Agreta

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

Composition:

Active substance: ticagrelor;

One film-coated tablet contains 60 mg of ticagrelor;

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

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

Pharmaceutical form. Film-coated tablets.

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

Pharmacotherapeutic group. Antithrombotic agents. Antiplatelet agents, excluding heparin. ATC code B01A C24.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Agréta® contains ticagrelor, which belongs to the chemical class of cyclopentyltriazolopyrimidines (CPTPs) and is an oral, direct-acting, selective, and reversibly binding P2Y12 receptor antagonist that prevents adenosine diphosphate (ADP)-mediated P2Y12-dependent activation and aggregation of platelets. 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 thrombotic complications of atherosclerosis, inhibition of platelet function has been shown to reduce the risk of cardiovascular (CV) events such as death, myocardial infarction (MI), or stroke.

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

Ticagrelor enhances adenosine-induced effects in healthy subjects and in patients with acute coronary syndrome (ACS), including vasodilation (as evidenced by increased coronary blood flow in healthy volunteers and ACS patients; headache), inhibition of platelet function (in whole human 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 was rapid. This was evidenced by a mean platelet aggregation inhibition (PAI) of approximately 41% 0.5 hours after administration of a 180 mg loading dose. Maximum PAI of 89% was achieved within 2–4 hours after dosing and was maintained for 2–8 hours. In 90% of patients, the final PAI value 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.

Data on switching between medications

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 switched from clopidogrel to ticagrelor without interruption of antiplatelet effect (see section "Dosage and administration").

Clinical efficacy and safety

Clinical evidence of efficacy and safety of ticagrelor was obtained in two Phase III trials:

The PLATO trial [PLATelet Inhibition and Patient Outcomes], which compared ticagrelor and clopidogrel when used in combination with ASA and other standard therapy.

The PEGASUS TIMI-54 trial [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 trial (acute coronary syndrome)

The PLATO trial included 18,624 patients with symptoms of unstable angina (UA), non-ST-elevation myocardial infarction (NSTEMI), or ST-elevation myocardial infarction (STEMI), initially treated medically or with percutaneous coronary intervention (PCI) or CABG.

Clinical efficacy

With background daily ASA use, 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, 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 of 54 ACS patients with ticagrelor instead of clopidogrel prevented one atherothrombotic event; treatment of 91 patients prevented one CV death.

The greater efficacy of ticagrelor compared to clopidogrel was independent of patient body weight or sex, presence of diabetes, transient ischemic attack (TIA), non-hemorrhagic stroke, revascularization, or concomitant therapy with medications including heparins, GpIIb/IIIa inhibitors, and proton pump inhibitors (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 UA/NSTEMI and STEMI patients.

The hazard ratio (HR) for PCE favored ticagrelor in countries outside North America, which accounted for approximately 10% of the total study population (interaction p-value = 0.045). A post hoc analysis suggests a possible dose-dependent interaction, as higher ASA doses were associated with reduced efficacy of ticagrelor. The recommended daily maintenance dose of ASA to be used concomitantly with Agréta® 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, Agréta® 90 mg twice daily in combination with low-dose ASA can be prescribed to patients with ACS (UA, NSTEMI, STEMI), including those undergoing medical therapy, PCI, or CABG.

PLATO genetic substudy

Genotyping of 10,285 patients for CYP2C19 and ABCB1 in the PLATO trial established associations between genotype groups and outcomes. The advantages of ticagrelor over clopidogrel in reducing the frequency of serious CV events were not significantly influenced by the patient's CYP2C19 or ABCB1 genotype. There was no difference in the overall frequency of major bleeding between ticagrelor and clopidogrel groups regardless of CYP2C19 or ABCB1 genotype. The frequency of non-CABG-related major bleeding as defined in the PLATO trial was increased with ticagrelor compared to clopidogrel in patients lacking one or more functional CYP2C19 alleles, but similar to 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 trial) 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 substudy

Based on Holter monitoring data from the PLATO trial, more patients in the ticagrelor group than in the clopidogrel group had episodes of ventricular pauses ≥ 3 seconds during the acute phase of ACS. Such episodes were more common in patients with chronic heart failure (CHF) compared to the general population, but 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 difference were observed in this patient population.

