Alminda

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALMINDA (ALMINDA)

Composition:

Active substance: ticagrelor (ticagrelor);

One film-coated tablet contains 60 mg of ticagrelor;

Excipients: mannite (E 421), calcium hydrogen phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hypromellose, titanium dioxide (E 171), polyethylene glycol 400, iron oxide black (E 172), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: pink, round, biconvex, film-coated tablets with engraving on one side and smooth on the reverse.

Pharmacotherapeutic group. Antithrombotic agent. Inhibitors of platelet aggregation, excluding heparin. ATC code B01A C24.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

The medicinal product Alminda contains ticagrelor, which belongs to the chemical class of cyclopentyltriazolopyrimidines (CPTPs) and is an oral, direct-acting, selective, and reversibly binding P2Y₁₂ receptor antagonist that inhibits adenosine diphosphate (ADP)-mediated P2Y₁₂-dependent activation and aggregation of platelets. Ticagrelor does not prevent ADP binding, but by binding to the P2Y₁₂ receptor, it blocks 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-mediated effects in healthy subjects and in patients with acute coronary syndrome (ACS), including vasodilation (as evidenced by increased coronary blood flow in healthy volunteers and ACS patients; headache), inhibition of platelet function (in 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 appeared rapidly, as indicated by a mean platelet aggregation inhibition (PAI) of approximately 41% 0.5 hours after administration of a 180 mg loading dose. Maximum PAI effect of 89% was achieved within 2–4 hours after dosing and was maintained for 2–8 hours. In 90% of patients, the final PAI value 2 hours after dosing was >70%.

Offset of Action

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

Data on Switching Between Medicinal Products

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:

• Study PLATO [PLATelet Inhibition and Patient Outcomes], which compared ticagrelor with clopidogrel when used in combination with ASA and other standard therapy.
• Study PEGASUS TIMI-54 [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) within the previous 24 hours, who were treated medically or with percutaneous coronary intervention (PCI) or CABG.

Clinical Efficacy

On a background of 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 cardiovascular (CV) death, myocardial infarction (MI), or stroke, with a reduction in the rates of CV death and MI. Patients received a loading dose of 300 mg clopidogrel (600 mg possible in case of PCI) or 180 mg ticagrelor.

The effect was rapid, with an absolute risk reduction (ARR) of 0.6% and a relative risk reduction (RRR) of 12% at 30 days, and was maintained throughout the 12-month treatment period, with an absolute risk reduction of 1.9% per year and a relative risk reduction of 16%. This supports the use of ticagrelor 90 mg twice daily for 12 months (see section "Dosage and Administration"). Treating 54 ACS patients with ticagrelor instead of clopidogrel prevents one atherothrombotic event; treating 91 patients with ticagrelor prevents one CV death (see Figure 1 and Table 4).

The superior efficacy of ticagrelor compared to clopidogrel was independent of patient body weight or sex, presence of diabetes, history of transient ischemic attack (TIA) or non-hemorrhagic stroke, revascularization, or concomitant therapy with medications including heparins, GpIIb/IIIa inhibitors, and proton pump inhibitors (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). Efficacy was independent of the treatment strategy chosen at randomization (invasive or medical) in both patients with UA/NSTEMI and those with STEMI.

The risk ratio (RR) for PCE favored ticagrelor in countries outside North America, which accounted for approximately 10% of the total study population (p-value = 0.045). A post-hoc analysis suggests a possible interaction with ASA dose, as higher ASA doses were associated with reduced efficacy of ticagrelor. The recommended maintenance dose of ASA to be used concomitantly with ticagrelor should be 75–150 mg daily (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use").

Figure 1 shows the estimated risk of first occurrence of any event in the composite efficacy endpoint.

Figure 1. Analysis of the primary composite clinical endpoint of CV death, MI, and stroke (PLATO study)

Ticagrelor reduced the rate of events in the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI population and the STEMI population (Table 1). Therefore, the medicinal product Alminda 90 mg twice daily, in combination with low-dose ASA, can be used in patients with ACS (unstable angina, NSTEMI, or STEMI), including those receiving standard medical therapy and those undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG).

