Brilinta, 60 mg 168 pcs

Pharmacotherapeutic group: anti-aggregant

ATX code: B01AC24

Pharmacological properties

Mechanism of action

The drug Brilinta^® contains ticagrelor, a member of the cyclopentyltriazolopyrimidine chemical class, which is an oral, selective and reversible direct-acting P2Y12 receptor antagonist and prevents adenosine diphosphate-mediated P2Y12-dependent platelet activation and aggregation. Ticagrelor does not prevent adenosine diphosphate (ADP) binding, but its interaction with the P2Y12 receptor of platelets prevents ADP-induced signal transduction. Because 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 cardiovascular death, myocardial infarction or stroke.

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

Adenosine is formed locally at sites of hypoxia and tissue damage by release from adenosine triphosphate and ADP. Because adenosine cleavage is essentially limited to the intracellular space, inhibition of ENT-1 by ticagrelor prolongs the half-life of adenosine and thereby increases its local extracellular concentration, enhancing the local adenosine response. Ticagrelor has no clinically significant direct effect on adenosine receptors (A1, A2A, A2B, A3) and is not metabolized to adenosine. Adenosine has several effects that include: vasodilation, cardioprotection, inhibition of platelet aggregation, modulation of inflammation and onset of dyspnea, which may affect the clinical profile of ticagrelor.

Ticagrelor has been shown to enhance the following effects of adenosine in healthy volunteers and in patients with acute coronary syndrome (ACS): vasodilation (assessed as increased coronary blood flow in healthy volunteers and in patients with ACS), inhibition of platelet function (in vitro in human whole blood), and dyspnea. However, the association of elevated local concentrations of adenosine with clinical outcomes (e.g., morbidity and mortality rates) has not been proven.

Pharmacodynamics

Beginning of action

In patients with stable coronary heart disease (CHD) against the background of acetylsalicylic acid (ASA), ticagrelor has a rapid onset of action, as evidenced by determination of the mean value of platelet aggregation inhibition (PIAT): 0.5 hours after a loading dose of 180 mg of ticagrelor, the average IAT value is approximately 41%; the maximum IAT value of 89% is reached 2-4 hours after drug administration and maintained for 2-8 hours. In 90% of patients the final IAT value of more than 70% is reached 2 hours after taking the drug.

End of action

In planning for aortocoronary bypass surgery (ACB), the risk of bleeding increases if ticagrelor is stopped less than 96 hours before the procedure.

Data on switching from one drug to another

The switch from clopidogrel 75 mg once daily to Brilinta^® 90 mg twice daily results in a 26.4% increase in absolute IAT, and changing therapy from ticagrelor to clopidogrel results in a 24.5% decrease in absolute IAT. Therapy can be changed from clopidogrel to ticagrelor without interruption of the antithrombotic effect (see section “Dosage and administration”).

Clinical efficacy and safety

strong>The PLATO (acute coronary syndrome)

. The PLATO study included 18624 patients who developed symptoms of unstable angina, myocardial infarction without ST-segment elevation, or myocardial infarction with ST-segment elevation within the past 24 hours and were treated conservatively or by percutaneous coronary intervention (PCI) or CABG. On daily ASA therapy, ticagrelor 90 mg twice daily was compared with clopidogrel 75 mg daily for efficacy in preventing the combined endpoint of cardiovascular death, myocardial infarction or stroke by affecting the incidence of cardiovascular death and myocardial infarction.

The PEGASUS Study (history of myocardial infarction)

. The PEGASUS TIMI-54 trial involving 21,162 patients was conducted to evaluate the prevention of atherothrombotic complications with ticagrelor 90 mg twice daily or 60 mg twice daily in combination with low-dose ASA compared with ASA monotherapy in patients with a history of myocardial infarction.

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

The drug Brilinta^® 60 mg twice daily and 90 mg twice daily in combination with ASA was effective in preventing atherothrombotic complications (combined endpoints of cardiovascular death, myocardial infarction and stroke), with maintenance of consistent therapy effect throughout the study period, resulting in a 16% reduction in relative risk (RR) and a 1.27% reduction in absolute risk (AR) with ticagrelor 60 mg and a 15% reduction in RR and 1.19% reduction in AR with ticagrelor 90 mg.

With comparable efficacy of ticagrelor 90 mg and 60 mg, ticagrelor 60 mg showed better tolerability and safety profile with respect to risk of bleeding and dyspnea.

The drug Brilinta^® 60 mg twice daily significantly reduced the primary combined endpoint of cardiovascular death, myocardial infarction and stroke, with reductions in each of its components: cardiovascular death SOR by 17%, myocardial infarction SOR by 16% and stroke SOR by 25%.

Ticagrelor 60 mg in combination with ASA reduced cardiovascular and all-cause mortality, although statistical significance was not achieved.

The efficacy of Brilinta^® 60 mg twice daily has been demonstrated in various subgroups of patients, regardless of body weight, sex, history, region, and is independent of the use of other cardiovascular agents, including hypolipidemic drugs, beta-adrenoblockers, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonists, slow calcium channel blockers, nitrates and proton pump inhibitors (see section “Interaction with other medicinal products”).

The THEMIS Study (Coronary Heart Disease and Type 2 Diabetes) The THEMIS Study involving 19220 patients was conducted to evaluate the prevention of atherothrombotic events with Brilinta® in combination with low-dose ASA compared to ASA monotherapy in patients with CHD and type 2 diabetes mellitus (DM2).

. The study included patients aged 50 years or older with CHD defined as a history of PCI (58% of the study population) or a history of ACE (29%) or without a history of coronary revascularization but with angiographically confirmed lumen stenosis ≥50% of at least 1 coronary artery (20%), and with DM2 who had received therapy with a hypoglycemic drug for at least 6 months before study entry. Patients with a history of myocardial infarction or stroke were not included in the study. In the overall THEMIS trial population, Brilinta^® twice daily in combination with ASA was effective in preventing atherothrombotic events (combined endpoint: cardiovascular death, myocardial infarction, and stroke) compared with ASA: hazard ratio (HR) 0.90 (95% confidence interval (CI): 0.81, 0.99, p=0.0378), corresponding to an OR of 10% and an ATS of 0.73%. The effect was attributable to reductions in individual components of the combined end point, myocardial infarction and stroke, with no difference for cardiovascular death.

In patients in the THEMIS trial who underwent PCI (n=11154), Brilinta^® therapy in combination with ASA compared with ASA monotherapy resulted in prevention of atherothrombotic events (combined endpoint: cardiovascular death, myocardial infarction and stroke): OR 0.85 (95% CI: 0.74, 0.97; nominal value p=0.0133), corresponding to an OR of 15%, CAP of 1.19% with a more favorable benefit-risk ratio than in the overall THEMIS study population. Brilinta^® therapy in combination with ASA compared with ASA monotherapy had fewer events for each component of the combined endpoint (cardiovascular death: 174 (3.1%) versus 183 (3.3%), OR 0.96 (95% CI 0.78, 1.18); myocardial infarction: 171 (3.1%) versus 216 (3.9%), OR 0.80 (95% CI 0.65, 0.97); stroke: 96 (1.7%) versus 131 (2.3%), OR 0.74 (95% CI 0.57, 0.96)).

