Agreta

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AGRÉTA® (AGRETA)

Composition:

Active substance: ticagrelor;

One film-coated tablet contains 90 mg of ticagrelor;

Excipients: mannitol (E 421), calcium hydrogen phosphate dihydrate, hydroxypropylcellulose, sodium croscarmellose, magnesium stearate;

Film coating: hypromellose, titanium dioxide (E 171), talc, macrogol, iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex film-coated tablets of light yellow to yellow color.

Pharmacotherapeutic group. Antithrombotic agents. Platelet aggregation inhibitors, excluding heparin. ATC code B01A C24.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Agrita® contains ticagrelor, which belongs to the chemical class of cyclopentyltriazolopyrimidines (CPTP) and is an oral, direct-acting, selective and reversible antagonist of P2Y12 receptors. It prevents adenosine diphosphate (ADP)-mediated P2Y12-dependent platelet activation and aggregation. Ticagrelor does not prevent ADP binding, but by binding to the P2Y12 receptor, it interferes with ADP-induced signal transduction. Since platelets are involved in the initiation and/or progression of atherosclerotic thrombotic events, inhibition of platelet function has been shown to reduce the risk of such cardiovascular (CV) events as death, myocardial infarction (MI), or stroke.

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

Ticagrelor has been shown to enhance adenosine-mediated effects in healthy volunteers and in patients with acute coronary syndrome (ACS), including vasodilation (as determined by increased coronary blood flow in healthy volunteers and ACS patients; headache), inhibition of platelet function (in human whole blood in vitro), and dyspnea. However, the relationship between the observed increase in adenosine levels and clinical outcomes (e.g., morbidity, mortality) has not been clearly established.

Pharmacodynamic effects

Onset of action

In patients with stable ischemic heart disease (IHD) receiving acetylsalicylic acid (ASA), the pharmacological effect of ticagrelor occurs rapidly. The mean platelet aggregation inhibition (PAI) by ticagrelor was approximately 41% at 0.5 hours after administration of a 180 mg loading dose, with maximum PAI effect reaching 89% at 2–4 hours post-dose, which was maintained for 2–8 hours. In 90% of patients, the final PAI value at 2 hours after dosing was >70%.

Offset of action

If coronary artery bypass grafting (CABG) is planned, the risk of bleeding in patients taking ticagrelor is increased compared to those receiving clopidogrel if therapy is discontinued less than 96 hours before the procedure.

Switching between agents

Switching from clopidogrel 75 mg to ticagrelor 90 mg twice daily results in an absolute increase in PAI of 26.4%, while switching from ticagrelor to clopidogrel results in an absolute decrease in PAI of 24.5%. Patients may be transitioned from clopidogrel to ticagrelor without altering the antiplatelet effect (see section "Dosage and administration").

Clinical efficacy and safety

Clinical evidence of efficacy and safety of ticagrelor was obtained in two Phase 3 studies:

• The PLATO study [PLATelet Inhibition and Patient Outcomes], which compared ticagrelor and clopidogrel when used in combination with ASA and other standard therapy.
• The PEGASUS TIMI-54 study [PrEvention with TicaGrelor of SecondAry Thrombotic Events in High-RiSk AcUte Coronary Syndrome Patients], which compared ticagrelor in combination with ASA versus ASA alone.

PLATO study (acute coronary syndrome)

The PLATO study included 18,624 patients with symptoms of unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), or ST-segment elevation myocardial infarction (STEMI) within the previous 24 hours, who were managed medically or with percutaneous coronary intervention (PCI) or CABG.

Clinical efficacy

In combination with ASA, ticagrelor 90 mg twice daily was more effective than clopidogrel 75 mg once daily in preventing the primary composite endpoint (PCE), which included CV death, MI, or stroke, primarily due to differences in rates of CV death and MI. Patients received a loading dose of 300 mg clopidogrel (600 mg possible in case of PCI) or 180 mg ticagrelor.

The effect was rapid and sustained throughout the 12-month treatment period, with an absolute risk reduction (ARR) of 1.9% per year and a relative risk reduction (RRR) of 16%. Treatment with ticagrelor instead of clopidogrel prevented one atherothrombotic event in every 54 ACS patients and one CV death in every 91 patients.

The greater efficacy of ticagrelor compared to clopidogrel was independent of body weight, sex, presence of diabetes mellitus (DM), transient ischemic attack (TIA), non-hemorrhagic stroke, revascularization, or concomitant therapy with drugs including heparins, GpIIb/IIIa inhibitors, and proton pump inhibitors (PPIs) (see section "Interaction with other medicinal products and other forms of interaction"). Efficacy was independent of the treatment strategy chosen at randomization (invasive or medical) in both patients with UA/NSTEMI and those with STEMI.

The hazard ratio (HR) for PCE favored ticagrelor in countries outside North America, which represented approximately 10% of the total study population (p for interaction = 0.045). A post hoc analysis suggests a possible interaction with ASA dose, as higher ASA doses were associated with reduced ticagrelor efficacy. ASA doses for continuous daily use in combination with Agrita® should be 75–150 mg (see sections "Dosage and administration" and "Special precautions for use").

Ticagrelor treatment reduced the frequency of PCE compared to clopidogrel in all ACS patients (UA/NSTEMI/STEMI). Therefore, Agrita® 90 mg twice daily in combination with low-dose ASA can be used in patients with ACS (UA, NSTEMI, or STEMI), including those managed medically, with PCI, or with CABG.

PLATO genetic study

Genotyping of 10,285 patients for CYP2C19 and ABCB1 in the PLATO study established an association between genotype groups and study outcomes. The advantages of ticagrelor over clopidogrel in reducing the frequency of serious CV events were not significantly dependent on the CYP2C19 or ABCB1 genotype of patients. The overall frequency of major bleeding as defined in the PLATO study did not differ between ticagrelor and clopidogrel groups regardless of CYP2C19 or ABCB1 genotype. The frequency of non-CABG-related major bleeding as defined in the PLATO study was increased with ticagrelor compared to clopidogrel in patients lacking one or more functional CYP2C19 alleles, but was similar to that observed with clopidogrel in patients without loss of functional alleles.

Composite efficacy and safety endpoint

The composite efficacy and safety endpoint (CV death, MI, stroke, or total number of major bleeds as defined in the PLATO study) indicates that the efficacy benefits of ticagrelor compared to clopidogrel are not offset by major bleeding events (ARR — 1.4%, RRR — 8%, HR — 0.92; p = 0.0257) over 12 months after ACS.

