Tigallant

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TIGALANT (TIGALANT®)

Composition:

Active substance: ticagrelor;

One film-coated tablet contains 90 mg of ticagrelor;

Excipients: microcrystalline cellulose, calcium hydrogen phosphate dihydrate, hypromellose, type 2910, sodium croscarmellose, magnesium stearate;

Film coating: coating mixture: hypromellose, type 2910, titanium dioxide (E 171), talc, propylene glycol, yellow iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: slightly brownish-yellow, round, biconvex film-coated tablets with the imprint "90" on one side.

Pharmacotherapeutic group. Antithrombotic agent. Inhibitors of platelet aggregation, excluding heparin. ATC code B01AC24.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Tigalant contains ticagrelor, which belongs to the chemical class of cyclopentyltriazolopyrimidines (CPTP) and is an oral, direct-acting, selective, and reversibly binding P2Y12 receptor antagonist that prevents adenosine diphosphate (ADP)-mediated P2Y12-dependent platelet activation and aggregation. Ticagrelor does not prevent ADP binding, but by binding to the P2Y12 receptor, it interferes with ADP-induced signal transduction. Since platelets are involved in the initiation and/or progression of 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).

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

Pharmacodynamic effects

Onset of action

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

Offset of action

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

Data on switching between agents

Switching from clopidogrel 75 mg to ticagrelor 90 mg twice daily results in an absolute increase in PAI of 26.4%, while switching from ticagrelor to clopidogrel results in an absolute decrease in PAI of 24.5%. Patients may be 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 from two Phase III studies:

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

The PEGASUS TIMI-54 study [PrEvention with TicaGrelor of SecondAry Thrombotic Events in High-RiSk AcUte Coronary Syndrome Patients], which compared ticagrelor in combination with ASA versus ASA alone.

PLATO study (acute coronary syndrome)

The PLATO study included 18,624 patients with symptoms of unstable angina (UA), myocardial infarction without ST-segment elevation (NSTEMI), or myocardial infarction with ST-segment elevation (STEMI), initially managed 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, 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 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%. 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 body weight, sex, presence of diabetes, transient ischemic attack (TIA), non-hemorrhagic stroke, revascularization, or concomitant therapy with drugs 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 risk ratio (RR) for PCE favored ticagrelor in countries outside North America, which constituted approximately 10% of the total study population (p for interaction = 0.045). A post hoc analysis suggests a possible interaction with ASA dose, as higher ASA doses were associated with reduced efficacy of ticagrelor. ASA doses for continuous daily use in combination with Tigalant should be 75–150 mg (see sections "Dosage and administration" and "Special precautions").

Treatment with Tigalant reduced the frequency of PCE compared to clopidogrel in all ACS patients (UA, NSTEMI, STEMI). Therefore, Tigalant 90 mg twice daily in combination with low-dose ASA can be prescribed for ACS patients (UA, NSTEMI, STEMI), including those managed medically, with PCI, or CABG.

PLATO genetic study

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

Integrated efficacy and safety component

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

Clinical safety

Holter monitoring sub-study of PLATO.

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

PEGASUS study (prior myocardial infarction)

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

Inclusion criteria were: age ≥ 50 years, prior MI (1–3 years before randomization), and at least one of the following atherothrombosis risk factors: age ≥ 65 years, diabetes requiring medication, prior second MI, evidence of multivessel coronary artery disease, or non-terminal stage 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 15% and 1.19% respectively 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 ticagrelor 60 mg twice daily in combination with ASA is recommended for the prevention of atherothrombotic events (CV death, MI, and stroke) in patients with prior MI and high risk of atherothrombotic events.

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

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

No benefit was demonstrated (no reduction in PCE frequency [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 study with parallel groups (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% before dosing and 56% two hours after dosing at steady state.