PEGASUS trial (prior myocardial infarction)

The PEGASUS TIMI-54 trial 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, diabetes requiring medication, prior second MI, evidence of multivessel coronary artery disease, 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, history of 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% for ticagrelor 60 mg, and RRR of 15% and ARR of 1.19% for 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 Agréta® 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 alone, ticagrelor 60 mg twice daily significantly reduced the frequency of the PCE (CV death, MI, and stroke). The reduction in PCE was driven by reductions in each of its components (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 efficacy and safety of ticagrelor use beyond 3 years are limited.

There was no evidence of benefit (no reduction in PCE [CV death, MI, and stroke] and increased frequency of major bleeding) 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%) compared to younger patients (range: 23–31%), with a difference compared to placebo exceeding 10% (42% vs. 29%) in patients aged > 75 years.

Children

In a randomized, double-blind, Phase III, parallel-group trial (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% two 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 subpopulations with acute coronary syndrome (ACS) and prior myocardial infarction (MI) (see section "Dosage and administration" for information on pediatric use).

Pharmacokinetics.

The pharmacokinetics of ticagrelor are linear, and exposure to ticagrelor and its active metabolite (AR-C124910XX) is approximately dose-proportional up to 1260 mg.

Absorption

Ticagrelor is rapidly absorbed, with a median tmax of approximately 1.5 hours. The main circulating metabolite of ticagrelor, AR-C124910XX (also active), is formed 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 was 529 ng/mL and AUC was 3451 ng*h/mL. The metabolite-to-parent ratio was 0.28 for Cmax and 0.42 for AUC. The pharmacokinetics of ticagrelor and AR-C124910XX in patients with prior MI were generally similar to those in the ACS patient population. According to population pharmacokinetic analysis of the PEGASUS trial, median Cmax of ticagrelor was 391 ng/mL and AUC was 3801 ng*h/mL at steady state with 60 mg dosing. 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 AUC of ticagrelor by 21% and decreased Cmax of the active metabolite by 22%, but did not affect Cmax of ticagrelor or AUC of the active metabolite. These changes are of minimal clinical significance; therefore, ticagrelor can be administered regardless 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, has bioavailability comparable to that of intact tablets, based on AUC and Cmax values of ticagrelor and its active metabolite. Initial exposure (0.5 and 1 hour after dosing) of crushed and water-mixed ticagrelor tablets was higher than that of intact tablets, but concentration profiles were generally similar thereafter (2–48 hours).

Distribution

The steady-state volume of distribution 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 receptors P2Y12. Systemic exposure to the active metabolite is about 30–40% of systemic exposure to ticagrelor.

Elimination

The main route of elimination of ticagrelor 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). Less than 1% of the dose was excreted in urine as ticagrelor or active metabolite. The main 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.

Special patient populations

Elderly patients

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

Children

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 trial, 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 pediatric tablets at doses of 15, 30, and 45 mg twice daily, respectively. Pharmacokinetic analysis in this population showed mean AUC of ticagrelor ranging from 1095 to 1458 ng*h/mL and mean Cmax from 143 to 206 ng/mL at steady state.

Gender

Women had higher exposure to ticagrelor and active metabolite than 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 of ticagrelor (90 mg daily dose) were 38% and 51% higher, respectively, when hemodialysis was not performed, 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 severe hepatic impairment has not been studied; pharmacokinetic data in patients with moderate hepatic impairment are lacking. In patients with moderate or marked baseline elevations of one or more liver function tests, 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 was 39% higher than in Caucasian patients. In patients of Black origin, bioavailability of ticagrelor was 18% lower than in Caucasian patients. In a clinical pharmacology study, exposure (Cmax and AUC) to ticagrelor in Japanese subjects was approximately 40% higher (20% higher after body weight adjustment) than in Caucasians. Drug exposure in patients of Spanish or Latin American 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) or
• history of myocardial infarction (MI) and high risk of developing atherothrombotic events (see sections "Dosage and administration" and "Pharmacodynamics").