Clinical safety

Holter monitoring in PLATO. Holter monitoring data from the PLATO study showed a higher incidence of episodes of ventricular asystole ≥3 seconds in the ticagrelor group compared to the clopidogrel group during the acute phase of ACS; such episodes were more frequently observed in patients with chronic heart failure (CHF) compared to the general population; however, no statistically significant difference between ticagrelor and clopidogrel groups was observed at 1 month. No adverse clinical consequences (including syncope or need for pacemaker implantation) related to this discrepancy were observed in this patient population.

PEGASUS study (prior myocardial infarction)

The PEGASUS TIMI-54 study was a randomized, double-blind, placebo-controlled, parallel-group, international, multicenter case-control study involving 21,162 patients, designed to evaluate the prevention of atherothrombotic events with ticagrelor at two doses (90 mg twice daily or 60 mg twice daily) in combination with low-dose ASA (75–150 mg) compared to ASA alone in patients with prior MI and additional risk factors for atherothrombosis.

Inclusion criteria were: age ≥50 years, prior MI (1–3 years before randomization), and at least one of the following risk factors for atherothrombosis: age ≥65 years, DM requiring medication, second prior MI, evidence of multivessel IHD, or non-terminal chronic kidney disease (CKD).

Exclusion criteria included planned use of a P2Y12 receptor antagonist, dipyridamole, cilostazol, or anticoagulant therapy during the study period; coagulation disorders, prior ischemic stroke or intracranial hemorrhage (ICH), central nervous system tumor or intracranial vascular anomaly; gastrointestinal bleeding within the previous 6 months, or major surgery within the previous 30 days.

Clinical efficacy

Ticagrelor 60 mg twice daily and 90 mg twice daily in combination with ASA were more effective than ASA alone in preventing atherothrombotic events (composite endpoint: CV death, MI, and stroke), with a consistent treatment effect throughout the study period, RRR of 16% and ARR of 1.27% with ticagrelor 60 mg, and RRR of 15% and ARR of 1.19% with ticagrelor 90 mg.

Given the similar efficacy profiles of the 90 mg and 60 mg doses, the lower dose demonstrated a better safety profile regarding bleeding risk and dyspnea. Therefore, only ticagrelor 60 mg twice daily in combination with ASA is recommended for the prevention of atherothrombotic events (CV death, MI, and stroke) in patients with prior MI and high risk of atherothrombotic events.

Compared to ASA monotherapy, ticagrelor 60 mg twice daily in combination with ASA significantly reduced the frequency of PCE (CV death, MI, and stroke). The reduction in PCE frequency was due to reductions in each component (RRR of CV death by 17%, RRR of MI by 16%, and RRR of stroke by 25%).

The RRR for the composite endpoint was similar from day 1 to day 360 (RRR 17%) and from day 361 onward (RRR 16%). Data on the efficacy and safety of ticagrelor with treatment continuation beyond 3 years are limited.

No evidence of benefit [lack of reduction in PCE (CV death, MI, and stroke) and increased frequency of major bleeding] was observed with ticagrelor 60 mg twice daily in clinically stable patients more than 2 years after prior MI or more than 1 year after discontinuation of prior ADP receptor inhibitor therapy (see also section "Dosage and administration").

Clinical safety

The frequency of premature discontinuation of ticagrelor 60 mg due to bleeding and dyspnea was higher in patients aged >75 years (42%) than in younger patients (range: 23–31%), with a difference compared to placebo exceeding 10% (42% vs. 29%) in patients aged >75 years.

Pediatric population

In a randomized, double-blind, Phase III parallel-group study (HESTIA 3), 193 pediatric patients (aged 2 to 18 years) with sickle cell anemia were randomized to placebo or ticagrelor at doses ranging from 15 mg to 45 mg twice daily depending on body weight. In the ticagrelor group, median platelet inhibition was 35% pre-dose and 56% at 2 hours post-dose at steady state.

No benefit of ticagrelor over placebo was observed regarding the frequency of vaso-occlusive crises.

The European Medicines Agency has waived the obligation to submit results of studies in all pediatric subgroups with acute coronary syndrome (ACS) and prior myocardial infarction (MI) (see section "Dosage and administration" for use in children).

Pharmacokinetics.

Ticagrelor pharmacokinetics are linear, and exposure to ticagrelor and its 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 main circulating metabolite of ticagrelor, AR-C124910XX (also active), occurs rapidly, with a median tmax of approximately 2.5 hours. After a single 90 mg oral dose of ticagrelor administered fasting to healthy volunteers, Cmax is 529 ng/mL and AUC is 3451 ng*h/mL. The metabolite-to-parent ratio is 0.28 for Cmax and 0.42 for AUC.

Pharmacokinetics of ticagrelor and AR-C124910XX in patients with prior MI were generally similar to those observed in the ACS patient population. According to population pharmacokinetic analysis of the PEGASUS study, median Cmax of ticagrelor was 391 ng/mL and AUC was 3801 ng*h/mL at steady state with a 60 mg dose. For ticagrelor 90 mg, Cmax was 627 ng/mL and AUC was 6255 ng*h/mL at steady state.

The mean absolute bioavailability of ticagrelor is estimated to be 36%. Consumption of a high-fat meal increased ticagrelor AUC by 21% and decreased Cmax of the active metabolite by 22%, but did not affect ticagrelor Cmax or AUC of the active metabolite. These changes are of minimal clinical significance; therefore, ticagrelor can be administered independently of food intake. Ticagrelor and its active metabolite are substrates of P-gp.

Ticagrelor administered as crushed tablets mixed with water, either orally or via nasogastric tube into the stomach, has bioavailability comparable to that of intact tablets regarding AUC and Cmax of ticagrelor and its active metabolite. Initial exposure (0.5 and 1 hour post-dose) of crushed and water-mixed ticagrelor tablets was higher than that of intact tablets, with generally similar concentration profiles thereafter (2–48 hours).

Distribution

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

Metabolism

CYP3A4 is the primary enzyme responsible for the metabolism of ticagrelor and the formation of the active metabolite, and its interaction with other CYP3A substrates ranges from induction to inhibition.

The main metabolite of ticagrelor is AR-C124910XX, which is also active, as evidenced by in vitro binding to platelet ADP P2Y12 receptors. Systemic exposure to the active metabolite is approximately 30–40% of systemic exposure to ticagrelor.

Elimination

The primary route of ticagrelor elimination is hepatic metabolism. After administration of radiolabeled ticagrelor, the mean recovery of radioactivity was approximately 84% (57.8% in feces and 26.5% in urine). The amount of ticagrelor and active metabolite in urine was less than 1% of the dose. The primary route of elimination of the active metabolite is likely biliary secretion. The mean t1/2 of ticagrelor is approximately 7 hours, and that of the active metabolite is 8.5 hours.

