregnancy.
Available pharmakodinamichesky, toxicological data at animals showed that ticagrelor and its active metabolites are emitted with milk. The risk for the newborn/baby cannot be excluded. It is not recommended to use the drug Brilinta® during feeding of the child a breast.
Overdose:
Ticagrelor is well transferred in a single dose of drug to 900 mg. In the only research with increase in a dose an adverse effect on digestive tract was dozolimitiruyushchy. An asthma and ventricular pauses were other clinically significant undesirable phenomena which could be observed at overdose. In case of overdose it is recommended to carry out observation regarding these undesirable phenomena and to carry out monitoring of an ECG.
Брилинта® it is not removed at a hemodialysis (see the section "Special Instructions"), the antidote is not known. At overdose it is necessary to carry out symptomatic therapy according to local standards. Due to the inhibition of thrombocytes increase in duration of bleeding is alleged pharmacological action of overdose by the drug Brilinta® therefore at development of bleeding it is necessary to hold the relevant supporting activities.
Storage conditions:
At a temperature not above 30 °C, in the place, unavailable to children. Period of validity 3 years. Not to apply after the period of validity specified on packaging.
Issue conditions:
According to the recipe
Packaging:
Tablets, film coated, 90 mg.
On 14 tablets in the blister from PVC/PVDH Is scarlet/. 1, 4 or 12 blisters with the instruction on a medical use in a cardboard pack with control of the first opening.