Compared to placebo, no benefit of ticagrelor 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 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 formation of the main circulating metabolite of ticagrelor, AR-C124910XX (also active), occurs rapidly, with a median tmax of approximately 2.5 hours. After a single 90 mg oral dose of ticagrelor administered fasting to healthy volunteers, Cmax was 529 ng/mL and AUC was 3451 ng*h/mL. The metabolite-to-parent compound 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 from the PEGASUS study, median Cmax of ticagrelor was 391 ng/mL and AUC was 3801 ng*h/mL at steady state with a 60 mg dose. For ticagrelor 90 mg, Cmax was 627 ng/mL and AUC was 6255 ng*h/mL at steady state.

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

Ticagrelor administered as crushed tablets mixed with water, either orally or via nasogastric tube into the stomach, has comparable bioavailability to intact tablets regarding AUC and Cmax 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, with generally similar concentration profiles thereafter (2–48 hours).

Distribution

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

Biological transformation

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 activation to inhibition.

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

Elimination

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

Special patient groups

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

Sex

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 undergoing hemodialysis, AUC and Cmax values of ticagrelor 90 mg when administered on a day without hemodialysis were 38% and 51% higher, respectively, compared to patients with normal renal function. A similar increase in exposure was observed when ticagrelor was administered immediately before dialysis (49% and 61%, respectively), indicating that ticagrelor is not removed by dialysis. Exposure to the active metabolite increased to a lesser extent (AUC 13–14% and 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. 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 elevation of one or more liver function tests at baseline, plasma concentrations of ticagrelor were on average similar or slightly higher compared to patients without baseline abnormalities. Dose adjustment is not required for patients with moderate hepatic impairment (see sections "Dosage and administration" and "Special precautions").

Ethnicity

In patients of Asian origin, mean bioavailability was 39% higher than in Caucasian patients. In patients of African descent, ticagrelor bioavailability 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 drug Tigranant 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 "Adverse reactions").

Active pathological bleeding.

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

Severe hepatic impairment (see sections "Dosage and administration", "Special 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 exposure to P-gp substrates. Ticagrelor is an inhibitor of breast cancer resistance protein (BCRP).

Effect of medicinal products and other agents on ticagrelor

Inhibitors of CYP3A4

• Strong CYP3A4 inhibitors – concomitant administration of ketoconazole and ticagrelor resulted in increases in Cmax and AUC of ticagrelor by 2.4 and 7.3 times, respectively. Cmax and AUC of the active metabolite decreased by 89% and 56%, respectively. Other strong CYP3A4 inhibitors (clarithromycin, nefazodone, ritonavir, and atazanavir) are expected to have a similar effect; therefore, concomitant use of strong CYP3A4 inhibitors with ticagrelor is contraindicated (see section "Contraindications").
• Moderate CYP3A4 inhibitors – concomitant administration of diltiazem with ticagrelor led to a 69% increase in Cmax and a 2.7-fold increase in AUC of ticagrelor, as well as a 38% decrease in Cmax of the active metabolite, while its AUC remained unchanged. No effect of ticagrelor on plasma levels of diltiazem was observed. Other moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, erythromycin, and fluconazole) are expected to have a similar effect; 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% reduction 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; therefore, their concomitant use with ticagrelor is not recommended.

Cyclosporine (inhibitor of P-gp and CYP3A)

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

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

Others

Clinical pharmacology 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 hemostasis should be used with caution in combination with ticagrelor.

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

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 adverse effects of simvastatin, 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 statins occurred in 93% of these patients.

Ticagrelor is a weak inhibitor of CYP3A4. Concomitant use of ticagrelor and 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 administration 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 concomitantly using P-gp-dependent medicinal products with a narrow therapeutic index, such as digoxin, and ticagrelor, appropriate clinical and/or laboratory monitoring is recommended.