Elderly patients

Population pharmacokinetic analysis showed higher exposures of ticagrelor (approximately 25% higher for both Cmax and AUC) and the active metabolite in elderly patients (≥75 years) with ACS compared to younger patients. These differences are not considered clinically significant (see section "Dosage and administration").

Pediatric population

Data on the use of ticagrelor in children with sickle cell anemia are limited (see sections "Dosage and administration" and "Pharmacodynamics").

In the HESTIA 3 study, patients aged 2 to 18 years with body weight ≥12 to ≤24 kg, >24 to ≤48 kg, and >48 kg received ticagrelor in the form of 15 mg chewable tablets at doses of 15, 30, and 45 mg twice daily, respectively. Pharmacokinetic analysis in this population showed mean AUC values of ticagrelor ranging from 1095 to 1458 ng*h/mL and mean Cmax values from 143 to 206 ng/mL at steady state.

Gender

Higher exposures of ticagrelor and the active metabolite were observed in women compared to men. These differences are not considered clinically significant.

Renal impairment

Exposure to ticagrelor was approximately 20% lower, and exposure to the 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 disease undergoing hemodialysis, AUC and Cmax values of 90 mg ticagrelor, when administered on a day without hemodialysis, were 38% and 51% higher, respectively, compared to patients with normal renal function. A similar increase in exposure was observed when ticagrelor was administered immediately before dialysis (49% and 61%, respectively), indicating that ticagrelor is not removed by dialysis. Exposure to the active metabolite increased to a lesser extent (AUC 13–14%, Cmax 17–36%). Platelet aggregation inhibition (PAI) by ticagrelor was independent of dialysis in patients with end-stage renal disease and was similar to that in patients with normal renal function (see section "Dosage and administration").

Hepatic impairment

Cmax and AUC of ticagrelor were 12% and 23% higher, respectively, in patients with mild hepatic impairment compared to healthy volunteers, but the PAI effect of ticagrelor was similar in both groups. Dose adjustment is not required for patients with mild hepatic impairment. The use of ticagrelor in patients with moderate or severe hepatic impairment has not been studied, and pharmacokinetic data in patients with moderate hepatic impairment are lacking. In patients with mild or moderate elevations in one or more liver function tests at baseline, plasma concentrations of ticagrelor were on average similar or slightly higher compared to patients without baseline abnormalities. Dose adjustment is not required for patients with moderate hepatic impairment (see sections "Dosage and administration" and "Special precautions for use").

Ethnicity

In patients of Asian origin, mean bioavailability is 39% higher than in Caucasian patients. In patients of Black African origin, ticagrelor bioavailability is 18% lower than in Caucasian patients. In a clinical pharmacology study, exposure (Cmax and AUC) of ticagrelor in Japanese subjects was approximately 40% higher (20% higher after body weight adjustment) than in Caucasian subjects. Drug exposure in patients of Hispanic or Latino origin was similar to that in Caucasian patients.

Clinical characteristics.

Indications.

The use of the medicinal product Agreta® in combination with acetylsalicylic acid (ASA) is indicated for the prevention of atherothrombotic events in adult patients with:

• acute coronary syndrome (ACS);
• history of myocardial infarction (MI) and high risk of atherothrombotic events (see sections "Method of administration and dosage" and "Pharmacodynamics").

Contraindications.

Hypersensitivity to the active substance or to any of the excipients (see section "Adverse reactions").

Active pathological bleeding.

History of intracranial haemorrhage (see section "Adverse reactions").

Severe hepatic impairment (see sections "Method of administration and dosage", "Special warnings and precautions for use", and "Pharmacokinetics").

Concomitant use of ticagrelor with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir) is contraindicated, as their concomitant use may lead to a significant increase in ticagrelor exposure (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Ticagrelor is primarily a substrate of CYP3A4 and a moderate inhibitor of CYP3A4. Ticagrelor is also a substrate of P-gp and a weak inhibitor of P-gp, and may increase the exposure of P-gp substrates.

Effect of medicinal products and other agents on ticagrelor

Inhibitors of CYP3A4

• Strong CYP3A4 inhibitors: concomitant administration of ketoconazole and ticagrelor resulted in a 2.4-fold and 7.3-fold increase in Cmax and AUC of ticagrelor, respectively. Cmax and AUC of the active metabolite decreased by 89% and 56%, respectively. Other strong CYP3A4 inhibitors (clarithromycin, nefazodone, ritonavir, and atazanavir) are expected to have a similar effect; therefore, concomitant use of strong CYP3A4 inhibitors with ticagrelor is contraindicated (see section "Contraindications").
• Moderate CYP3A4 inhibitors: concomitant administration of diltiazem with ticagrelor led to a 69% increase in Cmax and a 2.7-fold increase in AUC of ticagrelor, as well as a 38% decrease in Cmax of the active metabolite, while its AUC remained unchanged. No effect of ticagrelor on plasma levels of diltiazem was observed. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, erythromycin, and fluconazole) are expected to have a similar effect and may therefore be used concomitantly with ticagrelor.
• Daily consumption of large quantities of grapefruit juice (3 × 200 mL) resulted in a doubling of ticagrelor exposure. Such an increase in exposure is not expected to be clinically significant for most patients.

Inducers of CYP3A4

Concomitant administration of rifampicin with ticagrelor led to a 73% and 86% decrease in Cmax and AUC of ticagrelor, respectively. Cmax of the active metabolite remained unchanged, while AUC decreased by 46%. Other CYP3A inducers (e.g. phenytoin, carbamazepine, and phenobarbital) are also expected to reduce ticagrelor exposure.

Concomitant use of ticagrelor with strong CYP3A inducers may lead to reduced exposure and efficacy of ticagrelor, and is therefore not recommended.

Cyclosporine (inhibitor of P-gp and CYP3A)

Concomitant administration of cyclosporine (600 mg) and ticagrelor led to a 2.3-fold and 2.8-fold increase in Cmax and AUC of ticagrelor, respectively. In the presence of cyclosporine, AUC of the active metabolite increased by 32%, while Cmax decreased by 15%.

Data on concomitant use of ticagrelor with other active substances that are also strong inhibitors of P-gp and moderate inhibitors of CYP3A4 (e.g. verapamil, quinidine), which may cause increased exposure to ticagrelor, are lacking. If such combination cannot be avoided, concomitant use of these medicinal products should be undertaken with caution.