Table 1. Analysis of Primary and Secondary Efficacy Endpoints (PLATO study)

aARR – absolute risk reduction; RRR – relative risk reduction = (1 - hazard ratio) × 100%. A negative RRR value indicates an increase in the relative risk parameter.

b Except for silent myocardial infarction.

c SRI – serious recurrent ischemia; RI – recurrent ischemia; TIA – transient ischemic attack; ATP – arterial thrombotic event. Total number of MI events includes cases of silent MI; the event date was defined as the date of the event.

d Nominal significance level; all others formally statistically significant according to pre-specified hierarchical testing.

PLATO Genetic Substudy

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

Composite Efficacy and Safety Endpoint

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

Clinical Safety

Holter Substudy

To evaluate the occurrence of ventricular asystole and other arrhythmia episodes in the PLATO study, investigators performed Holter monitoring in a subgroup of nearly 3,000 patients, approximately 2,000 of whom had recordings both in the acute phase of ACS and at one month. The primary variable assessed was the occurrence of ventricular asystole ≥ 3 seconds. According to Holter monitoring data, more patients in the ticagrelor group had episodes of ventricular asystole ≥ 3 seconds during the acute phase of ACS (6.0%) compared to the clopidogrel group (3.5%), and 2.2% vs. 1.6% respectively at 1 month (see section "Special Warnings and Precautions for Use"); such episodes were more frequent in the ticagrelor group among patients with chronic heart failure (CHF) (9.2% vs. 5.4% in patients without CHF history; for clopidogrel group – 4.0% vs. 3.6%, respectively), although no statistically significant difference between ticagrelor and clopidogrel groups was observed at 1 month (2.0% vs. 2.1% for ticagrelor-treated patients with and without CHF, respectively, and 3.8% vs. 1.4% in the clopidogrel group). No adverse clinical consequences (including syncope or need for pacemaker implantation) related to this discrepancy 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, conducted to evaluate the prevention of atherothrombotic events with ticagrelor administered at two doses (90 mg twice daily or 60 mg twice daily) in combination with low-dose aspirin (75–150 mg), compared to aspirin alone in patients with prior MI and additional risk factors for atherothrombosis.

Inclusion criteria: age ≥ 50 years, history of MI (1–3 years prior to randomization), and at least one of the following risk factors for atherothrombosis: age ≥ 65 years, diabetes mellitus requiring medication, second prior MI, evidence of multivessel coronary artery disease, or non-end-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

Figure 2. Analysis of the primary composite clinical endpoint of cardiovascular death, MI, and stroke (PEGASUS study)

Table 2. Analysis of primary and secondary efficacy endpoints (PEGASUS study)

The risk ratios and p-values were calculated separately for ticagrelor and aspirin-only therapy using a Cox proportional hazards model with treatment group as the sole explanatory variable.

Kaplan–Meier percentage rates calculated at 36 months.

Note: The number of first events for the components of cardiovascular death, myocardial infarction (MI), and stroke represents the actual number of first events for each component and does not sum to the number of events in the composite endpoint.

(z) Indicates statistical significance.

CI – confidence interval; CV – cardiovascular; HR – hazard ratio; KM – Kaplan–Meier; MI – myocardial infarction; N – number of patients.

Treatment with ticagrelor 60 mg twice daily and 90 mg twice daily in combination with aspirin was more effective in preventing atherothrombotic events compared to aspirin alone (composite endpoint: CV death, MI, and stroke), with a consistent treatment effect throughout the study period, providing a 16% relative risk reduction (RRR) and 1.27% absolute risk reduction (ARR) with ticagrelor 60 mg, and 15% RRR and 1.19% ARR with ticagrelor 90 mg.

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

Compared to aspirin monotherapy, ticagrelor 60 mg twice daily significantly reduced the incidence of the primary composite clinical endpoint (CV death, MI, and stroke). The reduction in the primary composite endpoint was driven by a decrease in each component (17% RRR in CV death, 16% RRR in MI, and 25% RRR in stroke).

