Trobinta is

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TROBINTA IC

Composition:

active substance: ticagrelor;

1 tablet contains 60 mg or 90 mg of ticagrelor;

excipients: mannitol (E 421), calcium hydrogen phosphate dihydrate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hypromellose, polyethylene glycol, calcium carbonate.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex film-coated tablets.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The medicinal product Trobinta IC contains ticagrelor, a member of the chemical class of cyclopentyltriazolopyrimidines (CPTPs), which is an oral, selective and direct-acting reversible P2Y12 receptor antagonist that prevents adenosine diphosphate (ADP)-mediated P2Y12-dependent platelet activation and aggregation. Ticagrelor does not prevent binding to adenosine phosphate (ADP), 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 equilibrative nucleoside transporter subtype 1 (ENT-1).

In healthy subjects and in patients with acute coronary syndrome (ACS), ticagrelor has been shown to enhance adenosine-mediated effects such as vasodilation (as determined by increased coronary blood flow in healthy volunteers and ACS patients; headache), inhibition of platelet function (in vitro in human whole blood), and dyspnea. However, the relationship between the observed increase in adenosine levels and clinical outcomes (e.g., morbidity and mortality rates) 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. This is evidenced by measurements of mean platelet aggregation inhibition (PAI): 0.5 hours after administration of a 180 mg loading dose of ticagrelor, the mean PAI value is approximately 41%; maximum PAI of 89% is reached within 2–4 hours after dosing and maintained for 2–8 hours. In 90% of patients, the final PAI value exceeds 70% within 2 hours after dosing.

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 medicinal products

Switching from clopidogrel 75 mg to ticagrelor 90 mg twice daily results in a 26.4% increase in absolute PAI value, while switching from ticagrelor to clopidogrel results in a 24.5% decrease in absolute PAI value. 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 studies:

• the PLATO study [PLATelet Inhibition and Patient Outcomes], in which ticagrelor was compared with 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], in which ticagrelor in combination with ASA was compared with ASA monotherapy.

PLATO study (acute coronary syndrome)

The PLATO study included 18,624 patients who developed symptoms of unstable angina (UA), myocardial infarction without ST-segment elevation (NSTEMI), or myocardial infarction with ST-segment elevation (STEMI) within 24 hours prior to study entry, initially treated medically or with percutaneous coronary intervention (PCI) or CABG.

Clinical efficacy

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

The therapeutic effect was achieved rapidly (absolute risk reduction (ARR) of 0.6% and relative risk reduction (RRR) of 12% at 30 days) and was maintained throughout the 12-month treatment period, resulting in an ARR of 1.9% and RRR of 16% over one year. Results support the use of ticagrelor 90 mg twice daily for 12 months in patients with ACS (see section "Dosage and administration"). Treating 54 ACS patients with ticagrelor instead of clopidogrel prevented one atherothrombotic event; treating 91 patients with ticagrelor prevented one CV death.

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

A weak association between treatment efficacy and geographic region was observed. The risk ratio for the primary endpoint favored ticagrelor in countries outside North America, which accounted for approximately 10% of the total study population (interaction p-value = 0.045). Exploratory analysis suggests a possible association with ASA dose, as reduced efficacy of ticagrelor was observed with increasing ASA dose. Doses of ASA for continuous daily use with ticagrelor should be 75–150 mg (see sections "Special precautions" and "Dosage and administration").

Ticagrelor treatment reduced the incidence of the primary composite endpoint compared to clopidogrel in patients with UA, NSTEMI, and STEMI. Therefore, ticagrelor 90 mg twice daily in combination with low-dose ASA can be prescribed to patients with ACS (UA, NSTEMI, or STEMI), including those treated medically or with PCI or CABG.

Genetic substudy of PLATO

Genotyping of 10,285 patients for CYP2C19 and ABCB1 in the PLATO study established associations between genotype groups and outcomes. The advantages of ticagrelor over clopidogrel in reducing major CV events were not significantly dependent on patient CYP2C19 or ABCB1 genotype. The overall incidence of major bleeding in the PLATO study did not differ between ticagrelor and clopidogrel groups, regardless of CYP2C19 or ABCB1 genotype. The incidence of non-CABG-related major bleeding according to PLATO criteria was increased with ticagrelor compared to clopidogrel in patients with one or more loss-of-function CYP2C19 alleles, but was similar to that with clopidogrel in patients without loss-of-function alleles.

Comprehensive assessment of efficacy and safety

A comprehensive assessment of efficacy and safety (CV death, MI, stroke, or total major bleeding according to PLATO criteria) indicates that the efficacy benefits of ticagrelor over clopidogrel are not offset by major bleeding events (ARR 1.4%, RRR 8%, hazard ratio 0.92; p = 0.0257) over 12 months after ACS.