Others

Clinical pharmacology interaction studies showed that concomitant administration of ticagrelor with heparin, enoxaparin, ASA, or desmopressin did not affect the pharmacokinetics of ticagrelor or its active metabolite, or ADP-induced platelet aggregation compared to ticagrelor alone. When clinically indicated, medicinal products affecting haemostasis should be used with caution in combination with ticagrelor.

In patients with ACS receiving morphine, delayed and reduced exposure to oral P2Y12 inhibitors, including ticagrelor and its active metabolites (reduction in ticagrelor effect by 35%), was observed. This interaction may be related to reduced gastrointestinal (GI) motility and may apply to other opioid agents. The clinical significance of this interaction is unknown, but data suggest a possible reduction in efficacy of ticagrelor in patients receiving ticagrelor and morphine concomitantly. For patients with ACS in whom morphine cannot be delayed and rapid P2Y12 inhibition is considered life-saving, consideration should be given to using a parenteral P2Y12 inhibitor.

Effect of ticagrelor on other medicinal products

Medicinal products metabolized by CYP3A4

• Simvastatin: concomitant administration of ticagrelor with simvastatin increased Cmax of simvastatin by 81% and AUC by 56%, and increased Cmax of simvastatin acid by 64% and AUC by 52% (in individual cases, increases of 2–3 times were observed). Concomitant use of ticagrelor with simvastatin at doses exceeding 40 mg daily may enhance adverse effects of simvastatin, which should be weighed against potential benefit. No effect of simvastatin on plasma levels of ticagrelor was observed. Ticagrelor may have a similar effect on lovastatin. Concomitant use of ticagrelor with simvastatin or lovastatin at doses exceeding 40 mg is not recommended.
• Atorvastatin: concomitant administration of atorvastatin and ticagrelor increased Cmax of atorvastatin acid by 23% and AUC by 36%. A similar increase in AUC and Cmax was observed for all metabolites of atorvastatin acid. This increase is not considered clinically significant.
• A similar effect on other statins metabolized by CYP3A4 cannot be excluded. Participants in the PLATO study who received ticagrelor were taking various statins, and no statin-related safety issues occurred in 93% of such patients.

Ticagrelor is a weak inhibitor of CYP3A4. Concomitant use of ticagrelor with substrates of CYP3A4 with a narrow therapeutic index (e.g. cisapride or ergot alkaloids) is not recommended, as ticagrelor may increase exposure to these medicinal products.

P-gp substrates (including digoxin and cyclosporine)

Concomitant administration of ticagrelor increased Cmax of digoxin by 75% and AUC by 28%. Mean trough levels of digoxin increased by approximately 30% with concomitant use of ticagrelor, and in some cases, maximum increases of up to 2-fold were observed. In the presence of digoxin, Cmax and AUC of ticagrelor and its active metabolite remained unchanged. Therefore, when P-gp-dependent medicinal products with a narrow therapeutic index, such as digoxin, are used concomitantly with ticagrelor, appropriate clinical and/or laboratory monitoring is recommended.

No effect of ticagrelor on blood concentration of cyclosporine was observed. The effect of ticagrelor on other P-gp substrates has not been studied.

Medicinal products metabolized by CYP2C9

Concomitant administration of ticagrelor with tolbutamide did not alter plasma levels of these medicinal products, indicating that ticagrelor is not an inhibitor of CYP2C9, and therefore it is unlikely that the drug will affect CYP2C9-mediated metabolism of medicinal products such as warfarin and tolbutamide.

Rosuvastatin

Ticagrelor may affect renal excretion of rosuvastatin, thereby increasing the risk of its accumulation. Although the exact mechanism is unknown, in some cases, concomitant use of ticagrelor and rosuvastatin has led to worsening renal function, increased creatine phosphokinase levels, and rhabdomyolysis.

Oral contraceptives

Concomitant administration of ticagrelor with levonorgestrel and ethinylestradiol increased exposure to ethinylestradiol by approximately 20%, but did not alter the pharmacokinetics of levonorgestrel. Clinically significant impact on the efficacy of oral contraceptives is not expected when levonorgestrel and ethinylestradiol are used concomitantly with ticagrelor.

Medicinal products capable of causing bradycardia

Since cases of predominantly asymptomatic ventricular asystole and bradycardia have been observed, ticagrelor should be used with caution when administered concomitantly with medicinal products capable of causing bradycardia (see section "Special warnings and precautions for use"). However, in the PLATO study, no clinically significant adverse reactions (ARs) were observed after concomitant use of one or more medicinal products capable of causing bradycardia (e.g. 96% of patients received beta-blockers, 33% received calcium channel blockers diltiazem and verapamil, and 4% received digoxin).

Other concomitant therapy

In the PLATO study, ticagrelor was frequently used concomitantly with ASA, proton pump inhibitors (PPIs), statins, beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) for prolonged periods, as required by patients' comorbidities; as well as with heparin, low-molecular-weight heparin, and GpIIb/IIIa inhibitors administered intravenously for short periods (see section "Pharmacodynamics"). No signs of clinically significant adverse interactions with these medicinal products were observed.

Concomitant administration of ticagrelor with heparin, enoxaparin, or desmopressin did not affect activated partial thromboplastin time (aPTT), activated clotting time (ACT), or quantitative factor Xa assay results. However, due to possible pharmacodynamic interactions, ticagrelor should be used with caution when administered concomitantly with medicinal products capable of affecting haemostasis.

Given reports of pathological skin bleeding associated with the use of selective serotonin reuptake inhibitors (SSRIs) (e.g. paroxetine, sertraline, and citalopram), SSRIs should be used with caution together with ticagrelor, as this may increase the risk of bleeding.

Special precautions for use.

Bleeding risk

Ticagrelor should be used cautiously in patients with an increased risk of bleeding, with careful assessment of the benefit of the drug in preventing atherothrombotic events (see sections "Adverse reactions" and "Pharmacodynamics"). Ticagrelor should be used with caution in the following patient groups when clinically indicated:

• Patients with a tendency to bleeding (e.g., due to recent trauma or surgical procedures, coagulation disorders, active or recent gastrointestinal bleeding). Ticagrelor is contraindicated in patients with active pathological bleeding, history of intracranial hemorrhage (ICH), and patients with moderate to severe hepatic impairment (see section "Contraindications").
• Patients receiving concomitant medications that may increase bleeding risk (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, and/or fibrinolytic agents), within 24 hours of ticagrelor administration.

Platelet transfusion did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is unlikely to be effective in treating patients with bleeding. Since co-administration of ticagrelor with desmopressin did not reduce template bleeding time, it is unlikely that desmopressin will be effective in treating clinical bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Use of antifibrinolytic agents (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa may enhance hemostasis. Ticagrelor therapy may be resumed once the cause of bleeding has been identified and controlled.

