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

The drug 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 without a history of myocardial infarction and/or stroke and who have undergone percutaneous coronary intervention (PCI).

Active ingredient

Composition

Active ingredient: ticagrelor 60 mg

Ancillary substances: mannitol 84 mg, calcium hydrophosphate 42 mg, sodium carboxymethyl starch 6 mg, hyprolose 6 mg, magnesium stearate 2 mg; Pill coating: hypromellose 4.4 mg, titanium dioxide (E 171) 2.2 mg, macrogol 400 0.4 mg, iron oxide black dye 0.001 mg, iron oxide red dye 0.01 mg.

How to take, the dosage

For oral administration. Brilinta® can be taken regardless of meals.

For patients with difficulty swallowing, the tablet of Brilinta® 60 mg should be crushed to a fine powder, stirred in half a glass of drinking water and the resulting suspension should be drunk immediately. Mix the remainder with an additional half glass of drinking water and drink the resulting suspension. The suspension can also be injected through a nasogastric tube (CH8 or larger). After the suspension has been injected, the nasogastric tube should be flushed with water to ensure that the dose of the medication reaches the patient’s stomach completely.

Dosing

Patients must discontinue current antiaggregant therapy before starting Brilinta® (in combination with ASA).

Patients taking Brilinta® should take a low maintenance dose of ASA (75-150 mg) daily unless there are specific contraindications.

A history of myocardial infarction

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

Long-term therapy with Brilinta® is recommended unless there is a clinical need for early withdrawal of the drug (see section on Pharmacodynamics). There is no experience with Brilinta® 60 mg over three years in patients with a history of myocardial infarction.

Patients may begin therapy with Brilinta® 60 mg twice daily one year after myocardial infarction, regardless of prior antiplatelet therapy and the presence of interruptions in therapy.

Patients who started Brilinta® 90 mg twice daily during an ACS may continue therapy with Brilinta® 60 mg twice daily without interruption after one year.

Ischemic heart disease and type 2 diabetes mellitus in patients who have had coronary intervention

. Patients 50 years of age and older with CHF and DM2 without a history of myocardial infarction and/or stroke who have undergone PCI do not require a loading dose; the recommended dose is 60 mg twice daily. Long-term therapy with Brilinta® is recommended unless there is a clinical need for early withdrawal of the drug (see section “Pharmacodynamics”).

Missing a dose

Interruptions in therapy should be avoided. A patient who misses a dose of Brilinta® should only take one 60 mg tablet (next dose) at the scheduled time.

Timely withdrawal of therapy

Timely withdrawal of any antiplatelet therapy, including Brilintasup>®, may increase the risk of cardiovascular death, myocardial infarction, or stroke from the underlying disease. Premature discontinuation of the drug should be avoided.

Transfer to therapy

When patients are transferred to Brilinta®, the first dose should be given 24 hours after the last dose of another antiaggregant drug.

Special patient groups

Elderly patients

Dose adjustment is not required (see section on Pharmacokinetics).

Patients with impaired renal function

There is no need to adjust the dose of the drug in patients with impaired renal function (see section “Pharmacokinetics”).

Patients with hepatic impairment

There have been no studies of Brilinta® in patients with severe hepatic impairment and the drug is contraindicated in these patients (see “Contraindications. See section “Contraindications”). Information on therapy in patients with moderate hepatic impairment is limited. There is no need to adjust the dose of the drug in patients with mild to moderate hepatic dysfunction (see sections “Pharmacokinetics” and “Cautions”).

Children

The safety and effectiveness of Brilinta® in children younger than 18 years old for the approved indication in adults has not been established (see section “Contraindications”).

Interaction

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

The effects of other medicinal products on Brilinta®Drugs metabolized by CYP3A4 isoenzyme

CYP3A4 inhibitors

CYP3A4 inducers

The co-administration of rifampicin with ticagrelor reduces the Cmax and AUC of ticagrelor by 73% and 86%, respectively. The Cmax of the active metabolite is not changed, and the AUC is reduced by 46%. Other CYP3A4 inducers (e.g., phenytoin, carbamazepine, and phenobarbital) also appear to reduce exposure to ticagrelor. Co-administration of ticagrelor with potent CYP3A inducers may decrease exposure and efficacy of ticagrelor, so their co-administration with Brilinta® should be avoided.

Cyclosporine (P-gp and CYP3A inhibitor)

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

There are no data on co-administration of ticagrelor with other potent glycoprotein P inhibitors and moderate CYP3A4 inhibitors (such as verapamil and quinidine) that may increase ticagrelor exposure. If their co-administration cannot be avoided, it should be done with caution.