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

Medicinal products metabolized by CYP2C9

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

Rosuvastatin (BCRP substrate)

Ticagrelor has been shown to increase rosuvastatin concentration, which may lead to an increased risk of myopathy, including rhabdomyolysis. The benefits of preventing serious cardiovascular events with rosuvastatin should be weighed against the risks of increased plasma concentration of rosuvastatin.

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

Other concomitant therapy

In 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' comorbidities; as well as with heparin, low molecular weight heparin, and intravenous administration of 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 anti-factor Xa assay results. However, due to possible pharmacodynamic interactions, ticagrelor should be used with caution concomitantly with medicinal products capable of affecting hemostasis.

Due to reports of pathological skin bleeding associated with the use of selective serotonin reuptake inhibitors (SSRIs) (e.g., paroxetine, sertraline, and citalopram), SSRIs should be used with caution 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 in light of the benefit of the drug in preventing atherothrombotic events (see sections "Adverse reactions" and "Pharmacodynamics"). When clinically indicated, ticagrelor should be used with caution in the following patient groups:

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

In two randomized controlled trials (TICO and TWILIGHT) in patients with ACS who underwent stent placement via percutaneous coronary intervention (PCI), discontinuation of aspirin after 3 months of dual antiplatelet therapy (DAPT) with ticagrelor and aspirin, followed by continuation of ticagrelor as monotherapy for 9 or 12 months, respectively, was shown to reduce bleeding risk without an observed increase in the risk of major adverse cardiovascular events compared to continued DAPT. The decision to discontinue aspirin after 3 months of DAPT and continue ticagrelor as monotherapy for 9 months in patients at increased risk of bleeding should be based on clinical assessment weighing the risk of bleeding against 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 use of ticagrelor with desmopressin did not reduce template bleeding time, desmopressin is unlikely to be effective in managing 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 may be resumed once the cause of bleeding has been identified and controlled.

Surgical procedures

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

In the PLATO trial, 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 "Adverse reactions"). If a patient requires elective surgery and antiplatelet effect is undesirable, ticagrelor should be discontinued 5 days prior to surgery (see section "Pharmacodynamics").

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 trial).

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

Hepatic impairment

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

Patients at risk of bradycardia

Holter ECG monitoring revealed an increased frequency of predominantly asymptomatic ventricular pauses during ticagrelor treatment compared to clopidogrel. Patients at high risk of bradycardia (e.g., those without pacemakers and with sick sinus syndrome, second- or third-degree atrioventricular block, or syncope due to bradycardia) were not included in the main trials 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 trial, no signs of clinically significant adverse effects were observed after concomitant use of one or more bradycardia-inducing agents (e.g., 96% of patients received beta-blockers, 33% received calcium channel blockers diltiazem or verapamil, and 4% received digoxin) (see section "Interaction with other medicinal products and other forms of interaction").

In a Holter sub-study of the PLATO trial, episodes of ventricular asystole lasting ≥ 3 seconds during the acute phase of ACS were more frequently observed with ticagrelor than with clopidogrel. The increased frequency of Holter-detected ventricular asystole 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 drugs that reduce heart rate or affect cardiac conduction may be 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 and often resolved without the need to discontinue treatment. In patients with asthma (BA)/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 this phenomenon is not fully understood. If a patient reports onset, prolonged duration, or worsening of dyspnea, a full evaluation should be performed, and if intolerance to the drug is suspected, treatment with ticagrelor should be discontinued. See section "Adverse reactions" for detailed information.

Central sleep apnea

Central sleep apnea, including Cheyne-Stokes respiration, has 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

Serum 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 assessed one month after initiation of ticagrelor therapy, with particular attention to patients aged ≥ 75 years, those with moderate to severe renal impairment, and those concomitantly using 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. Use of ticagrelor in patients with uric acid nephropathy is not recommended.

Thrombotic thrombocytopenic purpura (TTP)

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

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

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

In patients receiving ticagrelor, false-negative results have been reported in platelet function tests (including the HIPA test, but not limited to it) for the diagnosis of HIT. This is due to ticagrelor's inhibition of P2Y12 receptors on donor platelets in the patient serum/plasma test. Information on concomitant ticagrelor therapy is required for correct interpretation of platelet function test results for HIT diagnosis.