Surgical procedures

Patients should be advised to inform physicians and dentists that they are taking ticagrelor prior to any planned surgical procedure and before initiating any new medication.

In the PLATO study, among patients undergoing coronary artery bypass grafting (CABG), bleeding events were more frequent in the ticagrelor group compared to the clopidogrel group when therapy was discontinued one day before surgery. However, major bleeding occurred at a similar frequency in both groups when therapy was stopped two or more days prior to surgery (see section "Adverse reactions"). If a patient requires elective surgery and antiplatelet effect is undesirable, ticagrelor should be discontinued five days before the procedure (see section "Pharmacodynamics").

Patients with prior ischemic stroke

Patients with acute coronary syndrome (ACS) who have had an ischemic stroke may be treated with ticagrelor for up to 12 months (PLATO study).

Patients with prior myocardial infarction (MI) and history of ischemic stroke were excluded from the PEGASUS study. Therefore, due to lack of data, treatment beyond one year is not recommended in such patients.

Hepatic impairment

Ticagrelor is contraindicated in patients with severe hepatic impairment (see sections "Posology and method of administration" and "Contraindications"). Experience with ticagrelor in patients with moderate hepatic impairment is limited; therefore, the drug should be used with caution in these patients (see sections "Posology and method of administration" and "Pharmacokinetics").

Patients at risk of bradycardia

Holter ECG monitoring revealed an increased frequency of predominantly asymptomatic ventricular pauses during ticagrelor treatment compared to clopidogrel. Patients at high risk of bradycardia (e.g., those without pacemakers who have sick sinus syndrome, second- or third-degree atrioventricular block, or syncope due to bradycardia) were excluded from the main studies evaluating the safety and efficacy of ticagrelor. Therefore, due to limited clinical experience, ticagrelor should be used cautiously in such patients (see section "Pharmacodynamics").

Concomitant use of ticagrelor with medicinal products that may cause bradycardia requires caution. However, in the PLATO study, no signs of clinically significant bradycardia were observed with concomitant use of one or more bradycardia-inducing agents (e.g., 96% of patients received beta-blockers, 33% received calcium channel blockers diltiazem or verapamil, and 4% received digoxin) (see section "Interaction with other medicinal products and other forms of interaction").

In a Holter substudy of the PLATO study, episodes of ventricular pauses lasting ≥3 seconds during the acute phase of ACS were more frequent with ticagrelor than with clopidogrel. The increase in ventricular pause frequency with ticagrelor was more pronounced in patients with heart failure (HF) compared to the overall study population during the acute phase of ACS, but this difference was no longer observed after one month of treatment or when compared to clopidogrel. No adverse clinical consequences related to this difference (including syncope or need for pacemaker implantation) were observed in this patient population (see section "Pharmacodynamics").

Dyspnea

Dyspnea has been reported in patients receiving ticagrelor. Dyspnea was usually mild to moderate in severity and often resolved without discontinuation of treatment. The absolute risk of dyspnea with ticagrelor is increased in patients with asthma (BA) and/or chronic obstructive pulmonary disease (COPD). Ticagrelor should be used cautiously in patients with a history of BA and/or COPD. The mechanism of this phenomenon is not fully understood. If a patient reports new, prolonged, or worsening dyspnea, a full clinical evaluation should be performed, and if intolerance to the drug is suspected, treatment with ticagrelor should be discontinued. See section "Adverse reactions" for details.

Central sleep apnea

Cases of central sleep apnea, including Cheyne-Stokes respiration, have been reported in the post-marketing period in patients taking ticagrelor. If central sleep apnea is suspected, additional clinical evaluation should be performed.

Increased creatinine levels

Renal function (serum creatinine levels) should be monitored approximately one month after initiation of ticagrelor therapy, with particular attention to patients aged ≥75 years, those with moderate to severe renal impairment, and those receiving concomitant angiotensin II receptor blockers (ARBs).

Elevated uric acid levels

Caution should be exercised when treating patients with a history of hyperuricemia or gouty arthritis. As a precaution, ticagrelor is not recommended in patients with uric acid nephropathy.

Thrombotic thrombocytopenic purpura (TTP)

Very rare cases of thrombotic thrombocytopenic purpura (TTP) have been reported during ticagrelor use. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia, neurological findings, renal dysfunction, and/or fever. TTP is a potentially life-threatening condition requiring urgent treatment with plasma exchange.

Effect on platelet function test results for diagnosis of heparin-induced thrombocytopenia (HIT)

In the heparin-induced platelet activation (HIPA) test, used to diagnose HIT, antibodies to the platelet factor 4/heparin complex in patient serum activate platelets from healthy donors in the presence of heparin.

False-negative results in platelet function tests (including the HIPA test) for the diagnosis of HIT have been observed in patients receiving ticagrelor. This is due to ticagrelor's inhibition of P2Y12 receptors on donor platelets in the patient serum/plasma test. Information on concomitant ticagrelor therapy is essential for correct interpretation of platelet function test results in the diagnosis of HIT.

In patients who develop HIT, the benefit-risk balance of continuing ticagrelor therapy should be carefully evaluated, considering both the prothrombotic state of HIT and the increased bleeding risk associated with concomitant anticoagulant and ticagrelor therapy.

Other

Due to the observed dependence between maintenance aspirin dose and the relative efficacy of ticagrelor compared to clopidogrel in the PLATO study, concomitant use of ticagrelor with high maintenance doses of aspirin (>300 mg) is not recommended (see section "Pharmacodynamics").

The medicinal product Agreta® contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

Early discontinuation of treatment

Premature discontinuation of any antiplatelet agent, including Agreta®, increases the risk of cardiovascular death, myocardial infarction, or stroke due to the patient's underlying condition. Therefore, premature discontinuation of therapy should be avoided.

Use during pregnancy or breastfeeding.

Women of reproductive potential

Women of reproductive potential should use appropriate contraceptive methods to avoid pregnancy during treatment with ticagrelor.

Pregnancy

Data on the use of ticagrelor in pregnant women are lacking or limited. Reproductive toxicity was observed in animal studies. Ticagrelor is not recommended for use during pregnancy.

Breastfeeding

Available pharmacodynamic/toxicological data from animal studies indicate that ticagrelor and its active metabolite are excreted in breast milk. Risk to the newborn/infant cannot be excluded. The decision whether to discontinue breastfeeding or discontinue/abandon ticagrelor therapy should be made, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Reproductive function

Ticagrelor had no effect on fertility in male and female animals.

Ability to influence the ability to drive and use machines.