Clinical safety

Substudy using Holter ECG monitoring

To determine the frequency of ventricular asystole episodes and other arrhythmias during the PLATO study, Holter ECG monitoring was performed in a subgroup of approximately 3,000 patients, of whom about 2,000 had ECG recordings during the acute phase of ACS and one month after the acute phase. According to Holter monitoring, the proportion of patients with ventricular asystole episodes ≥ 3 seconds was higher in the ticagrelor group (6.0%) than in the clopidogrel group (3.5%) during the acute phase of ACS; and 2.2% and 1.6%, respectively, one month after the acute phase (see section "Special precautions"). The increase in ventricular asystole frequency during the acute phase of ACS was more pronounced in patients with a history of chronic heart failure (CHF) receiving ticagrelor (9.2% vs. 5.4% in patients without CHF history; for clopidogrel patients: 4.0% vs. 3.6% without CHF history); one month after the acute phase, no imbalance was observed: 2.0% vs. 2.1% for ticagrelor patients with and without CHF history, respectively; and 3.8% vs. 1.4% for clopidogrel patients with and without CHF history. No adverse clinical consequences (including need for pacemaker implantation) related to this imbalance were observed in this patient population.

PEGASUS study (history of 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 90 mg twice daily or 60 mg twice daily in combination with low-dose ASA (75–150 mg) compared to ASA monotherapy in patients with prior MI and additional risk factors for atherothrombosis.

Patients included were aged ≥ 50 years with prior MI (1 to 3 years before randomization) and at least one of the following atherothrombosis risk factors: age ≥ 65 years, diabetes requiring medication, prior second MI, multivessel coronary artery disease, or chronic non-terminal stage renal impairment.

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). A consistent therapeutic effect was observed throughout the study period, resulting in 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.

Although efficacy profiles of ticagrelor 90 mg and 60 mg were similar, data suggest the lower dose has better tolerability and a more favorable safety profile regarding bleeding risk and dyspnea. Therefore, for prevention of atherothrombotic events (CV death, MI, and stroke) in patients with prior MI and high risk of atherothrombotic events, ticagrelor is recommended only at a dose of 60 mg twice daily in combination with ASA.

Compared to ASA alone, ticagrelor 60 mg twice daily significantly reduced the incidence of the primary composite endpoint (CV death, MI, and stroke), driven by reductions in each component (RRR of CV death: 17%, RRR of MI: 16%, RRR of stroke: 25%).

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

There was no evidence of benefit [no reduction in the primary composite endpoint (CV death, MI, and stroke) and increased incidence 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 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 > 75 years.

Children

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

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 ticagrelor studies in all pediatric subgroups with ACS and prior MI (see section "Children" for information on pediatric use).

Pharmacokinetics.

Ticagrelor pharmacokinetics 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 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, the maximum plasma concentration (Cmax) of ticagrelor was 529 ng/mL, and the area under the concentration-time curve (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 observed in the ACS patient population. According to population pharmacokinetic analysis of the PEGASUS study, at steady state with ticagrelor 60 mg, median Cmax of ticagrelor was 391 ng/mL and AUC was 3801 ng*h/mL. With ticagrelor 90 mg at steady state, Cmax was 627 ng/mL and AUC was 6255 ng*h/mL.

The mean absolute bioavailability of ticagrelor is 36%. A high-fat meal increases the AUC of ticagrelor by 21% and decreases the Cmax of the active metabolite by 22%, but does not affect the Cmax of ticagrelor or the AUC of the active metabolite. These minor changes are of minimal clinical significance; therefore, ticagrelor can be administered independently of food intake. Ticagrelor and its active metabolite are substrates of P-glycoprotein (P-gp).

Bioavailability of orally administered ticagrelor as crushed tablets mixed with water or administered via nasogastric tube into the stomach is comparable to that of intact tablets in terms of AUC and Cmax of ticagrelor and its active metabolite. Initial exposure to ticagrelor (0.5 and 1 hour after dosing) was higher with crushed and water-mixed tablets than with intact tablets, but concentration profiles were identical thereafter (2–48 hours).

Distribution

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

Biotransformation

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

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

Elimination

The primary route of elimination of ticagrelor is hepatic metabolism. After administration of radiolabeled ticagrelor, the mean level of radioactivity excreted was approximately 84% (57.8% in feces, 26.5% in urine). Less than 1% of the dose was excreted in urine as ticagrelor or active metabolite. The primary route of elimination of the active metabolite is likely biliary excretion. The mean elimination half-life (t1/2) of ticagrelor is approximately 7 hours, and that of the active metabolite is 8.5 hours.

Special patient groups

Elderly patients

Population pharmacokinetic analysis in elderly patients (≥ 75 years) with ACS showed 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 subsection "Pharmacodynamics" and section "Dosage and administration").

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

Gender

Higher exposure to ticagrelor and its active metabolite was 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 on hemodialysis, AUC and Cmax of ticagrelor after a 90 mg dose were 38% and 51% higher, respectively, when administered on a non-dialysis day compared to patients with normal renal function. Similar increases were observed when ticagrelor was administered immediately before dialysis (49% and 61%, respectively), indicating that ticagrelor is not dialyzable. Exposure to the active metabolite increased to a lesser extent (AUC by 13–14% and Cmax by 17–36%). In patients with end-stage renal disease, the effect of ticagrelor on PAI was independent of dialysis and 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 effect of ticagrelor on PAI was similar in both groups. Dose adjustment is not required in patients with mild hepatic impairment. Ticagrelor has not been studied in patients with severe hepatic impairment; pharmacokinetic data in patients with moderate hepatic impairment are lacking. In patients with moderate or marked baseline elevations in one or more liver function tests, plasma concentrations of ticagrelor were on average similar or slightly higher than in patients without baseline abnormalities. Dose adjustment is not required in patients with moderate hepatic impairment (see sections "Special precautions" and "Dosage and administration").