The effect of Brilinta^® therapy was comparable in patient subgroups formed based on patient characteristics, including body weight, gender, medical history, and geographic region.

Pharmacokinetics

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

Absorption

Ticagrelor is rapidly absorbed with a median Tmax of approximately 1.5 hours. Formation of the major circulating blood metabolite AR-C124910XX (also active) from ticagrelor is rapid with a median Tmax of approximately 2.5 hours. After an empty stomach dose of 90 mg of ticagrelor, Cmax is 529 ng/ml and AUC is 3451 ng*h/ml. The ratio of Cmax and AUC of the metabolite to ticagrelor is 0.28 and 0.42, respectively.

The average absolute bioavailability of ticagrelor is 36%. Fatty food intake results in a 21% increase in the AUC of ticagrelor and a 22% decrease in the Cmax of the active metabolite, but has no effect on the Cmax of ticagrelor or the AUC of the active metabolite. These small changes are of minimal clinical significance; therefore, ticagrelor can be administered regardless of food intake.

Ticagrelor as a suspension of crushed tablets in drinking water taken orally or administered to the stomach through a nasogastric tube is bioequivalent to ticagrelor taken orally as Brilinta tablets^® (AUC and Cmax of ticagrelor and the active metabolite range 80-125%). Initial exposure (0.5 and 1 hour after ingestion) was higher when taking the suspension than when taking ticagrelor as Brilinta^® tablets, but the concentration profile was essentially the same thereafter (2 to 48 hours).

Distribution

The volume of distribution of ticagrelor in equilibrium is 87.5 L. Ticagrelor and the active metabolite are actively bound to plasma proteins (> 99.0%).

Biotransformation

CYP3A4 is the major isoenzyme responsible for metabolizing ticagrelor and forming the active metabolite, and their interactions with other CYP3A substrates range from activation to inhibition. Ticagrelor and the active metabolite are weak inhibitors of glycoprotein P (P-gp).

The major metabolite of ticagrelor is AR-C124910XX, which is also active as evidenced by the results of an evaluation of binding to the P2Y12 receptor of platelet ADP in vitro. The systemic exposure of the active metabolite is approximately 30-40% of that of ticagrelor.

Elimation

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

Special patient populations Elderly patients

. Elderly patients (aged 75 years and older) with ACS showed higher exposure to ticagrelor (Cmax and AUC about 25% higher) and the active metabolite compared with younger patients. These differences are not considered clinically significant (see section “Dosage and administration”).

Children

Ticagrelor has not been evaluated in children (see section on Contraindications).

Gender

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

Kidney function impairment

The exposure of ticagrelor is approximately 20% lower and its active metabolite approximately 17% higher in patients with severe renal impairment (creatinine clearance < 30 ml/min) compared to patients with normal renal function.

In patients with terminal renal failure on hemodialysis, the AUC and Cmax of Brilinta^® 90 mg received daily without dialysis were 38% and 51% higher, respectively, compared to patients with normal renal function. A similar increase in exposure was noted when Brilinta^® was used immediately prior to dialysis, showing that Brilinta^® is not dialyzed. Exposure to the active metabolite was increased to a lesser extent. In patients with terminal renal failure, the effect of Brilinta^® on IAT was independent of dialysis and was similar to that observed in patients with normal renal function (see section “Administration and Doses”).

Hepatic dysfunction

. The Cmax and AUC of ticagrelor were 12% and 23% higher in patients with mild hepatic impairment compared to healthy volunteers, but the effect of Brilinta^® on IAT was comparable in both groups. No dose adjustment is required in patients with mild hepatic dysfunction. No studies have been performed on ticagrelor in patients with severe hepatic impairment, and there is no information about pharmacokinetic parameters in patients with moderate hepatic impairment (see sections

“Contraindications”, “Dosage and administration” and “Cautions”).

Ethnic groups

The average bioavailability of the drug in Asian patients is 39% higher than in Caucasian patients. The bioavailability of ticagrelor was 18% lower in non-Hispanic patients compared with Caucasian patients, and in clinical pharmacology studies, the exposure (Cmax and AUC) of ticagrelor was approximately 40% (20% after adjustment for body weight) higher in Japanese than in Caucasians. Exposure in Hispanic or Latino patients was similar to that in Caucasians.

Indications

Brilinta®, used simultaneously with acetylsalicylic acid, is indicated:

• for the prevention of atherothrombotic complications in adult patients with a history of myocardial infarction (myocardial infarction suffered one year or more ago) and a high risk of atherothrombotic complications;

• for the prevention of atherothrombotic complications in patients aged 50 years and older with coronary heart disease and type 2 diabetes mellitus, without a history of myocardial infarction and (or) stroke, who have undergone percutaneous coronary intervention (PCI).

Pharmacological effect

Pharmacotherapeutic group: antiplatelet agent

ATX code: B01AC24

Pharmacological properties

Mechanism of action

Brilinta® contains ticagrelor, a member of the cyclopentyltriazolopyrimidine chemical class, which is an oral, selective and reversible direct-acting P2Y12 receptor antagonist and prevents adenosine diphosphate-mediated P2Y12-dependent platelet activation and aggregation. Ticagrelor does not prevent adenosine diphosphate (ADP) binding, but its interaction with the P2Y12 platelet receptor prevents ADP-induced signal transduction. Because 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 cardiovascular death, myocardial infarction, or stroke.

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

Adenosine is formed locally in areas of hypoxia and tissue damage by release from adenosine triphosphate and ADP. Because adenosine degradation is essentially limited to the intracellular space, inhibition of ENT-1 by ticagrelor prolongs the half-life of adenosine and thereby increases its local extracellular concentration, enhancing the local adenosine response. Ticagrelor has no clinically significant direct effect on adenosine receptors (A1, A2A, A2B, A3) and is not metabolized to adenosine. Adenosine has several effects that include vasodilation, cardioprotection, inhibition of platelet aggregation, modulation of inflammation and dyspnea, which may influence the clinical profile of ticagrelor.

In healthy volunteers and patients with acute coronary syndrome (ACS), ticagrelor has been shown to potentiate the following effects of adenosine: vasodilation (assessed as an increase in coronary blood flow in healthy volunteers and patients with ACS), inhibition of platelet function (in vitro in human whole blood), and dyspnea. However, 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 coronary artery disease (CHD) on the background of the use of acetylsalicylic acid (ASA), ticagrelor begins to act quickly, which is confirmed by the results of determining the average value of platelet aggregation inhibition (IAT): 0.5 hours after taking a loading dose of 180 mg of ticagrelor, the average IAT value is approximately 41%, the maximum IAT value of 89% is achieved 2-4 hours after taking the drug and is maintained for 2-8 hours. In 90% of patients, the final IAT value of more than 70% is achieved 2 hours after taking the drug.

End of action

When planning coronary artery bypass grafting (CABG), the risk of bleeding increases if ticagrelor is stopped less than 96 hours before the procedure.

Data on switching from one drug to another

Switching from clopidogrel 75 mg once daily to Brilinta® 90 mg twice daily leads to an increase in the absolute value of IAT by 26.4%, and changing therapy from ticagrelor to clopidogrel leads to a decrease in the absolute value of IAT by 24.5%. You can change therapy from clopidogrel to ticagrelor without interrupting the antithrombotic effect (see section “Method of administration and dosage”).