Contraindications.

Hypersensitivity to the active substance or to any of the excipients (see section "Side effects").

Active pathological bleeding.

History of intracranial haemorrhage (see section "Side effects").

Severe hepatic impairment (see sections "Dosage and administration", "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-glycoprotein (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 resulted in 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; therefore, they may 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 resulted in 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 therefore is not recommended.

Cyclosporine (P-gp and CYP3A inhibitor)

Concomitant administration of cyclosporine (600 mg) and ticagrelor resulted in 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 P-gp inhibitors and moderate CYP3A4 inhibitors (e.g. verapamil, quinidine), which may increase ticagrelor exposure, are lacking. If such combination cannot be avoided, concomitant use of these medicinal products should be undertaken with caution.

Others

Clinical pharmacological interaction studies showed that concomitant administration of ticagrelor with heparin, enoxaparin, and 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 of oral P2Y12 inhibitors, including ticagrelor and its active metabolites, was observed (reduction in ticagrelor effect by 35%). This interaction may be related to reduced gastrointestinal (GI) motility and may also apply to other opioid agents. The clinical significance of this interaction is unknown, but data suggest a potential reduction in ticagrelor efficacy in patients receiving ticagrelor and morphine concomitantly. For patients with ACS in whom morphine administration cannot be delayed and rapid P2Y12 inhibition is considered life-saving, consideration may 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%, as well as 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/day may cause simvastatin-related adverse effects, which should be weighed against the 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 safety issues with statin use 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 concomitant use of P-gp-dependent medicinal products with a narrow therapeutic index, such as digoxin, with ticagrelor is necessary, 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 either medicinal product, indicating that ticagrelor is not an inhibitor of CYP2C9, and therefore it is unlikely that the medicinal product will affect CYP2C9-mediated metabolism of medicinal products such as warfarin and tolbutamide.

Rosuvastatin

Ticagrelor may affect renal excretion of rosuvastatin, increasing the risk of its accumulation. Although the exact mechanism is unknown, in some cases, concomitant administration of ticagrelor and rosuvastatin resulted in worsening renal function, increased CK 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 with concomitant use of levonorgestrel and ethinylestradiol with ticagrelor.

Medicinal products capable of causing bradycardia

Since cases of predominantly asymptomatic ventricular pauses and bradycardia have been observed, ticagrelor should be used with caution 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 administration 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 therapies

In clinical trials, ticagrelor was frequently used concomitantly with ASA, PPIs, statins, beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) for prolonged periods as required by patients' concomitant conditions; as well as with heparin, low-molecular-weight heparin, and intravenous GpIIb/IIIa inhibitors 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 concomitantly with medicinal products capable of affecting haemostasis.

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

Special precautions for use.

Bleeding risk

The use of ticagrelor in patients with known increased risk of bleeding should be carefully considered against the benefit of the medicinal product in preventing atherothrombotic events (see sections "Side effects" and "Pharmacodynamics"). Ticagrelor should be used with caution in the following patient groups when clinically indicated:

• Patients with a predisposition to bleeding (e.g., due to recent trauma or surgical procedures, coagulation disorders, active or recent gastrointestinal bleeding) or with an increased risk of trauma. Ticagrelor is contraindicated in patients with active pathological bleeding, history of intracranial hemorrhage (ICH), and patients with severe hepatic impairment (see section "Contraindications").
• Patients who are concurrently using (within 24 hours after ticagrelor administration) medicinal products capable of increasing the risk of bleeding (e.g., nonsteroidal anti-inflammatory drugs, oral anticoagulants, and/or fibrinolytic agents).