Ethnicity

In Asian patients, mean bioavailability of ticagrelor is 39% higher than in Caucasian patients. In Black patients, bioavailability of ticagrelor is 18% lower than in Caucasian patients. In clinical pharmacology studies, exposure (Cmax and AUC) to ticagrelor in Japanese patients was approximately 40% higher (20% higher after body weight adjustment) than in Caucasian patients. Exposure to ticagrelor in patients of Spanish or Latin American origin was similar to that in Caucasian patients.

Clinical characteristics.

Indications.

The use of the medicinal product Trobinta IC in combination with acetylsalicylic acid is indicated for the prevention of atherothrombotic events in adult patients with:

• acute coronary syndrome

or

• history of myocardial infarction and high risk of developing atherothrombotic events (see sections “Pharmacological properties” and “Dosage and administration”).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in the section “Composition” (see section “Adverse reactions”).

Active pathological bleeding.

History of intracranial hemorrhage (see section “Adverse reactions”).

Severe hepatic impairment (see subsection “Pharmacokinetics”, sections “Special warnings and precautions for use” and “Dosage and administration”).

Concomitant use of ticagrelor with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir) is contraindicated, as this 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 weak inhibitor of CYP3A4. Ticagrelor is also a substrate of P-gp and a weak inhibitor of P-gp, and may increase exposure to P-gp substrates.

Effects of medicinal products and other substances on ticagrelor

Inhibitors of CYP3A4

• Strong CYP3A4 inhibitors. Concomitant administration of ketoconazole and ticagrelor increases Cmax and AUC of ticagrelor by 2.4 and 7.3 times, respectively. Cmax and AUC of the active metabolite decrease 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 and ticagrelor increases Cmax of ticagrelor by 69%, AUC by 2.7 times, and decreases Cmax of the active metabolite by 38%, while AUC remains unchanged. Ticagrelor does not affect plasma concentrations of diltiazem. 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 (200 ml × 3) increases ticagrelor exposure by 2 times. Such an increase in exposure is not expected to be clinically significant for most patients.

Inducers of CYP3A4

Concomitant administration of rifampicin and ticagrelor decreases Cmax and AUC of ticagrelor by 73% and 86%, respectively. Cmax of the active metabolite remains unchanged, while AUC decreases 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 reduce ticagrelor exposure and efficacy; therefore, such concomitant use is not recommended.

Cyclosporine (inhibitor of P-gp and CYP3A)

Concomitant administration of cyclosporine (600 mg) and ticagrelor increases Cmax and AUC of ticagrelor by 2.3 and 2.8 times, respectively. AUC of the active metabolite increases by 32%, while Cmax decreases 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 also increase ticagrelor exposure, are lacking. If such combination cannot be avoided, concomitant use of these medicinal products should be performed with caution.

Others

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

In patients with ACS who received morphine, reduced exposure and prolonged time to onset of action of oral P2Y12 receptor inhibitors, including ticagrelor and its active metabolite (35% reduction in ticagrelor exposure), were observed. This interaction may be related to reduced gastrointestinal motility; other opioids may have a similar effect. The clinical significance of this interaction is unknown, but data suggest a possible reduction in ticagrelor efficacy in patients receiving concomitant ticagrelor and morphine. For patients with ACS in whom morphine administration cannot be delayed and rapid P2Y12 receptor inhibition is considered critically important, the use of a parenterally administered P2Y12 receptor inhibitor may be considered.

Effects of ticagrelor on other medicinal products

Medicinal products metabolized by CYP3A4

• Simvastatin. Concomitant administration of ticagrelor and simvastatin increases Cmax and AUC of simvastatin by 81% and 56%, respectively, and increases Cmax and AUC of simvastatin acid by 64% and 52%, respectively, with individual cases showing increases of 2–3 times. Concomitant use of ticagrelor with simvastatin doses exceeding 40 mg daily may cause simvastatin-related adverse effects and requires assessment of the benefit-risk ratio. Simvastatin does not affect plasma concentrations of ticagrelor. A similar effect of ticagrelor on lovastatin is possible. Concomitant use of ticagrelor with simvastatin or lovastatin at doses exceeding 40 mg is not recommended.
• Atorvastatin. Concomitant administration of ticagrelor and atorvastatin increases Cmax and AUC of atorvastatin acid by 23% and 36%, respectively. A similar increase in AUC and Cmax was observed for all metabolites of atorvastatin acid. Such an increase in parameters is not considered clinically significant.
• A similar effect on other statins metabolized by CYP3A4 cannot be excluded. In the PLATO study, participants receiving ticagrelor were taking various statins, and no safety issues related to statin use were identified in 93% of study participants who received these medicinal products.