Other

. According to the results of pharmacological interaction studies, concomitant use of ticagrelor with heparin, enoxaparin and ASA or desmopressin has no effect on the pharmacokinetics of ticagrelor, its active metabolite and ADP-induced platelet aggregation. In the presence of clinical indications for the prescription of drugs affecting hemostasis, they should be used with caution in combination with ticagrelor.

A 2-fold increase in exposure to ticagrelor has been observed with daily consumption of large amounts of grapefruit juice (200 ml 3 times daily). This increase in ticagrelor exposure is not expected to be clinically significant in most patients.

A slower and decreased exposure to oral P2Y12 inhibitors, including ticagrelor and its active metabolite, has been observed in patients receiving morphine therapy (approximately 35% lower exposure to ticagrelor). This interaction may be associated with decreased gastrointestinal motility and is therefore applicable to other opioids. The clinical relevance is unknown, but data indicate that the efficacy of ticagrelor may be reduced in patients receiving ticagrelor and morphine concomitantly. In ACS patients in whom the use of morphine cannot be delayed and rapid inhibition of P2Y12 is considered critical, a parenteral P2Y12 inhibitor may be considered.

Drugs metabolized by CYP3A4 isoenzyme

Ticagrelor is a weak CYP3A4 isoenzyme inhibitor. Co-administration of ticagrelor and CYP3A4 substrates with a narrow therapeutic index (e.g., cisapride or ergot alkaloids) is not recommended, because ticagrelor may increase exposure to these drugs.

P-gp substrates (including digoxin, cyclosporine)

Co-administration of ticagrelor with digoxin increased Cmax and AUC of digoxin by 75% and 28%, respectively. When co-administered with ticagrelor, the mean value of the minimum concentration of digoxin increased by approximately 30%, in some individual cases by a factor of two. Cmax and AUC of ticagrelor and its active metabolite did not change when using digoxin. Therefore, appropriate clinical and/or laboratory monitoring is recommended (heart rate and, if clinically indicated, also ECG and digoxin blood concentrations) when concomitant use of ticagrelor and P-gp-dependent drugs with a narrow therapeutic index, such as digoxin.

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

Drugs metabolized by CYP2C9 isoenzyme

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

Oral contraceptives

The co-administration of ticagrelor, levonorgestrel and ethinylestradiol increases ethinylestradiol exposure by approximately 20%, but has no effect on the pharmacokinetics of levonorgestrel. No clinically significant effect on contraceptive efficacy is expected with concomitant use of levonorgestrel, ethinylestradiol, and ticagrelor.

Drugs that may cause bradycardia

Due to the detection of mostly asymptomatic ventricular pauses and bradycardia, caution should be exercised when taking Brilinta® concomitantly with medications that can cause bradycardia (see

“Particular caution should be exercised when taking Brilinta

. See section

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

Other concomitant therapy

In clinical trials, Brilinta® was predominantly administered together with ASA, proton pump inhibitors, statins, beta-adrenoblockers, angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists as part of long-term treatment for comorbidities, and with heparin, low molecular weight heparins, glycoprotein IIb/IIIa receptor inhibitors for intravenous administration as part of short-term therapy. According to the results of these studies, no clinically significant adverse interactions were found.

The co-administration of Brilinta® with heparin, enoxaparin or desmopressin had no effect on activated partial thromboplastin time (APT), activated clotting time (ABC) and factor Xa study, but due to potential pharmacodynamic interaction, caution is required when using together with drugs that affect hemostasis.

Because of reports of subcutaneous hemorrhage with selective serotonin reuptake inhibitors (e.g., paroxetine, sertraline and citalopram), caution is recommended when these are combined with ticagrelor, because the risk of bleeding may increase.

Special Instructions

Risk of bleeding

If Brilinta® is prescribed to patients at increased risk of bleeding, the ratio of benefit of atherothrombotic complications prevention to risk of bleeding should be evaluated.

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

In a study involving healthy volunteers, platelet transfusion did not terminate the antiplatelet effect of Brilinta® and is likely to have no clinical effect in patients with bleeding. Because concomitant use of Brilinta® and desmopressin did not decrease 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 therapy with recombinant factor VIIa may enhance hemostasis. Once the cause of the bleeding has been established and it has resolved, therapy with ticagrelor may be resumed.

Surgical interventions

The patient should inform their physician that they are taking Brilinta® before any planned surgery or starting new medications.

In the PLATO study, patients undergoing ACS had more bleeding when using Brilinta® compared to clopidogrel when discontinuing therapy one day before surgery, but the rate of major bleeding after discontinuing therapy 2 or more days before surgery was similar compared to clopidogrel (see See section “Side effects”). If the patient undergoes elective surgery and antithrombotic effect is not desired, 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 may take Brilinta® for up to 12 months (PLATO study).