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

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

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

Early discontinuation of treatment

Premature discontinuation of any antiplatelet agent, including Tigalant, may increase the risk of cardiovascular death, MI, or stroke due to the patient's underlying condition. Therefore, early discontinuation of therapy should be avoided.

Use during pregnancy or breastfeeding.

Women of reproductive potential

Women of reproductive age 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 to discontinue breastfeeding or discontinue/avoid ticagrelor therapy should be made, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

Ticagrelor did not affect fertility in male or female animals.

Ability to drive and use machines.

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

Dosage and Administration

Dosage

Patients taking the medicinal product TIGALANT should also take daily maintenance doses of ASA (acetylsalicylic acid) of 75–150 mg, unless there are specific contraindications.

Acute Coronary Syndrome

Treatment with TIGALANT 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 TIGALANT 90 mg in patients with ACS is 12 months in the absence of clinical indications for early discontinuation (see section "Pharmacodynamics").

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

Prior Myocardial Infarction

The recommended dose of TIGALANT for patients with a history of MI occurring at least one year prior and at high risk of atherothrombotic events requiring long-term treatment 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 TIGALANT 90 mg or another adenosine diphosphate (ADP) receptor inhibitor that has lasted one year. Treatment may also be initiated within 2 years following a prior MI or within one year after completion of prior ADP receptor inhibitor therapy. Data on the efficacy and safety of ticagrelor for treatment duration beyond 3 years are limited.

If switching from another medicinal product to TIGALANT, the first dose of TIGALANT should be taken 24 hours after the last dose of the previous antiplatelet agent.

*Use the medicinal product ticagrelor at the appropriate dosage.

Missed Dose

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

Special Patient Populations

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 use of the medicinal product in such patients is contraindicated (see section "Contraindications"). Data on the use of the medicinal product in patients with moderate hepatic impairment are limited. Dose adjustment is not recommended, but ticagrelor should be used with caution (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics"). Dose adjustment is not required in patients with mild hepatic impairment (see section "Pharmacokinetics").

Administration

For oral use.

TIGALANT may be administered regardless of food intake.

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

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 potentially occurring in case of overdose include dyspnea and episodes of ventricular pauses (see section "Adverse Reactions").

In the event of overdose, the aforementioned potential adverse reactions may occur; therefore, ECG monitoring should be considered.

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

Adverse reactions

The safety profile of ticagrelor was evaluated in two large-scale Phase III clinical outcome studies (the PLATO and PEGASUS trials), which included 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 in patients receiving ticagrelor than in those receiving clopidogrel (7.4% vs. 5.4%). In the PEGASUS study, the rate of premature discontinuation due to 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 warnings and precautions for use").

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 (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

Adverse reactions by frequency and system organ class

Table 1

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

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

c Identified during the post-marketing period.

d Frequency determined based on laboratory data (increase in uric acid levels above the upper limit of normal from baseline levels that were below or within normal range; increase in creatinine levels by > 50% from baseline). This does not reflect the reporting frequency of the adverse reaction.

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.

Description of selected adverse reactions

• Bleeding *

• Bleeding events in the PLATO study *

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

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

Table 2

Definition of bleeding types:

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

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

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

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

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

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

There were no differences between ticagrelor and clopidogrel in the rates of major life-threatening/fatal 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 PLATO major and minor bleeds was higher in the ticagrelor group compared to the clopidogrel group. A small number of patients in the PLATO study experienced fatal bleeds: 20 (0.2%) in the ticagrelor group and 23 (0.3%) in the clopidogrel group (see section "Special warnings and precautions for use").