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 concomitant administration of ticagrelor with desmopressin did not reduce template bleeding time, desmopressin is unlikely to be effective in treating clinical bleeding (see section "Interaction with other medicinal products and other forms of interaction").

The 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, including dentists, that they are taking ticagrelor prior to any planned surgical procedure and before starting any new medicinal product.

In the PLATO study, in patients undergoing CABG, bleeding events were more frequent in the ticagrelor group than in the clopidogrel group when therapy was discontinued one day before surgery; however, major bleeding occurred with similar frequency in both groups when therapy was stopped two or more days before surgery (see section "Side effects"). If a patient requires elective surgery and an antiplatelet effect is undesirable, ticagrelor should be discontinued five days prior to surgery (see section "Pharmacodynamic properties").

Patients with prior ischemic stroke

Patients with 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 not included in the PEGASUS study. Therefore, due to lack of data, treatment beyond one year is not recommended for such patients.

Hepatic impairment

Ticagrelor is contraindicated in patients with severe hepatic impairment (see sections "Dosage and administration" and "Contraindications"). Experience with ticagrelor in patients with moderate hepatic impairment is limited; therefore, the medicinal product should be used with caution in these patients (see sections "Dosage and administration" and "Pharmacokinetic properties").

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 increased risk of bradycardia (e.g., patients without a pacemaker who have sick sinus syndrome, second- or third-degree atrioventricular block, or syncope due to bradycardia) were not included in the main studies evaluating the safety and efficacy of ticagrelor. Therefore, due to limited clinical experience, ticagrelor should be used with caution in such patients (see section "Pharmacodynamics").

Concomitant use of ticagrelor with medicinal products capable of causing bradycardia requires caution. However, in the PLATO study, no signs of clinically significant interactions 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) (see section "Interaction with other medicinal products and other forms of interaction").

During the Holter substudy of the PLATO study, episodes of ventricular pauses lasting ≥ 3 seconds were more frequently observed during the acute phase of ACS with ticagrelor than with clopidogrel. The increased frequency of Holter-detected ventricular pauses 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 with ticagrelor or 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").

During the post-marketing period, cases of bradyarrhythmia and atrioventricular block have been reported in patients taking ticagrelor, predominantly in patients with ACS, where myocardial ischemia and concomitant use of medicinal products that reduce heart rate or affect cardiac conduction are potential contributing factors. Before adjusting therapy, the patient's clinical status and concomitant medications should be evaluated as potential causes.

Dyspnea

Dyspnea has been observed in patients receiving ticagrelor. Dyspnea was usually mild or moderate in severity and often resolved without the need to discontinue treatment. The absolute risk of developing dyspnea with ticagrelor may be increased in patients with asthma (BA)/chronic obstructive pulmonary disease (COPD). Ticagrelor should be used with caution 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 evaluation should be performed, and if intolerance to the medicinal product is suspected, treatment with ticagrelor should be discontinued. For further information, see section "Side effects".

Central sleep apnea

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

Increase in creatinine levels

Creatinine levels may increase during treatment with ticagrelor. The mechanism of this phenomenon is not fully understood. Renal function should be monitored according to standard medical practice. In patients with ACS, renal function should also be checked one month after initiation of ticagrelor therapy, with particular attention to patients aged ≥ 75 years, patients with moderate to severe renal impairment, and those concomitantly using ACE inhibitors (ACEIs).

Increase in uric acid levels

Hyperuricemia may occur during treatment with ticagrelor (see section "Side effects"). Caution should be exercised when treating patients with a history of hyperuricemia or gouty arthritis. Use of ticagrelor in patients with uric acid nephropathy is not recommended.

Thrombotic thrombocytopenic purpura

Very rare cases of thrombotic thrombocytopenic purpura (TTP), characterized by thrombocytopenia and microangiopathic hemolytic anemia associated with neurological findings, renal dysfunction, or fever, have been reported during ticagrelor use. 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 heparin-induced thrombocytopenia (HIT), antibodies to the platelet factor 4/heparin complex in the patient's serum activate platelets from healthy donors in the presence of heparin.