Clinical efficacy and safety

PLATO Study (Acute Coronary Syndrome)

The PLATO study included 18,624 patients who developed symptoms of unstable angina, non-ST-segment elevation myocardial infarction, or ST-segment elevation myocardial infarction in the past 24 hours and were treated conservatively or with percutaneous coronary intervention (PCI) or CABG. During daily ASA therapy, ticagrelor 90 mg twice daily was compared with clopidogrel 75 mg daily for effectiveness in preventing the composite endpoint of cardiovascular death, myocardial infarction, or stroke through its effect on the incidence of cardiovascular death and myocardial infarction.

PEGASUS study (history of myocardial infarction)

The PEGASUS TIMI-54 study, involving 21,162 patients, was conducted to evaluate the prevention of atherothrombotic complications when using ticagrelor 90 mg twice daily or 60 mg twice daily in combination with low-dose ASA compared with ASA alone in patients with a history of myocardial infarction.

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

Brilinta 60 mg twice daily and 90 mg twice daily in combination with ASA was effective in preventing atherothrombotic complications (the composite endpoint of cardiovascular death, myocardial infarction and stroke), maintaining a constant treatment effect throughout the study period, resulting in a relative risk reduction (RRR) of 16% and an absolute risk reduction (ARR) of 16%. 1.27% when using ticagrelor 60 mg and a reduction in GOR by 15% and SAR by 1.19% when using ticagrelor 90 mg.

With comparable efficacy of ticagrelor 90 mg and 60 mg, ticagrelor 60 mg showed better tolerability and safety profile with respect to the risk of bleeding and shortness of breath.

Brilinta 60 mg twice daily significantly reduced the primary composite endpoint of cardiovascular death, myocardial infarction, and stroke, with each component reduced: RR for CV death by 17%, RR for myocardial infarction by 16%, and RR for stroke by 25%.

Ticagrelor 60 mg in combination with ASA reduced cardiovascular and all-cause death, although statistical significance was not achieved.

The effectiveness of Brilinta® 60 mg twice daily has been demonstrated in various subgroups of patients, regardless of body weight, gender, medical history, region, and is independent of the use of other cardiovascular drugs, including lipid-lowering drugs, beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonists, slow calcium channel blockers, nitrates and proton pump inhibitors (see section “Interaction with other drugs”).

THEMIS Study (Coronary Heart Disease and Type 2 Diabetes Mellitus) The THEMIS Study, involving 19,220 patients, was conducted to evaluate the prevention of atherothrombotic events when Brilinta® was used in combination with low-dose ASA compared with ASA monotherapy in patients with coronary artery disease and type 2 diabetes mellitus (T2DM).

The study included patients aged 50 years and older with coronary artery disease, defined as a history of PCI (58% of the study population) or a history of CABG (29%), or without a history of coronary revascularization, but with angiographically confirmed luminal stenosis ≥ 50% of at least 1 coronary artery (20%), and with T2DM, receiving therapy with a hypoglycemic drug for at least 6 months before the start of the study. Patients with a history of myocardial infarction or stroke were not included in the study. In the overall THEMIS study population, Brilinta® twice daily in combination with ASA was effective in preventing atherothrombotic events (composite endpoint of cardiovascular death, myocardial infarction and stroke) compared with ASA: hazard ratio (HR) 0.90 (95% confidence interval (CI): 0.81, 0.99, p = 0.0378), which corresponds to an RR of 10% and ATS at 0.73%. The effect was driven by reductions in the individual components of the composite endpoint, myocardial infarction and stroke, with no difference in cardiovascular death.

In THEMIS study patients undergoing PCI (n=11,154), treatment with Brilinta® in combination with ASA compared with ASA alone resulted in the prevention of atherothrombotic events (combined endpoint: cardiovascular death, myocardial infarction and stroke): RR 0.85 (95% CI: 0.74, 0.97; nominal value p=0.0133), which corresponds to a RR of 15%, a RR of 1.19%, with a more favorable benefit-risk ratio than in the overall THEMIS study population. When treated with Brilinta® in combination with ASA, compared with ASA monotherapy, fewer events were recorded for each of the components of the combined endpoint (cardiovascular death: 174 (3.1%) vs. 183 (3.3%), RR 0.96 (95% CI 0.78, 1.18); myocardial infarction: 171 (3.1%) vs. 216 (3.9%), RR 0.80 (95% CI 0.65, 0.97); stroke: 96 (1.7%) vs 131 (2.3%), RR 0.74 (95% CI 0.57, 0.96)).

The effect of treatment with Brilinta® was comparable in subgroups of patients based on patient characteristics, including body weight, gender, medical history and geographic region.

Pharmacokinetics

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

Absorption

Ticagrelor is rapidly absorbed with a median Tmax of approximately 1.5 hours. The formation of the main circulating metabolite AR-C124910XX (also active) from ticagrelor occurs rapidly with a median Tmax of approximately 2.5 hours. After taking ticagrelor on an empty stomach at a dose of 90 mg, Cmax is 529 ng/ml and AUC is 3451 ng*h/ml. The ratio of Cmax and AUC of the metabolite to ticagrelor is 0.28 and 0.42, respectively.

The average absolute bioavailability of ticagrelor is 36%. Ingestion of a high-fat meal results in a 21% increase in ticagrelor AUC and a 22% decrease in the Cmax of the active metabolite, but does not affect the Cmax of ticagrelor or the AUC of the active metabolite. These small changes are of minimal clinical significance; therefore, ticagrelor can be administered without regard to food intake.

Ticagrelor, as a suspension of crushed tablets in drinking water, taken orally or administered into the stomach through a nasogastric tube, is bioequivalent to ticagrelor taken orally as Brilinta® tablets (AUC and Cmax of ticagrelor and active metabolite in the range of 80-125%). In the case of taking the suspension, the initial exposure (0.5 and 1 hour after administration) was higher than when taking ticagrelor in the form of Brilinta® tablets, but subsequently (from 2 to 48 hours) the concentration profile was almost the same.

Distribution

The volume of distribution of ticagrelor at steady state is 87.5 L. Ticagrelor and the active metabolite are actively bound to plasma proteins (> 99.0%).

Biotransformation

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

The main metabolite of ticagrelor is AR-C124910XX, which is also active, as confirmed by the results of assessing binding to the P2Y12 platelet ADP receptor in vitro. Systemic exposure of the active metabolite is approximately 30-40% of the exposure of ticagrelor.

Removal

The main route of elimination of ticagrelor is through hepatic metabolism. When isotope-labeled ticagrelor is administered, on average, approximately 84% of the radioactivity is released (57.8% in feces, 26.5% in urine). Excretion of ticagrelor and the active metabolite in urine is less than 1% of the dose. The active metabolite is mainly excreted in bile. The mean half-lives of ticagrelor and the active metabolite were 7 and 8.5 hours, respectively.

Special patient populations Elderly patients

Elderly patients (aged 75 years and older) with ACS had higher exposure to ticagrelor (Cmax and AUC approximately 25% higher) and the active metabolite compared to younger patients. These differences are not considered clinically significant (see section “Dosage and Administration”).

Children

Ticagrelor has not been evaluated in children (see Contraindications section).