Ticagrelor has no or negligible influence on the ability to drive vehicles or operate machinery. Dizziness and confusion have been reported during ticagrelor treatment. Therefore, patients experiencing these symptoms should exercise caution when driving or operating machinery.

Method of Administration and Dosage

Dosage

Patients taking the medicinal product Areta® should also take acetylsalicylic acid (ASA) daily at a maintenance dose of 75–150 mg, unless there are specific contraindications to doing so.

Acute Coronary Syndrome (ACS)

Treatment with the medicinal product Areta® should be initiated with a single loading dose of 180 mg (two 90 mg tablets), followed by 90 mg twice daily. The recommended duration of treatment with Areta® 90 mg for patients with ACS is 12 months, unless there are clinical reasons for earlier discontinuation (see section "Pharmacodynamics").

History of Myocardial Infarction

The recommended dose of ticagrelor for patients with a history of myocardial infarction (MI) occurring at least one year prior and at high risk of atherothrombotic events, when long-term treatment is required, is 60* mg twice daily (see section "Pharmacodynamics"). Treatment of patients with ACS at high risk of atherothrombotic events may be initiated without interruption as a continuation of therapy following initial treatment with Areta® 90 mg or another adenosine diphosphate (ADP) receptor inhibitor that has lasted for one year. Treatment may also be initiated within 2 years following a prior MI or within one year after completion of prior ADP receptor inhibitor therapy. Data on the efficacy and safety of ticagrelor use beyond 3 years of continued treatment are limited.

If switching from another medicinal product to Areta®, the first dose of Areta® should be taken 24 hours after the last dose of the other antithrombotic agent.

Missed Dose

Patients should avoid missing doses. If a patient misses a dose of Areta®, they should take only the next scheduled dose at the usual time.

Special Patient Populations

Elderly Patients

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

Renal Impairment

Dose adjustment is not required in patients with renal impairment (see section "Pharmacodynamics").

Hepatic Impairment

The use of ticagrelor in patients with severe hepatic impairment has not been studied; therefore, it is contraindicated in these patients (see section "Contraindications"). Information on the use of ticagrelor in patients with moderate hepatic impairment is limited. Dose adjustment is not recommended, but ticagrelor should be used with caution (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics"). Dose adjustment is not required in patients with mild hepatic impairment (see section "Pharmacokinetics").

Method of Administration

For oral use.

Areta® may be administered independently of food intake.

For patients unable to swallow the tablet whole, the tablet may be crushed into a powder, mixed with half a glass of water, and taken immediately. The glass should then be rinsed with an additional half-glass of water, and the rinse water should also be consumed.

The mixture may also be administered via a nasogastric tube (size 8 French or larger). It is important to flush the nasogastric tube with water after administration.

* Administer ticagrelor at the appropriate dosage.

Children

The safety and efficacy of ticagrelor in children (under 18 years of age) have not been established.

There are no relevant data on the use of ticagrelor in children with sickle cell anaemia (see section "Pharmacological Properties").

Overdose

Ticagrelor is well tolerated at single doses up to 900 mg. Gastrointestinal toxicity was dose-limiting in studies with escalating single doses. Other clinically significant adverse reactions in case of overdose include dyspnoea and episodes of ventricular asystole (see section "Adverse Reactions").

In case of overdose, the above-mentioned potential adverse reactions may occur; therefore, ECG monitoring should be considered.

There is currently no known antidote for ticagrelor; ticagrelor is not removed by dialysis (see section "Pharmacokinetics"). Management of overdose should follow local standards of medical practice. The expected consequence of excessive ticagrelor dosing is prolonged bleeding risk due to platelet inhibition. Platelet transfusion is unlikely to be an effective treatment method in patients with bleeding (see section "Special Warnings and Precautions for Use"). In the event of bleeding, other appropriate supportive measures should be taken.

Adverse reactions

The safety profile of ticagrelor has been evaluated in two large-scale phase 3 clinical trials assessing treatment outcomes (the PLATO and PEGASUS studies), involving over 39,000 patients (see section "Pharmacodynamics").

In the PLATO study, the rate of premature discontinuation of treatment due to adverse reactions (ADRs) was higher in patients receiving ticagrelor than in those receiving clopidogrel (7.4% vs. 5.4%). In the PEGASUS study, the rate of premature discontinuation due to ADRs was higher in patients receiving ticagrelor compared to those receiving aspirin alone (16.1% with ticagrelor 60 mg plus aspirin vs. 8.5% with aspirin alone). The most commonly observed ADRs in patients treated with ticagrelor were bleeding and dyspnea (see section "Special precautions for use").

The adverse reactions listed below were identified during clinical trials or reported during post-marketing use of ticagrelor (see Table 1).

Adverse reactions are listed by organ systems according to the Medical Dictionary for Regulatory Activities (MedDRA). The frequency of adverse reactions is defined according to the following criteria: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

Table 1

Organ systems	Very common	Common	Uncommon	Frequency unknown
Benign, malignant and unspecified neoplasms (including cysts and polyps)			Bleeding from tumoura
Blood and lymphatic system disorders	Bleeding due to coagulation disorderb			Thrombotic thrombocytopenic purpurac
Immune system disorders			Hypersensitivity, including angioneurotic edemac
Metabolism and nutrition disorders	Hyperuricemiad	Gout / gouty arthritis
Psychiatric disorders			Confusion
Nervous system disorders		Dizziness, syncope, headache	Intracranial haemorrhagem
Eye disorders			Eye haemorrhage
Ear and labyrinth disorders		Vertigo (systemic dizziness)	Ear bleeding
Cardiac disorders				Bradyarrhythmia, atrioventricular blockc
Vascular disorders		Hypotension
Respiratory, thoracic and mediastinal disorders	Dyspnoea	Bleeding from respiratory tractf
Gastrointestinal disorders		Gastrointestinal haemorrhageg, nausea, diarrhoea, dyspepsia, constipation	Retroperitoneal haemorrhage
Skin and subcutaneous tissue disorders		Subcutaneous or skin haemorrhagesh, rash, pruritus
Musculoskeletal and connective tissue disorders			Haemorrhage into musclem
Renal and urinary disorders		Bleeding from urinary tractj
Reproductive system and breast disorders			Bleeding in reproductive systemk
Investigations		Increased blood creatinine level
Injury, poisoning and procedural complications		Bleeding after procedure, traumatic haemorrhagel

a For example: bleeding from a malignant tumour of the urinary bladder, stomach, or colon.

b For example: increased tendency to bruising, spontaneous haematoma, haemorrhagic diathesis.

c Identified during the post-marketing period.

d Frequency is based on laboratory data (increase in uric acid levels above the upper limit of normal from a baseline level that was below or within the normal range; increase in creatinine levels > 50% from baseline) and does not reflect the frequency of reported adverse events.

e For example: conjunctival haemorrhage, retinal haemorrhage, intraocular haemorrhage.

f For example: epistaxis, haemoptysis.

g For example: gingival bleeding, rectal bleeding, bleeding from a gastric ulcer.

h For example: ecchymosis, skin haemorrhage, petechiae.

i For example: haemarthrosis, muscle haemorrhage.

j For example: haematuria, haemorrhagic cystitis.

k For example: vaginal bleeding, haemospermia, postmenopausal bleeding.

l For example: contusion, traumatic haematoma, traumatic bleeding.

m That is, spontaneous, procedure-related, or traumatic intra-abdominal haemorrhages.