Ticagrelor is a weak inhibitor of CYP3A4. Concomitant use of ticagrelor with CYP3A4 substrates having 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 and digoxin increases Cmax and AUC of digoxin by 75% and 28%, respectively. When used concomitantly with ticagrelor, the mean trough concentration of digoxin increased by approximately 30%, with some cases showing up to a 2-fold increase in the parameter. Digoxin does not affect Cmax and AUC of ticagrelor and its active metabolite. Therefore, appropriate clinical and/or laboratory monitoring is recommended when using P-gp-dependent medicinal products with a narrow therapeutic index, such as digoxin, concomitantly with ticagrelor.

Ticagrelor does not affect plasma concentrations of cyclosporine. The effect of ticagrelor on other P-gp substrates has not been studied.

Medicinal products metabolized by CYP2C9

Concomitant administration of ticagrelor and tolbutamide did not affect plasma concentrations of either medicinal product, indicating that ticagrelor is not an inhibitor of CYP2C9. Therefore, it is unlikely to 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 use of ticagrelor and rosuvastatin has led to reduced renal function, increased creatine phosphokinase (CPK) levels, and rhabdomyolysis.

Oral contraceptives

Concomitant administration of ticagrelor with levonorgestrel and ethinylestradiol increased ethinylestradiol exposure by approximately 20%, but did not alter the pharmacokinetics of levonorgestrel. Clinically significant effects on the efficacy of oral contraceptives are 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 were observed with concomitant use of one or more medicinal products capable of causing bradycardia (e.g., 96% of patients received beta-blockers, 33% calcium channel blockers (diltiazem and verapamil), and 4% digoxin).

Other concomitant therapies

During clinical trials, ticagrelor was generally used concomitantly with ASA, proton pump inhibitors, statins, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) for prolonged periods as required by patients’ comorbidities, as well as with heparin, low-molecular-weight heparin, and intravenous glycoprotein IIb/IIIa inhibitors for short durations (see subsection “Pharmacodynamics”). No signs of clinically significant adverse interactions with these medicinal products were observed.

Concomitant use 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 affecting hemostasis.

Due to reports of skin hemorrhages associated 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

Prescribing ticagrelor to patients with known increased risk of bleeding requires careful assessment of the benefit of preventing atherothrombotic events against the risk of bleeding (see section "Pharmacodynamics" and section "Adverse reactions"). When clinically indicated, ticagrelor should be used with caution in the following patient groups:

• Patients with a predisposition to bleeding (e.g., due to recent trauma or surgery, coagulation disorders, active or recent history of 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 medicinal products that may increase the risk of bleeding (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, and/or fibrinolytic agents) within 24 hours after taking ticagrelor.

In two randomized controlled trials (TICO and TWILIGHT), in patients with ACS who underwent percutaneous coronary intervention (PCI) with a drug-eluting stent, discontinuation of aspirin (ASA) 3 months after initiation of dual antiplatelet therapy (DAPT) with ticagrelor and ASA, followed by continuation of ticagrelor as monotherapy for 9 or 12 months, respectively, was shown to reduce the risk of bleeding without an observed increase in the risk of major adverse cardiovascular events compared to continuing DAPT. The decision to discontinue ASA 3 months after initiation of DAPT and continue ticagrelor as monotherapy for 9 months in patients with an increased risk of bleeding should be based on clinical judgment, considering the risk of bleeding versus the risk of thrombotic events (see section "Dosage and administration").

Platelet transfusion did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is therefore unlikely to be effective in treating patients with bleeding. Since concomitant administration of ticagrelor and desmopressin did not reduce the standardized bleeding time, desmopressin is unlikely to be effective in managing 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 improve hemostasis. Ticagrelor administration may be resumed once the cause of bleeding has been identified and controlled.

Surgical procedures

Patients should be informed of the necessity to notify physicians, including dentists, that they are taking ticagrelor prior to any planned surgical procedure and before starting any new medication.

In the PLATO study, in patients undergoing coronary artery bypass graft (CABG) surgery, the incidence of bleeding was higher with ticagrelor than with clopidogrel when therapy was discontinued 1 day before surgery. However, when therapy was stopped 2 or more days before surgery, the frequency of major bleeding was similar between the ticagrelor and clopidogrel treatment groups (see section "Adverse reactions"). If a patient requires elective surgery and antiplatelet effect is undesirable, ticagrelor should be discontinued 5 days prior to surgery (see subsection "Pharmacodynamic properties").

Patients with history of ischemic stroke

Patients with ACS who have had an ischemic stroke may receive ticagrelor treatment for up to 12 months (PLATO study).

Patients with a history of myocardial infarction (MI) who have experienced an ischemic stroke were not included in the PEGASUS study. Therefore, due to lack of data, treatment beyond 1 year is not recommended in these patients.

Hepatic impairment

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

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., those without a pacemaker who have been diagnosed with sick sinus syndrome, second- or third-degree atrioventricular block, or syncope associated with 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 subsection "Pharmacodynamics").

Additionally, caution should be exercised when ticagrelor is used concomitantly with medicinal products capable of causing bradycardia. However, in the PLATO study, no clinically significant adverse reactions 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 and verapamil), and 4% received digoxin) (see section "Interaction with other medicinal products and other forms of interaction").