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

There was no evidence of benefit (lack of reduction in the primary composite clinical 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 rate 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, parallel-group Phase III study (HESTIA 3), 193 pediatric patients (aged 2 to 18 years) with sickle cell anemia were randomized to placebo or ticagrelor at doses ranging from 15 mg to 45 mg twice daily depending on body weight. In the ticagrelor group, median platelet inhibition was 35% before dosing and 56% two hours after dosing at steady state.

Compared to placebo, ticagrelor showed no benefit in reducing the frequency of vaso-occlusive crises.

The European Medicines Agency has waived the obligation to submit the results of Alminda medicinal product studies in all pediatric subpopulations with acute coronary syndrome (ACS) and history of 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. 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*hour/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 a history of MI were generally similar to those observed in the ACS patient population. According to the population pharmacokinetic analysis of the PEGASUS study, the median Cmax of ticagrelor was 391 ng/mL and AUC was 3801 ng*hour/mL at steady state with a 60 mg dose. For ticagrelor 90 mg, Cmax was 627 ng/mL and AUC was 6255 ng*hour/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 the Cmax of the active metabolite by 22%, but did not affect the Cmax of ticagrelor or the AUC of the active metabolite. These changes are of minimal clinical significance; therefore, ticagrelor can be administered regardless of food intake. Ticagrelor and its active metabolite are substrates of P-gp.

Crushed ticagrelor tablets mixed with water, when administered orally or via a nasogastric tube into the stomach, have bioavailability comparable to that of intact tablets with respect to AUC and Cmax of ticagrelor and its active metabolite. Initial exposure (at 0.5 and 1 hour after dose administration) was higher with crushed and water-mixed tablets compared to intact tablets, with generally similar concentration profiles thereafter (from 2 to 48 hours).

Distribution

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

Metabolism

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

Elimination

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

Special patient populations

Elderly patients

According to population pharmacokinetic analysis, elderly patients (aged ≥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 sections "Dosage and administration" and "Pharmacodynamics").

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

Gender

Higher exposures to ticagrelor and its active metabolite were observed in females compared to males. These differences are not considered clinically significant.

Renal impairment

Exposure to ticagrelor was approximately 20% lower, and exposure to the active metabolite was approximately 17% higher in patients with severe renal impairment (creatinine clearance <30 mL/min) compared to patients with normal renal function.

In patients with end-stage renal disease undergoing hemodialysis, AUC and Cmax of ticagrelor 90 mg were 38% and 51% higher, respectively, when the drug was administered on a non-dialysis day, 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 pharmacodynamic effect of ticagrelor was similar in both groups. Dose adjustment is not required for patients with mild hepatic impairment. The use of ticagrelor in patients with severe hepatic impairment has not been studied; pharmacokinetic data in patients with moderate hepatic impairment are not available. In patients with moderate or marked baseline elevation of one or more liver function tests, plasma concentrations of ticagrelor were on average similar or slightly higher compared to patients without baseline abnormalities. Dose adjustment is not required for patients with moderate hepatic impairment (see sections "Dosage and administration" and "Special warnings and precautions for use").

Ethnicity

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

Clinical characteristics.

Indications.

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

Inducers of CYP3A4

Concomitant administration of rifampicin with ticagrelor resulted in a 73% and 86% decrease in Cmax and AUC of ticagrelor, respectively. Cmax of the active metabolite remained unchanged, while AUC decreased by 46%. Other CYP3A inducers (e.g., phenytoin, carbamazepine, and phenobarbital) are also expected to reduce ticagrelor exposure. Concomitant use of ticagrelor with strong CYP3A inducers may lead to reduced exposure and efficacy of ticagrelor; therefore, their concomitant use with ticagrelor is not recommended.

Cyclosporine (P-gp and CYP3A inhibitor)

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 P-gp inhibitors and moderate CYP3A4 inhibitors (e.g., verapamil, quinidine), which may lead to increased ticagrelor exposure, are lacking. If such combinations cannot be avoided, concomitant use of these medicinal products should be performed with caution.