Floor

Women had higher exposure to ticagrelor and the active metabolite compared to men. These differences are not considered clinically significant.

Renal dysfunction

Exposure to ticagrelor is approximately 20% lower and its active metabolite approximately 17% higher in patients with severe renal impairment (creatinine clearance <30 mL/min) compared to patients with normal renal function.

In patients with end-stage renal failure on hemodialysis, the AUC and Cmax of Brilinta 90 mg received per day without dialysis were 38% and 51% higher, respectively, compared with patients with normal renal function. A similar increase in exposure was noted when Brilinta® was administered immediately before dialysis, indicating that Brilinta® is not dialyzable. Exposure to the active metabolite increased to a lesser extent. In patients with end-stage renal failure, the effect of Brilinta® on IAT did not depend on dialysis and was similar to that observed in patients with normal renal function (see section “Dosage and Administration”).

Liver dysfunction

Cmax and AUC of ticagrelor were 12% and 23% higher in patients with mild hepatic impairment compared with healthy volunteers, but the effect of Brilinta on IAT was comparable in both groups. No dose adjustment is required in patients with mild liver dysfunction. Ticagrelor has not been studied in patients with severe hepatic impairment and there is no information available on pharmacokinetics in patients with moderate hepatic impairment (see sections

“Contraindications”, “Method of administration and dosage” and “Special instructions”).

Ethnic groups

The average bioavailability of the drug in Asian patients is 39% higher than in Caucasian patients. Bioavailability of ticagrelor was 18% lower in black patients compared to Caucasian patients, and in clinical pharmacology studies, exposure (Cmax and AUC) to ticagrelor in Japanese subjects was approximately 40% (20% after adjustment for body weight) higher than in Caucasian subjects. Exposure in Hispanic or Latino patients was similar to that in Caucasians.

Special instructions

Risk of bleeding

When prescribing Brilinta® to patients with an increased risk of bleeding, the balance between the benefits of preventing atherothrombotic complications and the risk of bleeding should be assessed.

If clinically indicated, Brilinta® should be used with caution in the following situations:

Patients predisposed to bleeding (eg, due to recent trauma, recent surgery, bleeding disorders, moderate hepatic impairment, active or recent gastrointestinal bleeding) or patients at increased risk of injury. The use of Brilinta® is contraindicated in patients with active pathological bleeding, a history of intracranial hemorrhage, or severe liver dysfunction (see section “Contraindications”).
Concomitant use of drugs that may increase the risk of bleeding (for example, nonsteroidal anti-inflammatory drugs, oral anticoagulants and/or fibrinolytics taken within 24 hours before taking Brilinta®).

In a study in healthy volunteers, platelet transfusion did not reverse the antiplatelet effect of Brilinta and is likely to have no clinical effect in bleeding patients. Since the concomitant use of Brilinta® and desmopressin did not reduce the standardized bleeding time, it is unlikely that desmopressin will effectively stop clinically significant bleeding (see section “Interaction with other drugs”).

Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa therapy may enhance hemostasis. Once the cause of the bleeding has been determined and it has been controlled, ticagrelor therapy can be resumed.

Surgical interventions

Before a planned operation or starting to take new medications, the patient should inform the doctor that he is taking Brilinta®.

In the PLATO study, in patients undergoing CABG, Brilinta® had more bleeding compared with clopidogrel when discontinuing therapy one day before surgery, but the incidence of major bleeding when stopping therapy 2 or more days before surgery was similar compared with clopidogrel (see Adverse Reactions section). If the patient is undergoing elective surgery and the antithrombotic effect is not desired, then therapy with Brilinta® should be discontinued 5 days before surgery (see section “Pharmacodynamics”).

Patients with previous ischemic stroke

ACS patients with a previous ischemic stroke can take Brilinta® for up to 12 months (PLATO study).

The PEGASUS (history of myocardial infarction) and THEMIS (coronary artery disease and T2DM) studies did not include patients with a previous ischemic stroke. Therefore, in the absence of data, therapy for more than 1 year should be carried out with caution (for patients with a history of myocardial infarction).

Patients with moderate liver dysfunction

Experience with the use of Brilinta® in patients with moderate hepatic impairment is limited, so caution should be exercised. The use of Brilinta® is contraindicated in patients with severe liver dysfunction (see sections “Dosage and Administration”, “Contraindications” and “Pharmacokinetics”).

Bradyarrhythmia

24-hour Holter ECG monitoring showed an increase in the frequency of mostly asymptomatic ventricular pauses during therapy with ticagrelor compared with clopidogrel. In phase 3 studies assessing the safety and efficacy of Brilinta®, bradyarrhythmia events were recorded with a similar frequency for ticagrelor and comparator drugs (placebo, clopidogrel and ASA). Patients with an increased risk of developing bradycardia (eg, patients without a pacemaker, diagnosed with sick sinus syndrome, 2nd or 3rd degree atrioventricular heart block, syncope associated with bradycardia) were excluded from the Brilinta outcome studies. Therefore, due to limited clinical experience with the drug in these patients, it is recommended to prescribe ticagrelor to them with caution (see also section “Pharmacodynamics”).

Additional precautions should be taken when using Brilinta® together with drugs that can cause bradycardia. However, no clinically significant side effects were observed when used concomitantly with one or more drugs that can cause bradycardia (for example, 96% of patients were simultaneously taking beta-blockers, 33% were taking calcium channel blockers, diltiazem and verapamil, and 4% were taking digoxin) (see section “Interaction with other drugs”).

In the PLATO substudy using 24-hour Holter ECG monitoring, more patients in the acute phase of ACS had ventricular pauses ≥ 3 seconds in the ticagrelor group compared with clopidogrel. An increase in the number of ventricular pauses recorded using 24-hour Holter monitoring while taking ticagrelor was observed more often in patients with chronic heart failure compared to the general population in the acute phase of ACS, but not in the first month of therapy or compared with clopidogrel. Pauses in these patients were not associated with subsequent adverse clinical consequences (including syncope and pacemaker insertion).

During post-marketing use of Brilinta®, cases of bradyarrhythmia and atrioventricular block were noted (see section “Side Effects”), mainly in patients with ACS, in which myocardial ischemia and concomitant use of drugs that reduce heart rate or affect conduction could potentially have an effect. The patient’s clinical condition and concomitant medications should be assessed as potential causes before therapy is adjusted.

Dyspnea

Dyspnea has been reported in patients taking Brilinta®. Dyspnea is usually of mild or moderate intensity and often resolves without stopping therapy. In patients with bronchial asthma/COPD, the absolute risk of shortness of breath while taking Brilinta® may be increased (see section “Side effects”). Ticagrelor should be used with caution in patients with a history of asthma and/or COPD. The mechanism of shortness of breath while taking ticagrelor is not clear. If the patient develops a new episode of shortness of breath, shortness of breath persists or worsens while using Brilinta®, then a full examination should be carried out, and in case of intolerance, the drug should be discontinued.

Central sleep apnea

Cases of central sleep apnea, including Cheyne-Stokes respiration, have been reported with post-marketing use of Brilinta®. If central sleep apnea is suspected, the need for further clinical evaluation should be assessed.