During a substudy with Holter ECG monitoring in 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 ventricular pauses detected by Holter monitoring during ticagrelor treatment was more pronounced in patients with heart failure (HF) than in the overall study population during the acute phase of ACS, but no imbalance was observed 1 month after the acute event. No adverse clinical consequences related to this imbalance (including syncope or need for pacemaker implantation) were observed in this patient population (see subsection "Pharmacodynamics").

During the post-marketing period, cases of bradyarrhythmia and atrioventricular block have been reported in patients taking ticagrelor (see section "Adverse reactions"), mostly in patients with ACS, where myocardial ischemia and concomitant use of medications that reduce heart rate or affect cardiac conduction may have contributed. Before adjusting treatment, the patient's clinical status and concomitant medications should be evaluated as potential contributing factors.

Dyspnea

Dyspnea has been reported in patients receiving ticagrelor. Dyspnea associated with ticagrelor is usually mild or moderate in severity and often resolves without the need to discontinue treatment. In patients with asthma (BA) and/or chronic obstructive pulmonary disease (COPD), the absolute risk of developing dyspnea with ticagrelor may be increased. Ticagrelor should be used with caution in patients with a history of BA and/or COPD. The mechanism of dyspnea with ticagrelor is not fully understood. If a patient reports new-onset dyspnea, persistent dyspnea, or worsening dyspnea, a full evaluation should be performed, and treatment with ticagrelor should be discontinued if intolerance is confirmed. For further details, see section "Adverse reactions".

Central sleep apnea

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

Increase in creatinine levels

Ticagrelor treatment may lead to increased creatinine levels. The mechanism of this effect is not fully understood. Renal function should be monitored according to routine clinical practice. In patients with ACS, renal function should also be checked 1 month after starting ticagrelor, with particular attention to patients aged ≥ 75 years, those with moderate to severe renal impairment, and those receiving concomitant treatment with ACE inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs).

Increase in uric acid levels

Hyperuricemia may occur during treatment with ticagrelor (see section "Adverse reactions"). Caution should be exercised when treating patients with a history of hyperuricemia or gouty arthritis. As a preventive measure, ticagrelor is not recommended in patients with uric acid nephropathy.

Thrombotic thrombocytopenic purpura

Very rare cases of thrombotic thrombocytopenic purpura (TTP) have been reported with ticagrelor. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia, and may be accompanied by neurological abnormalities, renal dysfunction, or fever. TTP is a potentially life-threatening condition requiring immediate treatment, including plasma exchange.

Effect on functional platelet activity testing for diagnosis of heparin-induced thrombocytopenia

In the heparin-induced platelet activation (HIPA) test, used to diagnose heparin-induced thrombocytopenia (HIT), antibodies to the heparin-platelet factor 4 complex in the patient's serum activate platelets from healthy donors in the presence of heparin. In patients receiving ticagrelor, false-negative results have been observed in functional platelet activity assays (including the HIPA test) for the diagnosis of HIT. This is due to inhibition of P2Y12 receptors on donor platelets by ticagrelor present in the patient's serum/plasma during the test. When interpreting functional platelet activity test results for HIT diagnosis, concomitant treatment with ticagrelor should be taken into account.

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

Other

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

Early discontinuation of treatment

Premature discontinuation of any antiplatelet therapy, including the medicinal product Trobinta IC, may increase the risk of death due to cardiovascular events, myocardial infarction, or stroke due to the patient's underlying condition. Therefore, premature discontinuation of therapy should be avoided.

Sodium content

One tablet of the medicinal product Trobinta IC contains less than 1 mmol (or 23 mg) of sodium, i.e., the product is practically sodium-free.

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 during pregnancy.

Breastfeeding

Pharmacodynamic/toxicological animal studies indicate that ticagrelor and its active metabolite are excreted in breast milk. A risk to the newborn/infant cannot be excluded. The decision to discontinue breastfeeding or discontinue ticagrelor therapy should be made, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the mother.

Fertility

Ticagrelor had no effect on 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 or operate machinery. 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 Trobinta IC 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 Trobinta IC should be initiated with a single loading dose of 180 mg (2 tablets of 90 mg) followed by 90 mg twice daily. The recommended duration of treatment with Trobinta IC 90 mg twice daily in patients with ACS is 12 months, in the absence of clinical reasons for discontinuation (see section "Pharmacodynamics").

In ACS patients who have undergone percutaneous coronary intervention (PCI) and have an increased risk of bleeding, discontinuation of ASA may be considered 3 months after initiation of dual antiplatelet therapy with ticagrelor and ASA. In such cases, ticagrelor monotherapy should be continued for an additional 9 months (see section "Special Warnings and Precautions for Use").

History of Myocardial Infarction (MI)

For long-term treatment of patients with a history of MI (MI occurred 1 year or more ago) who are at high risk of atherothrombotic events, the recommended dose of Trobinta IC is 60 mg twice daily (see section "Pharmacodynamics"). Treatment of ACS patients at high risk of atherothrombotic events may be initiated without interruption as a continuation of therapy following initial treatment with Trobinta IC 90 mg twice daily for 12 months or with another P2Y₁₂ receptor inhibitor. Treatment may also be initiated within 2 years following the MI or within 1 year after discontinuation of prior therapy with a P2Y₁₂ receptor inhibitor. Data on the efficacy and safety of ticagrelor use beyond 3 years of continued treatment are limited.