Others

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

In patients with ACS receiving morphine, delayed and reduced exposure to oral P2Y12 inhibitors, including ticagrelor and its active metabolites, was observed (a 35% reduction in the effect of ticagrelor). 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. For patients with ACS in whom morphine administration cannot be delayed and rapid P2Y12 inhibition is considered life-saving, 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 simvastatin-related adverse effects, which should be weighed against the expected benefit. No effect of simvastatin on plasma levels of ticagrelor was observed. Ticagrelor may have a similar effect on lovastatin. Concomitant use of ticagrelor with simvastatin or lovastatin at doses exceeding 40 mg is not recommended.
• Atorvastatin: concomitant administration of atorvastatin and ticagrelor increased Cmax of atorvastatin acid by 23% and AUC by 36%. A similar increase in AUC and Cmax was observed for all metabolites of atorvastatin acid. This increase is not considered clinically significant.
• A similar effect on other statins metabolized by CYP3A4 cannot be excluded. Participants in the PLATO study who received ticagrelor were taking various statins, and no safety issues with statin use were reported in 93% of such patients.

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

Substrates of P-gp (including digoxin and cyclosporine)

Concomitant administration of ticagrelor increased Cmax of digoxin by 75% and AUC by 28%. Mean minimum digoxin levels increased by approximately 30% with concomitant use of ticagrelor, and in some cases, a maximum increase of 2-fold was 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 cyclosporine blood concentration was observed. The effect of ticagrelor on other P-gp substrates has not been studied.

Medicinal products metabolized by CYP2C9

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

Rosuvastatin (BCRP substrate)

It has been demonstrated that ticagrelor increases the concentration of rosuvastatin, which in turn may lead to an increased risk of myopathy, including rhabdomyolysis. When using rosuvastatin, the benefit of preventing serious cardiovascular events should be weighed against the risks associated with 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 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 concomitantly with medicinal products capable of causing bradycardia (see section "Special precautions"). 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 therapies

In clinical trials, ticagrelor was frequently used concomitantly with ASA, proton pump inhibitors (PPIs), statins, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) for prolonged periods as required by patients' comorbid conditions, 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 factor Xa assay results. However, due to possible pharmacodynamic interactions, ticagrelor should be used with caution concomitantly with medicinal products capable of affecting haemostasis.

Due to reports of 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 considered carefully, weighing the benefit of the medicinal product in preventing atherothrombotic events (see sections "Side effects" 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) or with an increased risk of trauma. The use of ticagrelor is contraindicated in patients with active pathological bleeding, history of intracranial hemorrhage (ICH), and patients with severe hepatic impairment (see section "Contraindications").
• Patients who are concurrently using (within 24 hours after ticagrelor administration) medicinal products capable of increasing the risk of bleeding (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, and/or fibrinolytic agents).

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

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

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

Surgical procedures

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

In the PLATO trial, among patients undergoing coronary artery bypass grafting (CABG), the incidence of bleeding was higher in the ticagrelor group than in the clopidogrel group when therapy was discontinued one day before surgery. However, major bleeding occurred with similar frequency in both groups when therapy was stopped two or more days before surgery (see section "Side effects"). If a patient requires elective surgery and antiplatelet effect is undesirable, ticagrelor should be discontinued five 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 ischemic stroke were excluded from the PEGASUS trial. Therefore, due to lack of data, treatment beyond one year is not recommended in such patients.

Hepatic impairment

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

Patients at risk of bradycardia

Holter ECG monitoring revealed an increased frequency of predominantly asymptomatic ventricular pauses during treatment with ticagrelor compared to clopidogrel. Patients at increased risk of bradycardia (e.g., patients without a pacemaker who have sick sinus syndrome, second- or third-degree atrioventricular block, or syncope due to bradycardia) were not included in the main 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 reactions (ARs) 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").

During additional Holter monitoring within the PLATO trial, episodes of ventricular pauses 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 pauses with ticagrelor was more pronounced in patients with heart failure (HF) compared to the overall study population during the acute phase of ACS, but this difference was no longer observed after one month of treatment with ticagrelor or compared to clopidogrel. No adverse clinical consequences related to this discrepancy (including syncope or need for pacemaker implantation) were observed in this patient population (see section "Pharmacodynamics").