The PEGASUS (history of myocardial infarction) and THEMIS (CHD and DM2) studies did not include patients with previous ischemic stroke. Therefore, in the absence of data, therapy of more than 1 year should be used with caution (for patients with a history of myocardial infarction).

Patients with moderate hepatic impairment

The experience of using Brilinta® in patients with moderate hepatic impairment is limited, therefore caution should be exercised. Brilinta® is contraindicated in patients with severe hepatic impairment (see sections “Dosage and administration”, “Contraindications” and “Pharmacokinetics”).

Bradyarrhythmia

In daily ECG Holter monitoring, an increased frequency of mostly asymptomatic ventricular pauses was noted during therapy with ticagrelor compared to clopidogrel. In phase 3 studies evaluating the safety and efficacy of Brilinta® bradyarrhythmia events were recorded with similar frequency for ticagrelor and comparison drugs (placebo, clopidogrel and ASA). Patients with an increased risk of bradycardia (e.g., patients without a pacemaker diagnosed with sinus node weakness syndrome, grade 2 or 3 atrioventricular heart block, bradycardia-related syncope) were excluded from Brilinta® outcome studies. Therefore, because of the limited clinical experience with the drug in these patients, it is recommended that ticagrelor be administered with caution (see also the section on Pharmacodynamics).

Additional caution should be exercised when co-administering Brilinta® with drugs that may cause bradycardia. However, there were no clinically significant adverse effects when co-administered with one or more drugs which may cause bradycardia (for example, 96% of patients concomitantly took beta-adrenoblockers, 33% took “slow” calcium channel blockers, diltiazem and verapamil, and 4% took digoxin) (see section “Interaction with other medicinal products”).

In the PLATO substudy using daily Holter ECG monitoring in the ticagrelor group compared with clopidogrel, more patients in the acute phase of ACS had ventricular pauses ≥3 seconds. Increased number of ventricular pauses registered by daily Holter monitoring during ticagrelor administration 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 to clopidogrel. Pauses in these patients were not accompanied by subsequent adverse clinical consequences (including syncope and pacemaker placement).

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

Dyspnea

The development of dyspnea has been reported in patients taking Brilinta®. Dyspnea is usually mild to moderate in intensity and often resolves without discontinuation of therapy. Patients with bronchial asthma/COPD may have an increased absolute risk of dyspnea when taking Brilinta® (see section “Side effects”). Ticagrelor should be taken with caution in patients with a history of bronchial asthma and/or COPD. The mechanism of dyspnea on taking ticagrelor has not been elucidated. If a patient develops a new episode of dyspnea, persists or worsens dyspnea while using Brilinta®, a full evaluation should be performed and if intolerance occurs, the drug should be discontinued.

Central sleep apnea

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

Elevated creatinine concentration

Creatinine concentration may increase during therapy with Brilinta®. The mechanism of this effect is unknown. Assessment of renal function 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, paying special attention to patients aged 75 years and older, patients with moderate or severe renal insufficiency and those receiving therapy with angiotensin II receptor antagonists.

Elevated uric acid concentration

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

Trombotic thrombocytopenic purpura (TTP)

TTP with Brilinta® has rarely been reported. TTP is a serious condition and requires immediate treatment.

Influence on laboratory results

Analysis of platelet function as part of the diagnosis of heparin-induced thrombocytopenia (HIT)

Synopsis

Contraindications

Side effects

Safety Profile Overview

The safety profile of Brilinta® was evaluated in three phase 3 studies (PLATO, PEGASUS and THEMIS) including over 58,000 patients, over 32,000 of whom were taking ticagrelor (see Pharmacological properties. See “Pharmacological properties”). Below are the adverse reactions reported in these clinical trials.

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 to 8.5% in the ASA monotherapy group). In the THEMIS study in patients undergoing PCI the rate of therapy discontinuation due to adverse events was 21.3% with Brilinta® in combination with ASA compared to 13.0% with ASA monotherapy.

The most frequently reported adverse reactions in patients taking ticagrelor were bleeding and dyspnea (see section “Special Precautions”).

List of adverse reactions in table form

Added reactions noted in clinical trials or in post-marketing use of Brilinta® are listed by organ system class and frequency of occurrence in descending order of severity. The frequency of adverse reactions is defined using the following symbols: very common (≥1/10), common (≥1/100, < 1/10), infrequent (≥1/1000, < 1/100), rare (≥1/10000, < 1/1000), very rare (< 1/10000), unspecified frequency (cannot be estimated from the data obtained).