In patients receiving ticagrelor, false-negative results in platelet function tests (including the HIPA test and others) for the diagnosis of HIT have been reported. This is due to the inhibition by ticagrelor of P2Y12 receptors on donor platelets in the patient's serum/plasma test. Information on concomitant ticagrelor therapy is necessary for the interpretation of platelet function test results in the diagnosis of HIT.

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

Other

Due to the observed relationship between maintenance dose of aspirin and the relative efficacy of ticagrelor compared to clopidogrel in the PLATO study, concomitant use of ticagrelor and 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., essentially sodium-free.

Early discontinuation of treatment

Premature discontinuation of any antiplatelet agent, including the medicinal product Agreta®, may increase the risk of cardiovascular death, MI, or stroke due to the underlying condition of the patient. Therefore, premature discontinuation of therapy should be avoided.

Use during pregnancy or breastfeeding.

Women of childbearing potential

Women of childbearing 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

Pharmacodynamic/toxicological animal studies indicate that ticagrelor and its active metabolite are excreted in breast milk. Risk to the newborn/infant cannot be excluded. The decision on whether to discontinue breastfeeding or to discontinue/abstain from 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 did not affect fertility in male and female animals.

Ability to affect reaction speed when driving or operating machinery.

Ticagrelor has no effect or a negligible effect on the ability to drive and use machinery. Cases of dizziness and confusion have been reported during treatment with ticagrelor. Therefore, patients experiencing these symptoms should exercise caution when driving or operating machinery.

Method of Administration and Dosage

Dosage

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

Acute Coronary Syndrome (ACS)

Treatment with the medicinal product Ageta® 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 Ageta® 90 mg in 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 Ageta® 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"). For patients with ACS at high risk of atherothrombotic events, treatment may be initiated without interruption as a continuation of therapy following initial treatment with Ageta® 90 mg or another adenosine diphosphate (ADP) receptor inhibitor for one year. Treatment may also be initiated within 2 years following the 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 Ageta®, the first dose of Ageta® should be taken 24 hours after the last dose of the previous antiplatelet medicinal product.

Missed Dose

Patients should avoid missing doses of the medicinal product. If a patient misses a dose of Ageta®, they should take only one tablet (the next dose) at the scheduled time.

Special Patient Groups

Elderly Patients

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

Renal Impairment

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

Hepatic Impairment

The use of ticagrelor in patients with severe hepatic impairment has not been studied, and therefore the medicinal product is contraindicated in such patients (see section "Contraindications"). Information regarding use in patients with moderate hepatic impairment is limited. Dose adjustment is not recommended; however, 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.

Ageta® may be administered regardless of food intake.

For patients unable to swallow the tablet whole, the tablet can be crushed into a powder, mixed with half a glass of water, and taken immediately. The glass should then be rinsed with another half glass of water, and the rinse water consumed. The mixture can also be administered via a nasogastric tube (size 8 or larger). It is important to flush the nasogastric tube with water after administration of the mixture.

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 anemia (see section "Pharmacological Properties").

Overdose

Ticagrelor is well tolerated at single doses up to 900 mg. Gastrointestinal toxicity was dose-limiting in a study with escalating single doses. Other clinically significant adverse reactions that may occur in overdose include dyspnea 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.

An antidote for ticagrelor is currently unknown; 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"). Appropriate supportive measures should be taken in case of bleeding.

Adverse reactions

The safety profile of ticagrelor was evaluated in two large-scale Phase III clinical trials designed to assess 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 (ARs) was higher among patients receiving ticagrelor compared to those receiving clopidogrel (7.4% vs. 5.4%). In the PEGASUS study, the rate of premature discontinuation due to ARs was higher among patients receiving ticagrelor compared to those receiving aspirin (ASA) alone (16.1% with ticagrelor 60 mg plus ASA vs. 8.5% with ASA alone). The most common ARs in patients treated with ticagrelor were bleeding and dyspnea (see section "Special precautions").