If switching to Trobinta IC is necessary, the first dose should be taken 24 hours after the last dose of another antiplatelet medicinal product.

Missed Dose

Patients should avoid missing doses. If a patient misses a dose of Trobinta IC, they should take only the next scheduled dose at the planned time; do not take a double dose to compensate.

Special Patient Groups

Elderly Patients

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

Renal Impairment

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

Hepatic Impairment

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

Method of Administration

For oral use.

Trobinta IC can be taken independently of food.

For patients unable to swallow the tablet whole, the tablet(s) should be crushed into a fine powder, mixed in ½ glass of drinking water, and the resulting suspension should be taken immediately. The glass should then be rinsed with an additional ½ glass of drinking water, and the rinse solution should also be consumed. The suspension can also be administered via a nasogastric tube (size NG8 or larger). It is important to flush the nasogastric tube with water after administration.

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 single ascending dose study. Other clinically significant adverse reactions that may occur in case of 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.

Currently, there is no known antidote to reverse the effects of ticagrelor, and ticagrelor is not dialyzable (see section "Pharmacokinetics"). Management of overdose should follow local standards of medical practice. The expected consequence of ticagrelor overdose is prolonged duration of increased bleeding risk associated with platelet inhibition. Platelet transfusion is unlikely to be an effective treatment for bleeding (see section "Special Warnings and Precautions for Use"). In the event of bleeding, other appropriate supportive measures should be taken.

Adverse Reactions

Short summary of safety profile

The safety profile of ticagrelor was evaluated in two large-scale phase III clinical trials designed to assess clinical outcomes (the PLATO and PEGASUS trials), involving over 39,000 patients (see section "Pharmacodynamics").

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

List of adverse reactions

The adverse reactions listed below were identified during clinical trials or reported during the post-marketing period of ticagrelor use.

Adverse reactions are listed by organ system classes according to the Medical Dictionary for Regulatory Activities (MedDRA). Within each organ system class, adverse reactions are categorized by frequency 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), and frequency not known (cannot be estimated from available data).

Psychiatric disorders: uncommon – confusion.

Nervous system disorders: common – dizziness, syncope, headache; uncommon – intracranial haemorrhage¹.

Eye disorders: uncommon – eye haemorrhage².

Ear and labyrinth disorders: common – vertigo; uncommon – ear haemorrhage.

Skin and subcutaneous tissue disorders: common – subcutaneous or skin haemorrhage³, rash, pruritus.

Musculoskeletal and connective tissue disorders: uncommon – muscle haematomas⁴.

Cardiac disorders: common – arterial hypotension; frequency not known – bradyarrhythmia, atrioventricular block⁵.

Blood and lymphatic system disorders: very common – bleeding related to blood disorders⁶; frequency not known – thrombotic thrombocytopenic purpura⁵.

Immune system disorders: uncommon – hypersensitivity reactions, including angioedema⁵.

Benign, malignant and unspecified neoplasms (including cysts and polyps): uncommon – tumour haemorrhage⁷.

Renal and urinary disorders: common – haemorrhage from urinary tract⁸.

Reproductive system and breast disorders: uncommon – genital haemorrhage⁹.

Gastrointestinal disorders: common – gastrointestinal haemorrhage¹⁰, diarrhoea, nausea, dyspepsia, constipation; uncommon – retroperitoneal haemorrhage.

Metabolism and nutrition disorders: very common – hyperuricaemia¹¹; common – gout/gouty arthritis.

Respiratory, thoracic and mediastinal disorders: very common – dyspnoea; common – haemorrhage from respiratory organs¹².

Investigations: common – increased blood creatinine¹¹.

Injury, poisoning and procedural complications: common – procedural haemorrhage, traumatic haemorrhage¹³.

________________________________________________________________________________

¹ i.e., spontaneous, procedure-related or traumatic intracranial haemorrhage.

² e.g., conjunctival haemorrhage, retinal haemorrhage, intraocular haemorrhage.

³ e.g., ecchymoses, skin haemorrhages, petechiae.

⁴ e.g., haemarthrosis, muscle haemorrhage.

⁵ Identified during the post-marketing period.

⁶ e.g., increased tendency to bruising, spontaneous haematoma, haemorrhagic diathesis.

⁷ e.g., haemorrhage from malignant bladder tumour, malignant stomach tumour, malignant colorectal tumour.

⁸ e.g., haematuria, haemorrhagic cystitis.

⁹ e.g., vaginal bleeding, haemospermia, postmenopausal bleeding.

¹⁰ e.g., gingival bleeding, rectal bleeding, bleeding from gastric ulcer.

¹¹ Frequency refers to laboratory parameter abnormalities (increase in uric acid concentration above the upper limit of normal from a baseline value within normal range or below the lower limit of normal; increase in creatinine concentration by > 50% from baseline), not frequency of reported adverse events.