Increased creatinine concentration

During therapy with Brilinta®, creatinine concentrations may increase. The mechanism of this effect is unknown. Renal function assessment should be performed in accordance with routine clinical practice. In patients with ACS, renal function assessment is also recommended one month after initiation of ticagrelor therapy, with particular attention to patients aged 75 years and older, patients with moderate or severe renal impairment, and those receiving angiotensin II receptor antagonist therapy.

Increased uric acid concentration

During therapy with Brilinta®, the concentration of uric acid may increase (see section “Side effects”). Caution should be exercised in patients with a history of hyperuricemia or gouty arthritis. As a preventive measure, the use of ticagrelor should be avoided in patients with hyperuricemic nephropathy.

Thrombotic thrombocytopenic purpura (TTP)

TTP during the use of Brilinta® was observed very rarely. TTP is a serious condition and requires immediate treatment.

Effect on laboratory test results

Platelet function analysis as part of the diagnosis of heparin-induced thrombocytopenia (HIT)

False-negative platelet function test results for the diagnosis of heparin-induced thrombocytopenia (HIT) have been reported in patients taking ticagrelor. This is due to the inhibition of P2Y12 receptors by ticagrelor on platelets from healthy donors when tested in the patient’s serum/plasma. When interpreting the results of platelet function tests as part of the diagnosis of HIT, information about concomitant therapy with ticagrelor should be taken into account.

Before considering discontinuation of ticagrelor, the benefits and risks of continuing therapy should be assessed, taking into account both the prothrombotic state due to HIT and the increased risk of bleeding during co-administration of the anticoagulant and ticagrelor.

Other

Based on the relationship observed in the PLATO study between the maintenance dose of ASA and the relative effectiveness of ticagrelor compared with clopidogrel, coadministration of ticagrelor and a high maintenance dose of ASA (more than 300 mg) is not recommended.

Concomitant use of Brilinta® with strong CYP3A4 inhibitors (for example, ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir) is contraindicated (see section “Contraindications”), as it may lead to a significant increase in the exposure of Brilinta® (see section “Interactions with other drugs”).

Concomitant use of Brilinta® with strong CYP3A4 inducers (for example, rifampicin, phenytoin, carbamazepine and phenobarbital) is not recommended, as their combined use may reduce the exposure and effectiveness of ticagrelor (see section “Interaction with other drugs”).

Co-administration of Brilinta with CYP3A4 substrates with a narrow therapeutic index (eg, cisapride and ergot alkaloids) is not recommended as ticagrelor may increase the exposure of these drugs. The combined use of Brilinta® with simvastatin or lovastatin at a dose of more than 40 mg is not recommended (see section “Interaction with other drugs”).

When using digoxin and Brilinta® together, careful clinical and laboratory monitoring (heart rate and, if clinically indicated, also ECG and digoxin concentration in the blood) is recommended.

There are no data on coadministration of ticagrelor with strong P-glycoprotein inhibitors and moderate CYP3A4 inhibitors (eg, verapamil and quinidine), which may increase ticagrelor exposure. If their combined use cannot be avoided, it should be used with caution (see sections “With caution”, “Interaction with other drugs”).

Early termination of therapy

Early discontinuation of any antiplatelet therapy, including Brilinta, may increase the risk of cardiovascular death, myocardial infarction, or stroke as a result of the underlying disease. Premature discontinuation of the drug should be avoided.

Impact on the ability to drive vehicles and other mechanisms

There have been no studies of the effect of Brilinta® on the ability to drive vehicles and operate machinery. It is assumed that Brilinta® does not affect or only slightly affects the ability to drive vehicles and operate machines. Dizziness and confusion have been reported during therapy with Brilinta®. If these phenomena develop, patients should be careful when driving vehicles and other mechanisms.

Active ingredient

Ticagrelor

Composition

Active ingredient: ticagrelor 60 mg

Excipients: mannitol 84 mg, calcium hydrogen phosphate 42 mg, sodium carboxymethyl starch 6 mg, hyprolose 6 mg, magnesium stearate 2 mg; tablet shell: hypromellose 4.4 mg, titanium dioxide (E 171) 2.2 mg, macrogol 400 0.4 mg, iron dye black oxide 0.001 mg, iron dye red oxide 0.01 mg.

Pregnancy

Women of reproductive age

Women of reproductive potential should use appropriate methods of contraception to avoid pregnancy during therapy with Brilinta®.

Pregnancy

There are no or limited data on the use of ticagrelor in pregnant women.

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

Breastfeeding period

Available pharmacodynamic and toxicological data in animals have shown that ticagrelor and its active metabolites are excreted in milk. A risk to the newborn/infant cannot be excluded. The decision to stop breastfeeding or discontinue therapy with Brilinta® must be made taking into account the benefits of breastfeeding for the child and the benefits of therapy for the mother.

Fertility

Ticagrelor had no effect on the fertility of male and female animals.

Contraindications

Hypersensitivity to ticagrelor or any excipient of the drug.
Active pathological bleeding.
History of intracranial hemorrhage.
Severe liver dysfunction.
Concomitant use of ticagrelor with potent inhibitors of the CYP3A4 isoenzyme (for example, ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir).
Children under 18 years of age (due to the lack of data on the effectiveness and safety of use in this group of patients).
Pregnancy and breastfeeding period.
With caution

Side Effects

Security Profile at a Glance

The safety profile of Brilinta® was assessed in three phase 3 studies (PLATO, PEGASUS and THEMIS), which included more than 58,000 patients, of which more than 32,000 received ticagrelor (see section “Pharmacological properties”). The following are the adverse reactions observed in these clinical studies.

In the PLATO study, patients receiving Brilinta® were more likely to discontinue therapy due to adverse events than patients receiving clopidogrel (7.4% versus 5.4%). In the PEGASUS study, the rate of treatment discontinuation due to adverse events was higher with Brilinta® than with ASA monotherapy (16.1% in the ticagrelor 60 mg + ASA group compared with 8.5% in the ASA monotherapy group). In the THEMIS study in patients undergoing PCI, the rate of discontinuation of therapy due to adverse events was 21.3% when taking Brilinta® in combination with ASA compared to 13.0% when taking ASA alone.

The most commonly reported adverse reactions in patients taking ticagrelor were bleeding and shortness of breath (see section “Special Instructions”).

List of adverse reactions in table form

Adverse reactions observed in clinical studies or during post-marketing use of Brilinta® are presented by organ system class and frequency of occurrence and are listed in descending order of severity. The frequency of adverse reactions is determined using the following conventions: 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 (cannot be estimated from the data obtained).