Description of selected adverse reactions

Bleeding

Bleeding events in the PLATO study

Overall results on the frequency of bleeding events in the PLATO study are presented in Table 2.

Table 2. Analysis of total bleeding events: Kaplan-Meier estimate over 12 months (PLATO)

Bleeding events	Ticagrelor 90 mg, twice daily N = 9235	Clopidogrel N = 9186	p-value*
Major bleeds according to PLATO criteria	11.6	11.2	0.4336
Major fatal/threatening bleeds according to PLATO criteria	5.8	5.8	0.6988
Non-CABG-related major bleeds according to PLATO criteria	4.5	3.8	0.0264
Non-procedure-related major bleeds according to PLATO criteria	3.1	2.3	0.0058
Major + minor bleeds according to PLATO criteria	16.1	14.6	0.0084
Non-procedure-related major + minor bleeds according to PLATO criteria	5.9	4.3	<0.0001
Major bleeds according to TIMI criteria	7.9	7.7	0.5669
Major + minor bleeds according to TIMI criteria	11.4	10.9	0.3272

Definition of bleeding types:

Major fatal/life-threatening bleeds: clinically overt bleeding with a decrease in hemoglobin level > 50 g/L or transfusion of ≥ 4 units of packed red blood cells; or fatal; or intracranial; or intracardiac with cardiac tamponade; or associated with hypovolemic shock or severe arterial hypotension requiring use of vasopressor agents or surgical intervention.

Other major bleeds: clinically overt bleeding with a decrease in hemoglobin level of 30–50 g/L or transfusion of 2–3 units of packed red blood cells; or resulting in permanent loss of function.

Minor bleeds: requiring medical intervention to treat or manage the bleeding.

Major bleeds according to TIMI criteria: clinically overt bleeding with a decrease in hemoglobin level > 50 g/L or intracranial hemorrhage (ICH).

Minor bleeds according to TIMI criteria: clinically overt bleeding with a decrease in hemoglobin level of 30–50 g/L.

*p-value calculated using the Cox proportional hazards model, with treatment group as the sole covariate.

There were no differences between ticagrelor and clopidogrel in the rate of major fatal/life-threatening bleeds according to PLATO criteria, total number of major bleeds, or the rate of major or minor bleeds according to TIMI criteria. However, the rate of combined PLATO major and minor bleeds was higher in the ticagrelor group compared to the clopidogrel group. A small number of patients in the PLATO study experienced fatal bleeds: 20 (0.2%) in the ticagrelor group and 23 (0.3%) in the clopidogrel group (see section “Special warnings and precautions for use”).

Age, sex, body weight, race, geographic region, concomitant conditions, concomitant medications, and medical history, including prior stroke or transient ischemic attack (TIA), were not predictive factors for overall bleeding rate or rate of major bleeding in the PLATO study unrelated to procedures. Therefore, no subgroup was identified as being at increased risk of bleeding of any type.

Bleeding related to CABG. In the PLATO study, 42% of the 1584 patients (12% of the cohort) who underwent coronary artery bypass grafting (CABG) experienced a major fatal/life-threatening bleed according to PLATO study criteria, with no statistically significant difference between treatment groups. Fatal bleeding related to CABG occurred in 6 patients in each treatment group (see section “Special warnings and precautions for use”).

Bleeding unrelated to CABG and bleeding unrelated to procedures. Ticagrelor and clopidogrel did not differ in the rate of CABG-unrelated fatal/life-threatening major bleeds according to PLATO criteria; however, the overall rate of major bleeds according to PLATO criteria, the rate of major bleeds according to TIMI criteria, and the overall rate of major + minor bleeds according to TIMI criteria were higher in the ticagrelor treatment group. Similarly, when all procedure-related bleeds were excluded, the bleeding rate was higher in the ticagrelor group compared to the clopidogrel group (Table 2). Discontinuation of treatment due to non-procedure-related bleeding occurred more frequently in the ticagrelor group (2.9%) than in the clopidogrel group (1.2%; p < 0.001).

Intracranial hemorrhage (ICH). More non-procedure-related ICH events occurred with ticagrelor (n = 27 bleeds in 26 patients, 0.3%) than with clopidogrel (n = 27 bleeds, 0.2%), of which 11 bleeds in the ticagrelor group and 1 bleed in the clopidogrel group were fatal. There was no difference in the overall rate of fatal bleeds.

Bleeding events in the PEGASUS study

Overall results on bleeding rates in the PEGASUS study are presented in Table 3.

Table 3. Analysis of total bleeding events: Kaplan-Meier estimate over 36 months (PEGASUS)

Safety Endpoints	Ticagrelor, 60 mg, twice daily + ASA N = 6958		ASA alone N = 6996	p-value
	% KM	Hazard ratio (95% CI)	% KM
Types of bleeding by TIMI criteria
Major bleeds by TIMI criteria	2.3	2.32 (1.68, 3.21)	1.1	< 0.0001
Fatal bleeds	0.3	1.00 (0.44, 2.27)	0.3	1.0000
CRNM	0.6	1.33 (0.77, 2.31)	0.5	0.3130
Other major bleeds by TIMI criteria	1.6	3.61 (2.31, 5.65)	0.5	< 0.0001
Major + minor bleeds by TIMI criteria	3.4	2.54 (1.93, 3.35)	1.4	< 0.0001
Major or minor bleeds by TIMI criteria or those requiring medical attention	16.6	2.64 (2.35, 2.97)	7.0	< 0.0001
Types of bleeding by PLATO criteria
Major bleeds	3.5	2.57 (1.95, 3.37)	1.4	< 0.0001
Fatal / life-threatening bleeds	2.4	2.38 (1.73, 3.26)	1.1	< 0.0001
Other major bleeds	1.1	3.37 (1.95, 5.83)	0.3	< 0.0001
Major + minor bleeds	15.2	2.71 (2.40, 3.08)	6.2	< 0.0001

Definition of bleeding types:

Major bleeds according to TIMI criteria: fatal bleeds or any intracranial hemorrhage (ICH), or bleeding associated with clinical symptoms and a decrease in hemoglobin (Hb) level ≥ 50 g/L; or, if Hb levels are unavailable, a 15% reduction in hematocrit (Hct).