¹² e.g., epistaxis (nosebleed), haemoptysis.

¹³ e.g., bruising, traumatic haematoma, traumatic haemorrhage.

Description of selected adverse reactions

Bleeding

Bleeding events in the PLATO trial

Overall results on bleeding frequency in the PLATO trial are presented in Table 1.

Table 1. Analysis of total number of bleeding events, Kaplan-Meier estimate over 12 months (PLATO)

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

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

Definition of bleeding categories

Major fatal/threatening bleeding according to PLATO criteria: clinically evident bleeding accompanied by a decrease in hemoglobin concentration of more than 50 g/L, or requiring transfusion of 4 or more units of packed red blood cells; or fatal; or any intracranial hemorrhage (ICH); or pericardial bleeding with cardiac tamponade; or associated with hypovolemic shock or severe arterial hypotension requiring vasopressor therapy or surgical intervention.

Other major bleeding according to PLATO criteria: clinically evident bleeding accompanied by a decrease in hemoglobin concentration of 30–50 g/L, or requiring transfusion of 2–3 units of packed red blood cells; or bleeding leading to permanent loss of function.

Minor bleeding according to PLATO criteria: bleeding requiring medical intervention to stop or treat the bleeding.

Major bleeding according to TIMI criteria: clinically evident bleeding accompanied by a decrease in hemoglobin concentration of more than 50 g/L; or ICH.

Minor bleeding according to TIMI criteria: clinically evident bleeding accompanied by a decrease in hemoglobin concentration of 30–50 g/L.

The incidence of major bleeding events according to PLATO criteria, major fatal/threatening bleeding according to PLATO criteria, major bleeding according to TIMI criteria, or minor bleeding according to TIMI criteria was not different between the ticagrelor and clopidogrel treatment groups (Table 1). However, the incidence of combined major and minor bleeding according to PLATO criteria was higher in the ticagrelor group compared to the clopidogrel group. A small number of patients in the PLATO study experienced fatal bleeding: 20 (0.2%) in the ticagrelor group and 23 (0.3%) in the clopidogrel group (see section "Special precautions for use").

Age, sex, body weight, race, geographic region, concomitant diseases, concomitant therapy, and medical history, including prior stroke or prior transient ischemic attack, were not predictive factors for the incidence of major bleeding according to PLATO criteria or for non-procedure-related major bleeding according to PLATO criteria. Therefore, no patient subgroups at increased risk of bleeding of any category were identified.

Bleeding related to CABG

In the PLATO study, major fatal/threatening bleeding occurred in 42% of the 1,584 patients (12% of the cohort) who underwent CABG, with no significant difference between treatment groups. Fatal bleeding related to CABG occurred in 6 patients in each treatment group (see section "Special precautions for use").

Non-CABG-related bleeding and non-procedure-related bleeding

The incidence of non-CABG-related fatal/threatening major bleeding according to PLATO criteria was similar between the ticagrelor and clopidogrel groups. However, the incidence of major bleeding according to PLATO criteria, major bleeding according to TIMI criteria, and major + minor bleeding according to TIMI criteria was higher in the ticagrelor group compared to the clopidogrel group. When all procedure-related bleeding events were excluded, more bleeding events occurred with ticagrelor than with clopidogrel (Table 1). 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 events in 26 patients, 0.3%) than with clopidogrel (n = 14 events, 0.2%), of which 11 were fatal in the ticagrelor group and 1 in the clopidogrel group. There was no significant difference in the overall number of fatal bleeding events.

Bleeding events in the PEGASUS study

Overall results on bleeding incidence in the PEGASUS study are presented in Table 2.

Table 2. Analysis of total number of bleeding events, assessed by Kaplan-Meier method over 36 months (PEGASUS)

Safety Endpoints	Ticagrelor 60 mg twice daily + ASA N = 6958		ASA monotherapy N = 6996
	CM %	Hazard Ratio (95% CI)	CM %	p-value
BLEEDING CATEGORIES BY TIMI CRITERIA
Major Bleeding by TIMI	2.3	2.32 (1.68–3.21)	1.1	< 0.0001
Fatal	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	1.6	3.61 (2.31–5.65)	0.5	< 0.0001
Major + minor bleeds by TIMI	3.4	2.54 (1.93–3.35)	1.4	< 0.0001
TIMI major or minor bleeds or bleeds requiring medical attention	16.6	2.64 (2.35–2.97)	7.0	< 0.0001
BLEEDING CATEGORIES BY PLATO CRITERIA
Major Bleeding by PLATO	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 by PLATO	15.2	2.71 (2.40–3.08)	6.2	< 0.0001

Definition of bleeding categories

Major bleeding according to TIMI criteria: fatal bleeding, or any intracranial hemorrhage (ICH), or clinically significant bleeding accompanied by a hemoglobin decrease of 50 g/L or more, or a hematocrit reduction of 15%, if hemoglobin levels are unavailable.

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

ICH: intracranial hemorrhage.

Other major bleeding according to TIMI criteria: non-fatal major bleeding not related to ICH, as defined by TIMI criteria.

Minor bleeding according to TIMI criteria: clinically significant bleeding accompanied by a hemoglobin decrease of 30–50 g/L.