Table 1. Adverse reactions by frequency and organ system class

System class

organs

Very often

Often

Uncommon

Frequency

unknown

Benign, malignant and

unspecified neoplasms (including cysts and

polyps)

Bleeding from a tumora

Blood and lymphatic system disorders

Bleeding associated with blood diseasesb

Thrombotic thrombocytopenic

purpuras

Violations with

side of the immune

Reactions

hypersensitive

systems

diseases, including angioedema

sky otex

Violations with

aspects of metabolism and nutrition

Hyperuricemiad

Gout/gouty arthritis

Mental disorders

Confusion

consciousness

Nervous system disorders

Dizziness, fainting, headache

Intracranial hemorrhage

Central sleep apnea, including Cheyne’s breathing

Stokes

Violations with

sides of the organ of vision

Bleeding in the eye

Hearing and labyrinthine disorders

violations

Vertigo

Ear bleeding

Heart disorders

Bradyaritis miyas, atrioventricular

blockade

Violations with

sides of vessels

Arterial

hypotension

Disorders of the respiratory system, chest organs and

mediastinum

Dyspnea

Bleeding from the respiratory systemf

Gastrointestinal disorders

intestinal tract

Gastrointestinal bleedingg, diarrhea, nausea,

dyspepsia, constipation

Retroperitoneal bleeding

Skin and subcutaneous tissue disorders

Subcutaneous or skin bleedingh, skin itching,

skin rash

Musculoskeletal and connective tissue disorders

fabrics

Muscle bleeding

Renal and urinary disorders

ways

Bleeding from the urinary tractj

Disorders of the genital organs and breast

glands

Bleeding from the genitals

Laboratory and instrumental data

Increased creatinine concentration in

bloodd

Injuries, intoxications and complications of manipulations

Bleeding after manipulation, traumatic

bleeding

a For example, bleeding from a bladder tumor, from a stomach tumor, from a colon tumor.

b for example, increased tendency to bruise, spontaneous hematoma, bleeding diathesis.

c noted during post-marketing use.

d shows the incidence of laboratory abnormalities (increased uric acid concentration above the upper limit of normal from a baseline value that was within the normal range or less than the lower limit of normal. Increased creatinine concentration > 50% of baseline), rather than the incidence of adverse events reported.

e for example, conjunctival, retinal, intraocular hemorrhage.

f for example, epistaxis (nosebleeds), hemoptysis.

g e.g. gingival bleeding, rectal bleeding, bleeding from stomach ulcers.

h for example, ecchymosis, cutaneous hemorrhage, petechiae.

i for example, hemarthrosis, hemorrhage into the muscle.

j for example, hematuria, hemorrhagic cystitis.

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

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

m i.e. spontaneous, procedure-related, or traumatic intracranial hemorrhage.

Description of some adverse reactions

Bleeding

The following definitions of bleeding were used in the PLATO, PEGASUS and THEMIS studies:

Major lethal/life-threatening bleeding according to PLATO definition: lethal, or any intracranial hemorrhage, or bleeding into the pericardial cavity with cardiac tamponade; or with hypovolemic shock or severe hypotension requiring the use of vasoconstrictors/inotropes or surgery, or clinically overt bleeding accompanied by a decrease in hemoglobin concentration of more than 50 g/L, or a transfusion of 4 or more units of red blood cells.

For THEMIS research only. For bleeding associated with CABG: fatal bleeding or perioperative intracranial bleeding, or reoperation after sternotomy incision closure to control bleeding, or transfusion of ≥5 units of whole blood or packed red blood cells within 48 hours (transfusion through the Cell Saver system will not be counted toward blood product calculations), or chest tube drainage >2 L within 24 hours.

Major other bleeding as defined by PLATO: causing significant disability of the patient, or clinically obvious bleeding, accompanied by a decrease in hemoglobin concentration by 30-50 g/L, or a transfusion of 2-3 units of red blood cells.
Minor bleeding as defined by PLATO: requires medical intervention to stop or treat the bleeding.
Major bleeding as defined by TIMI: fatal, or any intracranial hemorrhage, or clinically overt bleeding associated with a decrease in hemoglobin concentration of 50 g/L or more, or, if hemoglobin data are not available, a decrease in hematocrit of ≥15%.

For THEMIS research only. For bleeding associated with CABG: fatal bleeding or perioperative intracranial bleeding, or reoperation after sternotomy incision closure to control bleeding, or transfusion of ≥5 units of whole blood or packed red blood cells within 48 hours (transfusion through the Cell Saver system will not be counted toward blood product calculations), or chest tube drainage >2 L within 24 hours.

Major other bleeding by TIMI definition: non-fatal, non-intracranial major bleeding by definition
Minor bleeding according to TIMI definition: clinically obvious bleeding, accompanied by a decrease in hemoglobin concentration by 30-50 g/l.

For THEMIS research only. Minor bleeding as defined by TIMI: clinically obvious bleeding accompanied by a decrease in hemoglobin concentration of 30-50 g/L or a decrease in hematocrit of ≥10% to <15%, or in the absence of observed blood loss, a decrease in hemoglobin concentration of ≥40 g/L or a decrease in hematocrit of ≥12%.

Bleeding requiring medical attention, as defined by TIMI, requires medical attention or results in hospitalization or urgent evaluation.
Lethal Hemorrhage: Leads to the death of the patient within 7 days.

Data on bleeding events in the PLATO study (Kaplan-Meier estimate (%) at 12 months)

Brilinta® and clopidogrel did not differ in the incidence of major bleeding overall according to PLATO criteria (11.6% and 11.2%, respectively), or fatal/life-threatening bleeding according to PLATO criteria (5.8% in both groups). However, the incidence of combined major and minor bleeding according to PLATO criteria was higher in the ticagrelor group (16.1%) compared with clopidogrel (14.6%, p = 0.0084). There were several cases of fatal bleeding: 20 (0.2% of patients) in the ticagrelor group and 23 (0.3% of patients) in the clopidogrel group.

Age, sex, weight, ethnicity, geographic region, comorbidities, concomitant therapies, and medical history, including previous stroke and transient ischemic attack, did not influence the incidence of overall and nonprocedure-related major bleeding according to PLATO criteria. No groups were identified with an increased risk of bleeding.

CABG-Related Bleeding: In the PLATO study, 42% of 1584 patients (12% of the cohort) undergoing CABG experienced major fatal/life-threatening bleeding, with no difference in either treatment group. Fatal bleeding associated with CABG surgery occurred in 6 patients in each treatment group (see section “Special Instructions”).

Non-CABG vs. non-procedure-related bleeding: Brilinta and clopidogrel did not differ in the incidence of major fatal/life-threatening non-CABG bleeding based on PLATO criteria, but ticagrelor was more likely to experience major bleeding overall based on PLATO criteria (4.5% vs. 3.8%; p=0.0264). When removing procedure-related bleeding events, there were more bleeding events in the ticagrelor group (3.1%) than in the clopidogrel group (2.3%; P = 0.0058). Discontinuation due to non-procedure-related bleeding was more common with ticagrelor (2.9%) compared with clopidogrel (1.2%, p < 0.001).

Intracranial hemorrhage: More nonprocedure-related intracranial hemorrhage occurred in the ticagrelor group (n=27 hemorrhages in 26 patients, 0.3%) than in the clopidogrel group (n=14 hemorrhages, 0.2%), of which 11 hemorrhages on ticagrelor and 1 on clopidogrel were fatal. However, there were no significant differences in the total number of fatal bleeding events. The percentage of intracranial hemorrhage was low in both treatment groups, given the significant comorbidities and risk factors for cardiovascular complications in the study population.

Data on bleeding events in the PEGASUS study (Kaplan-Meier estimate (%) at 36 months)

In the PEGASUS study, major bleeding as determined by TIMI occurred more frequently with Brilinta® 60 mg twice daily (2.3%) than with ASA monotherapy (1.1%). There was no increase in the risk of fatal bleeding, but only a slight increase in the incidence of intracranial hemorrhage (0.6%) compared with ASA monotherapy (0.5%). Several cases of fatal bleeding were noted: 11 (0.3%) in the Brilinta® 60 mg group and 12 (0.3%) in the ASA monotherapy group. The increased risk of TIMI major bleeding with Brilinta 60 mg was primarily due to a higher incidence of other TIMI major bleeding due to gastrointestinal events.