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

Dyspnea

Dyspnea has been observed in patients receiving ticagrelor. Dyspnea was usually mild or moderate in severity and often resolved without the need to discontinue treatment. 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 asthma 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 medicinal product is suspected, treatment with ticagrelor should be discontinued. For further information, see section "Side effects".

Central sleep apnea

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

Elevated creatinine levels

Creatinine levels may increase during treatment with ticagrelor. The mechanism of this phenomenon is not fully understood. Renal function should be assessed according to standard medical practice. In patients with ACS, renal function should also be evaluated 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 ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs).

Elevated uric acid levels

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

Thrombotic thrombocytopenic purpura (TTP)

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

False-negative results in platelet function tests (including the HIPA test and others) for the diagnosis of HIT have been reported in patients receiving ticagrelor. This is due to ticagrelor's inhibition of P2Y12 receptors on platelets from healthy donors in the patient serum/plasma test. Information about 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 with concomitant anticoagulant and ticagrelor therapy.

Other

Due to the observed relationship 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 Alminda contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Early discontinuation of treatment

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

Use during pregnancy or breastfeeding.

Women of reproductive potential

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

Pregnancy

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

Breastfeeding

Pharmacodynamic/toxicological studies in animals 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 to discontinue/forego 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 and female animals.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Dosage

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

Acute Coronary Syndrome (ACS)

Treatment with the medicinal product Alminda 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 Alminda 90 mg in patients with ACS is 12 months, in the absence of clinical indications for earlier discontinuation (see section "Pharmacodynamics").

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

History of Myocardial Infarction

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

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

Missed Dose

Patients should avoid missing doses of the medicinal product. If a patient misses a dose of Alminda, 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 "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, the use of the medicinal product in such patients is contraindicated (see section "Contraindications"). Information on the use of the medicinal product in patients with moderate hepatic impairment is limited. Dose adjustment is not recommended, but ticagrelor should be used with caution (see sections "Special Instructions" and "Pharmacokinetics"). Dose adjustment in patients with mild hepatic impairment is not required (see section "Pharmacokinetics").

Method of Administration

For oral use.

Alminda may be administered independently of food intake.

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

Children

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

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

Overdose

Ticagrelor is well tolerated at single doses up to 900 mg. Gastrointestinal toxicity was dose-limiting in studies with escalating single doses. 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.

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 for patients with bleeding (see section "Special Instructions"). In the event 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), involving over 39,000 patients (see section "Pharmacodynamics").

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

The adverse reactions listed below were identified during clinical trials or reported during post-marketing use of ticagrelor (Table 3).

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

Table 3. Adverse reactions by frequency and system organ class

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

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

c Identified during the post-marketing period.

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

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

d For example, epistaxis, haemoptysis.

e For example, gingival bleeding, rectal bleeding, bleeding from gastric ulcer.

z For example, ecchymosis, skin haemorrhage, petechiae.

z For example, haemarthrosis, muscle haemorrhage.

i For example, haematuria, haemorrhagic cystitis.

i For example, vaginal bleeding, haemospermia, postmenopausal bleeding.

i For example, contusion, traumatic haematoma, traumatic bleeding.

ї That is, spontaneous, procedure-related, or traumatic intracranial haemorrhages.

Description of selected adverse reactions

Bleeding

Bleeding events in the PLATO study

The overall results regarding the frequency of bleeding events in the PLATO study are presented in Table 4.

Table 4. Analysis of total bleeding events, Kaplan-Meier estimate over 12 months (PLATO)

Definition of bleeding types:

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

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

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

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

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

* p-value calculated using the Cox proportional hazards model, for treatment group as an exploratory endpoint.

The rates of major fatal/life-threatening bleeds according to PLATO criteria, total number of major bleeds according to PLATO criteria, and the rates of major or minor bleeds according to TIMI criteria did not differ between ticagrelor and clopidogrel. 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").