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

Adverse reactions are listed by MedDRA system organ class. Within each system organ class, adverse reactions are categorized by frequency. Frequency groupings are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Table 1. Adverse reactions by frequency and system organ class

| System organ class | Very common (≥ 1/10) | Common (≥ 1/100 to < 1/10) | Uncommon (≥ 1/1,000 to < 1/100) | Rare (≥ 1/10,000 to < 1/1,000) | Very rare (< 1/10,000) | Frequency not known | |--------------------|----------------------|----------------------------|----------------------------------|-------------------------------|------------------------|-----------------------| | Infections and infestations | | | | | | | | | | | | | | | | Blood and lymphatic system disorders | | | | | | | | | | | | | | | | Immune system disorders | | | | | | | | | | | | | | | | Metabolism and nutrition disorders | | | | | | | | | | | | | | | | Psychiatric disorders | | | | | | | | | | | | | | | | Nervous system disorders | | | | | | | | | | | | | | | | Eye disorders | | | | | | | | | | | | | | | | Ear and labyrinth disorders | | | | | | | | | | | | | | | | Cardiac disorders | | | | | | | | | | | | | | | | Vascular disorders | | | | | | | | | | | | | | | | Respiratory, thoracic and mediastinal disorders | Dyspnea¹ | | | | | | | | | | | | | | | Gastrointestinal disorders | | Nausea, Diarrhea, Vomiting | | | | | | | | | | | | | | Hepatobiliary disorders | | | | | | | | | | | | | | | | Skin and subcutaneous tissue disorders | | | | | | | | | | | | | | | | Musculoskeletal and connective tissue disorders | | | | | | | | | | | | | | | | Renal and urinary disorders | | | | | | | | | | | | | | | | Reproductive system and breast disorders | | | | | | | | | | | | | | | | General disorders and administration site conditions | | | | | | | | | | | | | | | | Investigations | | | | | | | | | | | | | | |

¹ See section "Special precautions" for important information on dyspnea.
Note: The table above is incomplete as per the source text; additional adverse reactions may be listed in the full version of the document.

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 established based on laboratory data (increase in uric acid levels above the upper limit of normal from baseline, where baseline was below or within the normal range; increase in creatinine levels by > 50 % from baseline). This does not reflect the reporting frequency of the adverse event.

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

f For example, epistaxis, haemoptysis.

g For example, gingival bleeding, rectal bleeding, bleeding from 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 intracranial haemorrhages.

Description of selected adverse reactions

Bleeding events

Bleeding events in the PLATO study

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

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

Definition of Bleeding Types

Major fatal/life-threatening bleeds: Clinically evident 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 evident 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 persistent loss of functional capacity.

Minor bleeds: Require medical intervention to stop or manage the bleeding.

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

Minor bleeds according to TIMI criteria: Clinically evident 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 rates of major fatal/life-threatening bleeds according to PLATO criteria, total number of major bleeds, or rates of major or minor bleeds according to TIMI criteria. However, the rate of combined major and minor bleeds in the PLATO study 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 TIA, were not predictive factors for overall bleeding rate or rate of major bleeds 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 bleeds related to CABG occurred in 6 patients in each treatment group (see section "Special Warnings and Precautions for Use").

Bleeding not related to CABG and bleeding not related to procedures. The ticagrelor and clopidogrel treatment groups did not differ in the rate of non-CABG-related fatal/life-threatening major bleeds according to PLATO study 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 combined major and 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 ICHs occurred with ticagrelor (n = 27 bleeds in 26 patients, 0.3%) than with clopidogrel (n = 14 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

General results regarding bleeding rates in the PEGASUS study are presented in Table 3.

Table 3. Analysis of total number of bleeding events, assessed by Kaplan-Meier method over 36 months (PEGASUS)

Determination of bleeding type

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

Fatal bleeding: a case of bleeding directly leading to death within 7 days.