With the use of Brilinta® 60 mg, there was an increase in the frequency of major or minor bleeding according to the TIMI definition (3.4% with Brilinta® 60 mg compared to 1.4% with ASA monotherapy), major bleeding according to the PLATO definition (3.5% compared to 1.4%) and major or minor bleeding according to the PLATO definition (15.2% compared to 6.2%). Treatment discontinuation due to bleeding was more common with Brilinta 60 mg than with ASA monotherapy (6.2% and 1.5%, respectively). Most of these bleeds were less severe (classified as bleeds requiring medical attention, as defined by TIMI), such as epistaxis, bruising, and hematomas.

The profile of TIMI major bleeding, TIMI major or minor bleeding, and PLATO major bleeding for Brilinta 60 mg was comparable across several prespecified subgroups (eg, age, sex, weight, race, geographic region, comorbidities, concomitant medications, and medical history).

Intracranial hemorrhage: Spontaneous intracranial hemorrhage was observed with a similar frequency when using Brilinta® 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 Brilinta 60 mg (n=15 hemorrhages, 0.2%) compared with ASA monotherapy (n=10 hemorrhages, 0.1%). There were 6 fatal intracranial hemorrhages when taking Brilinta® 60 mg and 5 when taking ASA monotherapy. The incidence of intracranial hemorrhage was low in both treatment groups, given the significant comorbidities and cardiovascular risk factors in the study population.

Data on bleeding events in the THEMIS study in patients undergoing PCI Data on bleeding events in the THEMIS study in patients undergoing PCI are shown in Table 2.

Table 2. Bleeding Incidence Analysis: Bleeding Rates by Treatment Group at 36 Months, Kaplan-Meier Estimated (PCI Patients, THEMIS Study)

Brilinta® twice daily + ASA

N=5536

ASA monotherapy

N=5564

Security endpoints

KM%

Risk ratio

(95% CI)

KM%

p-value

TIMI bleeding categories

Major bleeding

TIMI definition

2.4%

2.03 (1.48, 2.76)

1.3%

<0.0001

Major or minor bleeding

according to TIMI definition

3.4%

2.23 (1.70, 2.92)

1.7%

<0.0001

Major or minor bleeding, or requiring medical attention

TIMI definition

13.1%

2.28 (1.99, 2.62)

6.3%

<0.0001

PLATO bleeding categories

Major bleeding

PLATO definition

3.8%

2.22 (1.72, 2.86)

1.9%

<0.0001

Lethal/life threatening

bleeding

2.5%

2.10 (1.54, 2.86)

1.3%

<0.0001

Major other bleeding

PLATO definition

1.5%

2.53 (1.64, 3.93)

0.6%

<0.0001

Several cases of fatal bleeding were noted: 6 in the Brilinta® drug group in combination with ASA and 6 in the ASA monotherapy group. The number of patients with intracranial hemorrhage in the Brilinta® drug group in combination with ASA was 33, and in the ASA monotherapy group – 31.

Treatment discontinuation due to bleeding in patients undergoing PCI was more common with Brilinta in combination with ASA compared to ASA alone (4.7% and 1.3%, respectively). The most common types of bleeding leading to discontinuation of Brilinta® were nosebleeds and bruising.

Dyspnea

In the PLATO study, adverse events of dyspnea occurred in 13.8% of patients receiving ticagrelor 90 mg twice daily and in 7.8% of patients receiving clopidogrel 75 mg once daily. Most cases of shortness of breath were of mild to moderate intensity and often resolved without discontinuation of therapy. Typically, shortness of breath developed at the beginning of therapy and in 87% of patients it was a single episode. Dyspnea as a serious adverse event was reported in 0.7% of patients receiving ticagrelor and in 0.4% of patients receiving clopidogrel. Patients who reported developing dyspnea were older and often initially had dyspnea, congestive heart failure, COPD, or asthma. Data from the PLATO trial do not indicate that the higher incidence of dyspnea with Brilinta is associated with the development of new or worsening heart or lung disease. Brilinta® does not affect respiratory function parameters (see section “Special instructions”).

In the PEGASUS study, shortness of breath was observed in 14.2% of patients taking Brilinta 60 mg twice daily and in 5.5% of patients taking ASA monotherapy. As in the PLATO study, most cases of dyspnea were mild to moderate in intensity (see section “Special Instructions”).

In the THEMIS study among patients undergoing PCI, shortness of breath was observed in 22.0% of patients taking Brilinta® twice daily in combination with ASA, and in 7.5% of patients receiving ASA monotherapy. Most cases of shortness of breath were of mild to moderate intensity (see section “Special Instructions”).

Laboratory and instrumental data

Increased uric acid concentrations: In the PLATO study, serum uric acid concentrations increased above the upper limit of normal in 22% of patients receiving ticagrelor compared with 13% of patients receiving clopidogrel. The corresponding numbers in the PEGASUS study were 9.1%, 8.8% and 5.5% in the ticagrelor 90 mg, 60 mg and placebo groups, respectively. Mean serum uric acid concentrations increased by approximately 15% with ticagrelor compared with approximately 7.5% with clopidogrel, and after discontinuation of therapy decreased to approximately 7% in the ticagrelor group, with no decrease in the clopidogrel group. In the PEGASUS study, there was a reversible increase in mean serum uric acid concentrations of 6.3% and 5.6% with ticagrelor 90 mg and 60 mg, respectively, compared with a 1.5% decrease in the placebo group. In the PLATO study, the incidence of gouty arthritis was 0.2% with ticagrelor versus 0.1% with clopidogrel. The incidence of gout/gouty arthritis in the PEGASUS study was 1.6%, 1.5% and 1.1% in the ticagrelor 90 mg, 60 mg and placebo groups, respectively.

Interaction

Ticagrelor is primarily a CYP3A4 substrate and a weak CYP3A4 inhibitor. Ticagrelor is also a P-glycoprotein (P-gp) substrate and a weak P-gp inhibitor, and may increase exposure to P-gp substrates.

Effect of other drugs on Brilinta®

Drugs metabolized by the CYP3A4 isoenzyme

CYP3A4 inhibitors

Potent CYP3A4 inhibitors: Coadministration of ketoconazole with ticagrelor increases the Cmax and AUC of ticagrelor by 2.4 and 7.3 times, respectively. Cmax and AUC of the active metabolite are reduced by 89% and 56%, respectively. Other strong CYP3A4 inhibitors (clarithromycin, nefazodone, ritonavir and atazanavir) will have the same effects, therefore the combined use of strong CYP3A4 inhibitors with Brilinta® is contraindicated (see section “Contraindications”).
Moderate inhibitors of CYP3A4: co-administration of diltiazem with ticagrelor increases the Cmax of ticagrelor by 69% and the AUC by 2.7 times, and reduces the Cmax of the active metabolite by 38%, and the AUC does not change. Ticagrelor does not affect plasma concentrations of diltiazem. Other moderate CYP3A4 inhibitors (eg, amprenavir, aprepitant, erythromycin, fluconazole) will have similar effects and may also be co-administered with Brilinta.