Age, sex, body weight, race, geographic region, concomitant conditions, concomitant medications, and medical history, including prior stroke or 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: the rate of major life-threatening/fatal bleeds according to PLATO criteria in patients who underwent CABG was similar between the ticagrelor and clopidogrel treatment groups.

Bleeding unrelated to CABG and bleeding unrelated to procedures: ticagrelor and clopidogrel did not differ in the rate of CABG-unrelated life-threatening/fatal major bleeds according to PLATO criteria; however, the overall rate of PLATO-defined major bleeds, the rate of TIMI-defined major bleeds, and the overall rate of TIMI-defined major and minor bleeds 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.

Intracranial hemorrhage: more non-procedure-related intracranial hemorrhages (ICH) occurred with ticagrelor (0.3%) than with clopidogrel (0.2%). 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.

Kaplan-Meier estimate of total bleeding events over 36 months (PEGASUS)

Table 3

Definition of bleeding types:

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

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

ICH: intracranial hemorrhage.

Other major TIMI bleedings: non-fatal major bleedings according to TIMI criteria not related to ICH.

Minor TIMI bleedings: clinically apparent with a decrease in Hb level by 30–50 g/L.

Medically significant bleedings according to TIMI criteria: requiring intervention OR leading to hospitalization OR requiring examination.

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

Other major bleedings according to PLATO criteria: leading to permanent disability OR clinically apparent with a decrease in Hb level by 30–50 g/L OR transfusion of 2–3 units of packed red blood cells.

Minor bleedings according to PLATO criteria: requiring medical intervention to stop or manage bleeding.

In the PEGASUS study, major bleedings (TIMI) occurred more frequently in the ticagrelor 60 mg twice daily treatment group than in the aspirin-only group. No increased risk of fatal bleeding was observed; in addition, only a slight increase in the frequency of ICH was observed compared to aspirin-only treatment. There were several cases of fatal bleeding in the study: 11 (0.3%) with ticagrelor 60 mg and 12 (0.3%) with aspirin-only. The observed increase in risk of major bleeding (TIMI) with ticagrelor 60 mg was mainly due to a higher frequency of other major bleedings (TIMI), among which gastrointestinal disorders predominated.

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

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

Intracranial hemorrhage (ICH): spontaneous ICH occurred at a similar frequency with ticagrelor 60 mg and with aspirin-only (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-only (n = 10, 0.1%). There were 6 fatal ICH events with ticagrelor 60 mg and 5 with aspirin-only. The frequency of ICH was low in both treatment groups, considering the significant comorbidities and cardiovascular risk factors in the study population.

Dyspnea

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

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

Approximately 30% of dyspnea episodes resolved within 7 days. The PLATO study 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 Tigalant discontinued study treatment prematurely due to dyspnea compared to 0.1% of patients receiving clopidogrel. The higher frequency of dyspnea with Tigalant is not associated with the development of new or worsening pre-existing heart or lung disease (see section "Special precautions for use"). Tigalant 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-only. As in the PLATO study, in most cases, dyspnea was mild or moderate (see section "Special precautions for use"). Patients who experienced dyspnea were typically elderly and had baseline dyspnea, COPD, or bronchial asthma.

Laboratory test data

Increased 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. Corresponding values in the PEGASUS study were 9.1%, 8.8%, and 5.5% with ticagrelor 90 mg, 60 mg, and placebo, respectively. Mean serum uric acid levels increased by approximately 15% with ticagrelor compared to approximately 7.5% with clopidogrel; after discontinuation of treatment, levels decreased by approximately 7% with ticagrelor but did not decrease with clopidogrel. In the PEGASUS study, a reverse increase in mean serum uric acid levels 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 and 0.1% with clopidogrel. Corresponding rates for gout/gouty arthritis in the PEGASUS study 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 medicinal product authorization is important. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

No special storage conditions are required for this medicinal product. Store in a place inaccessible to children.

Packaging. 14 tablets in a blister pack, 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer's address and location of business operations.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.