Bleeding requiring medical attention according to TIMI criteria: bleeding requiring medical intervention, or leading to hospitalization, or requiring diagnostic evaluation.

Major fatal/life-threatening bleeding according to PLATO criteria: fatal bleeding, or any ICH, or pericardial bleeding with cardiac tamponade, or bleeding associated with hypovolemic shock or severe arterial hypotension requiring vasopressor/inotropic agents or surgical intervention, or clinically significant bleeding accompanied by a hemoglobin decrease of more than 50 g/L, or requiring transfusion of 4 or more units of packed red blood cells.

Other major bleeding according to PLATO criteria: bleeding leading to permanent disability, or clinically significant bleeding accompanied by a hemoglobin decrease of 30–50 g/L, or requiring transfusion of 2–3 units of packed red blood cells.

Minor bleeding according to PLATO criteria: bleeding requiring medical intervention to stop or treat the bleeding.

In the PEGASUS trial, major bleeding events according to TIMI criteria occurred more frequently with ticagrelor 60 mg twice daily compared to aspirin monotherapy. No increase in fatal bleeding was observed, and only a slight increase in ICH incidence compared to aspirin monotherapy. A few fatal bleeding events were reported in the study: 11 (0.3%) with ticagrelor 60 mg and 12 (0.3%) with aspirin alone. The increased risk of major bleeding according to TIMI criteria with ticagrelor 60 mg was primarily due to a higher incidence of other major TIMI bleedings caused by gastrointestinal disorders.

An increased bleeding frequency similar to that of major TIMI bleedings was also observed for major or minor TIMI bleedings, major PLATO bleedings, and major or minor PLATO bleedings (see Table 2). Discontinuation of treatment due to bleeding was more frequent with ticagrelor 60 mg than with aspirin monotherapy (6.2% vs. 1.5%, respectively). Most of these bleeding events were less severe (classified as bleedings requiring medical attention according to TIMI criteria), particularly epistaxis, bruising, and hematomas.

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

Intracranial hemorrhage

Spontaneous ICH occurred at a similar frequency with ticagrelor 60 mg and aspirin alone (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%) than with aspirin monotherapy (n = 10; 0.1%). Six fatal ICH events occurred with ticagrelor 60 mg and five with aspirin monotherapy. The incidence of ICH was low in both treatment groups, considering the significant comorbidities and cardiovascular risk factors in the study population.

Dyspnea

Patients receiving ticagrelor reported dyspnea and shortness of breath. In the PLATO study, adverse events such as dyspnea (dyspnea, dyspnea at rest, exertional dyspnea, paroxysmal nocturnal dyspnea, and nocturnal dyspnea) were observed overall in 13.8% of patients taking ticagrelor and in 7.8% of patients taking clopidogrel. According to investigator assessment, dyspnea was treatment-related in 2.2% of patients receiving ticagrelor and in 0.6% of patients receiving clopidogrel; some cases of dyspnea were serious (0.14% in the ticagrelor group; 0.02% in the clopidogrel group) (see section "Special precautions"). In most cases, dyspnea was mild or moderate in severity, and patients mostly reported a single episode occurring soon after initiation of treatment.

Compared to patients taking clopidogrel, patients with asthma/COPD taking 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 precautions").

Approximately 30% of dyspnea episodes resolved within 7 days. The PLATO study included patients with baseline congestive heart failure, COPD, or asthma; these patients, as well as elderly patients, reported dyspnea more frequently. 0.9% of patients receiving ticagrelor discontinued the study drug 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 precautions"). Ticagrelor does not affect pulmonary function test results.

In the PEGASUS study, dyspnea was observed in 14.2% of patients receiving ticagrelor 60 mg twice daily and in 5.5% of patients receiving aspirin alone. As in the PLATO study, dyspnea was mostly mild or moderate in severity (see section "Special precautions"). Patients who experienced dyspnea were typically elderly and more likely to have baseline dyspnea, COPD, or asthma.

Laboratory and instrumental findings

Elevated uric acid levels

In the PLATO study, serum uric acid concentration increased above the upper limit of normal in 22% of patients receiving ticagrelor compared to 13% of patients receiving clopidogrel. In the PEGASUS study, these values were 9.1%, 8.8%, and 5.5% with ticagrelor 90 mg, 60 mg, and placebo, respectively. Mean serum uric acid concentration increased by approximately 15% with ticagrelor compared to approximately 7.5% with clopidogrel, and after discontinuation of treatment, it decreased to about 7% in the ticagrelor group without a decrease in the clopidogrel group. In the PEGASUS study, a reversible increase in mean serum uric acid concentration of 6.3% and 5.6% was observed with ticagrelor 90 mg and 60 mg, respectively, compared to a 1.5% decrease in the placebo group. In the PLATO study, the incidence of gouty arthritis was 0.2% with ticagrelor versus 0.1% with clopidogrel. In the PEGASUS study, these values 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 https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 6 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Limited liability company "INTERKHIM".

Manufacturer's address and location of business activity.

Ukraine, 65025, Odessa, 21st km of Starokyivska Road, 40-A.