Fatal bleeds: cases of bleeding directly leading to death within 7 days.

ICH: intracranial hemorrhage.

Other major bleeds according to TIMI criteria: non-ICH, non-fatal major bleeds meeting TIMI criteria.

Minor bleeds according to TIMI criteria: clinically overt bleeding with a decrease in Hb level of 30–50 g/L.

Medically attended bleeds according to TIMI criteria: require intervention or hospitalization, or investigation.

Major fatal/life-threatening bleeds according to PLATO criteria: fatal bleeds or any ICH, or cardiac tamponade due to intracardiac bleeding; or hypovolemic shock or acute arterial hypotension requiring vasopressor/inotropic agents or surgical intervention, or clinically overt bleeding with a decrease in Hb level of ≥ 50 g/L or transfusion of ≥ 4 units of packed red blood cells.

Other major bleeds according to PLATO criteria: leading to permanent disability or clinically overt bleeding with a decrease in Hb level of 30–50 g/L, or transfusion of 2–3 units of packed red blood cells.

Minor bleeds according to PLATO criteria: require medical intervention to stop or manage the bleeding.

In the PEGASUS trial, the incidence of major bleeding according to TIMI criteria in the ticagrelor 60 mg twice daily treatment group was higher than in the aspirin-only treatment group. Compared with aspirin-only therapy, no increase in fatal bleeding was observed, and only a slight increase in the risk of ICH was noted. There were few fatal bleeding events during the study: 11 (0.3%) in the ticagrelor 60 mg treatment group and 12 (0.3%) in the aspirin-only treatment group. The increased risk of major bleeding according to TIMI criteria observed in the ticagrelor 60 mg treatment group was primarily due to a higher incidence of other major bleeds according to TIMI criteria, most of which were gastrointestinal disorders.

A similar trend toward increased bleeding frequency, as observed for major bleeds according to TIMI criteria, was also seen for the following types of bleeding: major or minor bleeds according to TIMI criteria, major bleeds according to PLATO criteria, and major or minor bleeds according to PLATO criteria (see Table 3). Discontinuation of treatment due to bleeding occurred more frequently in the ticagrelor 60 mg treatment group than in the aspirin-only treatment group (6.2% vs. 1.5%, respectively). Most of these bleeding events were of lower severity (classified as medically attended bleeds according to TIMI criteria), such as epistaxis, bruising, and hematomas.

The bleeding profile of ticagrelor 60 mg was consistent across many predefined subgroups (i.e., by age, sex, weight, race, geographic region, comorbidities, and medical history) for major bleeds according to TIMI criteria, major or minor bleeds according to TIMI criteria, and major bleeds according to PLATO criteria.

Intracranial hemorrhage. Spontaneous ICH was reported at a similar frequency in both the ticagrelor 60 mg treatment group and the aspirin-only treatment group (n = 13, 0.2% in both treatment groups). A slightly higher frequency of trauma- or procedure-related ICH was observed in the ticagrelor 60 mg treatment group (n = 15, 0.2%) compared to the aspirin-only treatment group (n = 10, 0.1%). During the study, 6 fatal ICH events occurred in the ticagrelor 60 mg treatment group and 5 in the aspirin-only treatment group. The incidence of ICH was low in both treatment groups, considering the significant number of comorbidities and cardiovascular risk factors in the study population.

Dyspnea

Patients treated with ticagrelor reported dyspnea and a sensation of breathlessness. In the PLATO trial, 13.8% of patients treated with ticagrelor and 7.8% of patients treated with clopidogrel reported this adverse reaction (dyspnea, dyspnea at rest, exertional dyspnea, paroxysmal nocturnal dyspnea, and nocturnal dyspnea). In the PLATO trial, dyspnea was considered treatment-related by investigators in 2.2% of patients in the ticagrelor group and 0.6% in the clopidogrel group; some of these cases were serious (0.14% in the ticagrelor group; 0.02% in the clopidogrel group) (see section "Special precautions"). Most dyspnea symptoms were mild or moderate; in most cases, a single episode occurred shortly after initiation of treatment.

Compared with clopidogrel use, patients with asthma/COPD receiving ticagrelor have an increased risk of non-serious dyspnea events (3.29% with ticagrelor vs. 0.53% with clopidogrel) and serious dyspnea events (0.38% with ticagrelor vs. 0.00% with clopidogrel). In absolute terms, this risk was higher than in the overall study population of PLATO. Ticagrelor should be used with caution in patients with a history of asthma and/or COPD (see section "Special precautions").

Approximately 30% of dyspnea episodes resolved within 7 days. The PLATO trial included patients with baseline conditions such as heart failure, COPD, or asthma; these patients, as well as elderly patients, were more prone to developing dyspnea. 0.9% of patients receiving ticagrelor discontinued study treatment prematurely due to dyspnea, compared with 0.1% of patients receiving clopidogrel. The higher incidence of dyspnea with ticagrelor is not associated with the development of new or worsening pre-existing heart or lung disease (see section "Special precautions"). Ageta® does not affect pulmonary function test results.

Laboratory findings

Increased uric acid levels: in the PLATO trial, serum uric acid concentration increased above the upper limit of normal in 22% of patients in the ticagrelor group compared to 13% in the clopidogrel group. Corresponding values in the PEGASUS trial were 9.1%, 8.8%, and 5.5% with ticagrelor 90 mg, 60 mg, and placebo, respectively. Mean serum uric acid levels increased by approximately 15% with ticagrelor compared to approximately 7.5% with clopidogrel; after discontinuation of treatment, levels decreased by approximately 7% with ticagrelor but did not decrease with clopidogrel. In the PEGASUS trial, reversible increases in mean serum uric acid levels of 6.3% and 5.6% were observed in the ticagrelor 90 mg and 60 mg groups, respectively, compared to a 1.5% decrease in the placebo group. In the PLATO trial, the incidence of gouty arthritis was 0.2% in the ticagrelor group and 0.1% in the clopidogrel group. Corresponding rates for gout/gouty arthritis in the PEGASUS trial were 1.6%, 1.5%, and 1.1% in the ticagrelor 90 mg, 60 mg, and placebo groups, respectively.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Packaging. 10 tablets in a blister. 6 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and location of business activity.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.