CYP3A4 inducers

Coadministration of rifampicin with ticagrelor reduced the Cmax and AUC of ticagrelor by 73% and 86%, respectively. The Cmax of the active metabolite does not change, and the AUC decreases by 46%. Other CYP3A4 inducers (eg, phenytoin, carbamazepine, and phenobarbital) are also likely to decrease ticagrelor exposure. Concomitant use of ticagrelor with strong CYP3A inducers may reduce the exposure and effectiveness of ticagrelor, so their combined use with Brilinta should be avoided.

Cyclosporine (P-gp and CYP3A inhibitor)

Co-administration of cyclosporine (600 mg) with ticagrelor increases the Cmax and AUC of ticagrelor by 2.3 and 2.8 times, respectively. In this case, there is an increase in the AUC of the active metabolite by 32% and a decrease in Cmax by 15% in the presence of cyclosporine.

There are no data on coadministration of ticagrelor with other strong P-glycoprotein inhibitors and moderate CYP3A4 inhibitors (eg, verapamil and quinidine), which may increase ticagrelor exposure. If their combined use cannot be avoided, it should be used with caution.

Other

Based on the results of pharmacological interaction studies, 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 the use of drugs that affect hemostasis, they should be used with caution in combination with ticagrelor.

With daily consumption of large volumes of grapefruit juice (200 ml 3 times a day), a 2-fold increase in ticagrelor exposure was noted. This increase in ticagrelor exposure is not expected to be clinically significant in most patients.

Delayed and decreased exposure to oral P2Y12 inhibitors, including ticagrelor and its active metabolite, was observed in patients treated with morphine (approximately 35% decrease in ticagrelor exposure). This interaction may be due to decreased gastrointestinal motility and therefore applies to other opioids. The clinical significance is unknown, but data indicate the potential for decreased efficacy of ticagrelor in patients receiving ticagrelor and morphine concomitantly. In patients with ACS in whom morphine cannot be delayed and rapid P2Y12 inhibition is considered critical, the use of a parenteral P2Y12 inhibitor may be considered.

Effect of Brilinta® on other drugs

Drugs metabolized by the CYP3A4 isoenzyme

Simvastatin: Concomitant use of ticagrelor and simvastatin increases the Cmax and AUC of simvastatin by 81% and 56%, respectively, and increases the Cmax and AUC of simvastatin acid by 64% and 52%, respectively, with, in some cases, these indicators increasing by 2-3 times. Concomitant use of simvastatin at a dose higher than 40 mg/day. with ticagrelor may lead to the development of side effects of simvastatin, and the balance of potential risk and benefit must be assessed. Simvastatin had no effect on plasma concentrations of ticagrelor. Ticagrelor may have a similar effect on lovastatin. Concomitant use of ticagrelor with simvastatin or lovastatin at a dose exceeding 40 mg is not recommended.
Atorvastatin: Concomitant use of atorvastatin and ticagrelor increases the Cmax and AUC of atorvastatin acid by 23% and 36%, respectively. A similar increase in AUC and Cmax values ​​is observed for all metabolites of atorvastatin acid. This increase was considered clinically insignificant.
A similar effect on other statins metabolized by the CYP3A4 isoenzyme cannot be excluded. In the PLATO trial, patients receiving ticagrelor took various statins, with no safety concerns reported in 93% of patients taking this group of drugs.

Ticagrelor is a weak inhibitor of the CYP3A4 isoenzyme. Concomitant use of ticagrelor and CYP3A4 substrates with a narrow therapeutic index (eg, cisapride or ergot alkaloids) is not recommended as ticagrelor may increase the exposure of these drugs.

P-gp substrates (including digoxin, cyclosporine)

Concomitant use of ticagrelor with digoxin increased the Cmax and AUC of digoxin by 75% and 28%, respectively. When co-administered with ticagrelor, the mean trough concentration of digoxin increased by approximately 30%, in some individual cases twice as much. The Cmax and AUC of 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, if clinically indicated, also ECG and digoxin blood concentrations) during the simultaneous use of ticagrelor and P-gp-dependent drugs with a narrow therapeutic index, like digoxin.

There was no effect of ticagrelor on the concentration of cyclosporine in the blood. The effect of ticagrelor on other P-gp substrates has not been studied.

Drugs metabolized by the CYP2C9 isoenzyme

Concomitant use of ticagrelor and tolbutamide did not change plasma concentrations of either drug, indicating that ticagrelor is not a CYP2C9 inhibitor and is unlikely to affect the CYP2C9-mediated metabolism of drugs like warfarin and tolbutamide.

Oral contraceptives

Concomitant use of ticagrelor, levonorgestrel and ethinyl estradiol increases the exposure of ethinyl estradiol by approximately 20%, but does not affect the pharmacokinetics of levonorgestrel. No clinically significant effect on contraceptive efficacy is expected with simultaneous use of levonorgestrel, ethinyl estradiol and ticagrelor.

Medicines that can cause bradycardia

Due to the detection of mostly asymptomatic ventricular pauses and bradycardia, caution should be taken when taking Brilinta® simultaneously with drugs that can cause bradycardia (see section

“Special instructions”). However, in the PLATO study, no clinically significant adverse events were observed when coadministered with one or more drugs that can cause bradycardia (eg, 96% of patients were concomitantly taking beta-blockers, 33% were taking calcium channel blockers, diltiazem and verapamil, and 4% were taking digoxin).

Other concomitant therapy

In clinical studies, Brilinta® was predominantly prescribed in combination with ASA, proton pump inhibitors, statins, beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists as part of long-term use for the treatment of concomitant diseases, as well as with heparin, low molecular weight heparins, glycoprotein IIb/IIIa receptor inhibitors for intravenous administration as part of short-term therapy. The results of these studies did not reveal clinically significant adverse interactions.

Co-administration of Brilinta® with heparin, enoxaparin or desmopressin had no effect on activated partial thromboplastin time (APTT), activated clotting time (ACT) and factor Xa studies, however, due to potential pharmacodynamic interactions, caution is required when combined with drugs that affect hemostasis.

Due to reports of subcutaneous hemorrhage with the use of selective serotonin reuptake inhibitors (for example, paroxetine, sertraline and citalopram), caution is recommended when taking them together with ticagrelor, as there may be an increased risk of bleeding.

Overdose

Ticagrelor is well tolerated in a single dose of up to 900 mg. In the only dose-escalation study, gastrointestinal adverse effects were dose-limiting. Other clinically significant adverse reactions that may occur during overdose are shortness of breath and ventricular pauses (see section “Side Effects”). In case of overdose, monitor for these potential adverse reactions, with possible ECG monitoring.

Currently, there is no known antidote to eliminate the effects of ticagrelor; ticagrelor is not eliminated by hemodialysis (see section “Pharmacokinetics”). In case of overdose, symptomatic therapy should be carried out in accordance with local standards. Due to platelet inhibition, increased bleeding time is an expected pharmacological effect of Brilinta overdose. If bleeding develops, appropriate supportive measures must be taken.

Storage conditions

At a temperature not exceeding 30 °C. Keep out of the reach of children.

Shelf life

3 years. Do not use after expiration date.

Manufacturer

AstraZeneca AB, Sweden