Organ system class

organs

very often

often

Frequently

Frequently

/p>

unknown

Benign, malignant and

unspecified neoplasms (including cysts and/em>

polips)

/p>

Tumor bleedinga

Disorders of the blood and lymphatic system

Bleeding related to blood disordersb

Thrombotic thrombocytopenic

purpurac

Disorders from

the immune side

Hypersensitivity reactions

/td>

systems

including angioedemac

disorders with

demMetabolism and nutrition

Hyperuricemiad

Gout/podagra arthritis

Mental disorders

Confusion

consciousness

Nervous system disorders

Dizziness, fainting, headache

Intracranial hemorrhage

sup>m

Central sleep apnea, including Chane-

Stokesc

Disorders with

Subcutaneous or skin bleedingh, skin itching,

cutaneous rash

Musculoskeletal and connective tissue disorders

Tissue disorders

Muscle bleedingi

Kidney and urinary tract disorders

pathways

Bleeding from the urinary tractj

Gland

Bleeding from the genitals

p-value

TIMI bleeding categories

major bleeding by

TIMI definition

2.4%

2.03 (1.48, 2.76)

1.3%

< 0.0001

Major or minor bleeding

by TIMI definition

3.4%

2.23 (1.70, 2.92)

1.7%

< 0.0001

Major or minor bleeding, or requiring medical intervention by

TIMI definition

13.1%

6.3%

strong>

< 0.0001

Categories of bleeding by PLATO

Major bleeding according to

the PLATO definition

3.8%

2.22 (1.72, 2.86)

1.9%

< 0.0001

lethal/lifethreatening

bleeding

strong>

2.5%

2.10 (1.54, 2.86)

1.3%

< 0.0001

Major other bleeding by

the PLATO definition

1.5%

2.53 (1.64, 3.93)

/td>

0.6%

/p>

< 0.0001

Few cases of fatal bleeding have been reported: 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 group of Brilinta® in combination with ASA was 33 and in the ASA monotherapy group – 31.

The discontinuation of treatment due to bleeding in patients who underwent PCI was more frequent with Brilinta® therapy in combination with ASA compared with ASA monotherapy (4.7% and 1.3%, respectively). The most common types of bleeding leading to discontinuation of Brilinta® were nasal bleeding and bruising tendency.

Dyspnea

. In the PLATO study, adverse events in the form of dyspnea developed in 13.8% of patients receiving ticagrelor 90 mg twice daily and in 7.8% of patients taking clopidogrel 75 mg once daily. Most cases of dyspnea were of mild to moderate intensity and often resolved without discontinuation of the therapy. Usually dyspnea developed at the beginning of therapy and in 87% of patients it was a single episode. Dyspnea in the form of a serious adverse event was noted in 0.7% of patients receiving ticagrelor, and in 0.4% of patients receiving clopidogrel. Patients who developed dyspnea were older and often at baseline with dyspnea, congestive heart failure, COPD, or bronchial asthma. The PLATO study data do not suggest that the higher incidence of dyspnea with Brilinta® is associated with the development of new or worsening existing heart or lung disease. Brilinta® has no effect on measures of external respiratory function (see section “Special Precautions”).

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

In the THEMIS study among PCI patients, dyspnea occurred 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 dyspnea were mild to moderate in intensity (see section “Special Indications”).

Laboratory and instrumental data

Elevated uric acid concentration: In the PLATO study, serum uric acid concentrations rose 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 about 15% with ticagrelor compared with about 7.5% with clopidogrel, and decreased to about 7% in the ticagrelor group after discontinuation of therapy, with no decrease in the clopidogrel group. In the PEGASUS study, there was a reversible increase of 6.3% and 5.6% in mean serum uric acid concentration with ticagrelor 90 mg and 60 mg, respectively, compared with a decrease of 1.5% 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/podagric arthritis in the PEGASUS study was 1.6%, 1.5% and 1.1% in the ticagrelor 90 mg, 60 mg and placebo groups, respectively.

Overdose

Pregnancy use

Women of reproductive age

Women of reproductive age should use appropriate 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, decreased viability of the newborn animal and its body weight, and stunted growth. The drug Brilinta® is not recommended during pregnancy.

Breastfeeding period

The available pharmacodynamic, toxicological data in animals showed that ticagrelor and its active metabolites are excreted with milk. Risks to the newborn/infant cannot be ruled out. The decision to discontinue breastfeeding or discontinue therapy with Brilinta® should be based on the benefit of breastfeeding to the baby and the benefit of therapy to the mother.

Fertility

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