ICH: intracranial hemorrhage.

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

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

Bleeding requiring medical attention according to TIMI criteria: bleeding requiring intervention OR leading to hospitalization OR requiring investigation.

Major fatal/threatening bleeding according to PLATO criteria: fatal bleeding OR any type of ICH OR intracardiac bleeding with cardiac tamponade; OR bleeding associated with 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 bleeding according to PLATO criteria: bleeding 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 bleeding according to PLATO criteria: bleeding requiring medical intervention to stop or manage the bleeding.

In the PEGASUS trial, major bleeding (TIMI) occurred more frequently in the ticagrelor 60 mg twice daily treatment group compared to the aspirin-only treatment group. No increase in the risk of fatal bleeding was observed; additionally, only a slight increase in the incidence of ICH was observed compared to aspirin-only treatment. There were a few cases of fatal bleeding in the study: 11 (0.3%) with ticagrelor 60 mg and 12 (0.3%) with aspirin-only treatment. The observed increase in the risk of major bleeding (TIMI) with ticagrelor 60 mg was primarily due to a higher frequency of other major bleeding (TIMI), predominantly gastrointestinal disorders.

A similar trend toward increased bleeding frequency, as seen with major TIMI bleeding, was also observed for major or minor TIMI bleeding and major PLATO bleeding, as well as for major or minor PLATO bleeding. Premature discontinuation of treatment due to bleeding occurred more frequently with ticagrelor 60 mg compared to aspirin-only treatment (6.2% vs. 1.5%, respectively). Most of these bleeding events were less severe (classified as TIMI bleeding requiring medical attention), such as epistaxis, bruising, and hematomas.

The bleeding profile with ticagrelor 60 mg was consistent across all predefined subgroups (e.g., by age, sex, body weight, race, geographic region, comorbidities, concomitant medications, and medical history) regarding major TIMI, major or minor TIMI, and major PLATO bleeding.

Intracranial hemorrhage (ICH): spontaneous ICH occurred at similar frequencies with ticagrelor 60 mg and aspirin-only treatment (n = 13, 0.2% in both treatment groups). Traumatic and procedure-related ICH occurred slightly more frequently with ticagrelor 60 mg (n = 15, 0.2%) compared to aspirin-only treatment (n = 10, 0.1%). There were 6 fatal ICH cases with ticagrelor 60 mg and 5 fatal ICH cases with aspirin-only treatment. The incidence of ICH was low in both treatment groups, considering the significant comorbidities and cardiovascular risk factors in the study population.

Dyspnea

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

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

Approximately 30% of dyspnea episodes resolved within 7 days. The PLATO trial included patients with baseline conditions such as congestive heart failure, COPD, or bronchial asthma; these patients, as well as elderly patients, were more prone to developing dyspnea. 0.9% of patients receiving ticagrelor discontinued the study drug prematurely due to dyspnea compared to 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 warnings and precautions for use"). Ticagrelor does not affect pulmonary function test results.

In the PEGASUS trial, dyspnea was observed in 14.2% of patients receiving ticagrelor 60 mg twice daily and in 5.5% of patients receiving aspirin-only treatment. As in the PLATO trial, most cases of dyspnea were mild or moderate (see section "Special warnings and precautions for use"). Patients who experienced dyspnea were typically elderly and had baseline dyspnea, COPD, or bronchial asthma.

Laboratory findings

Increased uric acid levels: in the PLATO trial, serum uric acid concentrations increased above the upper normal limit in 22% of patients receiving ticagrelor compared to 13% of patients receiving clopidogrel. 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, and decreased by approximately 7% after discontinuation of 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 with ticagrelor 90 mg and 60 mg, respectively, compared to a 1.5% decrease in the placebo group. In the PLATO trial, the incidence of gouty arthritis was 0.2% with ticagrelor and 0.1% with clopidogrel. 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 of 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, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: 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 category. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.