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

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

Bleeding not related to CABG and bleeding not related to procedures: Ticagrelor and clopidogrel did not differ in the rate of CABG-unrelated fatal/life-threatening major bleeds according to PLATO criteria. However, the overall rate of major bleeds according to PLATO criteria, the rate of major bleeds according to TIMI criteria, and the overall rate of combined major and minor bleeds according to TIMI criteria were higher in the ticagrelor treatment group. Similarly, when all procedure-related bleeds were excluded, the bleeding rate was higher in the ticagrelor group compared to the clopidogrel group (Table 5). Discontinuation of treatment due to non-procedure-related bleeding occurred more frequently in the ticagrelor treatment group (2.9%) than in the clopidogrel group (1.2%; p < 0.001).

Intracranial hemorrhage (ICH): More non-procedure-related ICH events occurred with ticagrelor (n = 27 bleeds in 26 patients, 0.3%) than with clopidogrel (n = 14 bleeds, 0.2%), of which 11 bleeds in the ticagrelor group and 1 bleed in the clopidogrel group were fatal. There was no difference in the overall rate of fatal bleeds.

Bleeding events in the PEGASUS study

General results regarding bleeding rates in the PEGASUS study are presented in Table 5.

Table 5. Analysis of total number of bleeding events, assessed by Kaplan-Meier method over 36 months (PEGASUS)

Definition of bleeding types:

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

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

ICH: intracranial hemorrhage.

Other major bleeds according to TIMI criteria: non-fatal, non-ICH major bleeds as defined by TIMI criteria.

Minor bleeds according to TIMI criteria: clinically evident bleeding with a reduction in Hb levels of 30–50 g/L.

Medically significant bleeds according to TIMI criteria: those requiring intervention, leading to hospitalization, or necessitating diagnostic evaluation.

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

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

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

In the PEGASUS study, major bleeds (TIMI) occurred more frequently in the group treated with ticagrelor 60 mg twice daily compared to the group treated with aspirin alone. No increased risk of fatal bleeding was observed; however, there was only a slight increase in the incidence of ICH compared to aspirin alone. There were several cases of fatal bleeding in the study: 11 (0.3%) with ticagrelor 60 mg and 12 (0.3%) with aspirin alone. The observed increase in risk of major bleeds (TIMI) with ticagrelor 60 mg was primarily due to a higher incidence of other major bleeds (TIMI), most of which were gastrointestinal disorders.

A similar trend toward increased bleeding frequency, as seen for major bleeds by TIMI criteria, was also observed for major or minor bleeds by TIMI criteria, major bleeds by PLATO criteria, and major or minor bleeds by PLATO criteria (see Table 5). Premature discontinuation of treatment due to bleeding occurred more frequently with ticagrelor 60 mg than with aspirin alone (6.2% vs. 1.5%, respectively). Most of these bleeds were less severe (classified as requiring medical attention according to TIMI), such as epistaxis, bruising, and hematoma.

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

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

Dyspnea

Patients treated with the medicinal product Alminda reported dyspnea and sensation of breathlessness. In the PLATO study, 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 0.6% of those 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 soon after initiation of treatment.

Compared to patients receiving clopidogrel, patients with asthma/COPD receiving ticagrelor may have an increased risk of non-serious dyspnea 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 PLATO. 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 ticagrelor discontinued study medication prematurely due to dyspnea, compared to 0.1% of patients receiving clopidogrel. The higher incidence of dyspnea with ticagrelor is not associated with the development of new or worsening pre-existing heart or lung disease (see section "Special precautions for use"). 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, most cases of dyspnea were 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 findings

Increased uric acid levels: In the PLATO study, uric acid concentrations increased above the upper limit of normal in 22% of patients receiving ticagrelor compared to 13% of patients receiving clopidogrel. Corresponding figures 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 about 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, reversible increases in mean serum uric acid levels of 6.3% and 5.6% were observed with ticagrelor 90 mg and 60 mg, respectively, compared to a 1.5% decrease in the placebo group. In the PLATO 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 of adverse reactions

Reporting of adverse reactions after medicinal product registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Keep out of reach of children.

Packaging.

14 tablets per blister, 4 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

AstraZeneca AB/AstraZeneca AB.

Manufacturer's address and location of operations.

Gertunavagen, Sodertalje, 152 57, Sweden/Gartunavagen, Sodertalje, 152 57, Sweden.