Brilinta

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BRI LIN TA (BRILINTA®)

Composition:

Active substance: ticagrelor;

One film-coated tablet contains 60 mg of ticagrelor;

Excipients: mannite (E 421), calcium hydrogen phosphate, sodium starch glycolate, hydroxypropylcellulose, 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. Platelet aggregation inhibitors, excluding heparin. ATC code B01A C24.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The medicinal product Brilinta contains ticagrelor, which belongs to the chemical class of cyclopentyltriazolopyrimidines (CPTP) and is an oral, direct-acting, selective and reversible antagonist of P2Y₁₂ receptors, preventing adenosine diphosphate (ADP)-mediated P2Y₁₂-dependent activation and aggregation of platelets. Ticagrelor does not prevent ADP binding, but when bound 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-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 was rapid, as indicated by a mean platelet aggregation inhibition (PAI) of approximately 41% within 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 a coronary artery bypass graft (CABG) procedure 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:

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

With background daily ASA therapy, 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, myocardial infarction (MI), or stroke, with a difference in rates of CV death and MI. Patients received a loading dose of 300 mg clopidogrel (600 mg possible in case of PCI) or 180 mg ticagrelor.

The effect was rapid, with an absolute risk reduction (ARR) of 0.6% at 30 days and a relative risk reduction (RRR) of 12%, 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 benefit of ticagrelor treatment at a dose of 90 mg twice daily for 12 months (see section "Dosage and administration"). Treating 54 ACS patients with ticagrelor instead of clopidogrel would prevent one atherothrombotic event; treating 91 patients with ticagrelor would prevent one CV death (see Figure 1 and Table 4).

Greater efficacy of ticagrelor compared to clopidogrel was independent of patient body weight or sex, presence of diabetes, transient ischemic attack (TIA) or non-hemorrhagic stroke, revascularization, or concomitant medication use, 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 the 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 dose of ASA for concomitant chronic daily use with ticagrelor should be 75–150 mg (see sections "Dosage and administration" and "Special precautions").

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

Figure 1. Analysis of the primary clinical composite 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). Thus, the medicinal product Brilinta 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)

	Ticagrelor, 90 mg twice daily (% of patients with events) N = 9333	Clopidogrel, 75 mg once daily (% of patients with events) N = 9291	ARRa (%/year)	RRIa (%) (95% CI)	p-value
CV death, MI (excluding silent MI), or stroke	9.3	10.9	1.9	16 (8; 23)	0.0003
Invasive strategy	8.5	10.0	1.7	16 (6; 25)	0.0025
Medication strategy	11.3	13.2	2.3	15 (0.3; 27)	0.0444g
CV death	3.8	4.8	1.1	21 (9; 31)	0.0013
MI (excluding silent MI)b	5.4	6.4	1.1	16 (5; 25)	0.0045
Stroke	1.3	1.1	-0.2	-17 (-52; 9)	0.2249
Death from any cause, MI (excluding silent MI), or stroke	9.7	11.5	2.1	16 (8; 23)	0.0001
CV death, total number of MIs, STEMI, NSTEMI, TIA, or other revascularization procedurec	13.8	15.7	2.1	12 (5; 19)	0.0006
All-cause mortality	4.3	5.4	1.4	22 (11; 31)	0.0003g
Definite stent thrombosis	1.2	1.7	0.6	32 (8; 49)	0.0123g

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

b Except for asymptomatic MI.

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

d Nominal significance level; all others 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 trial. The advantages of ticagrelor over clopidogrel in reducing the rate of major adverse cardiovascular events were not substantially influenced by 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 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 in the PLATO study) indicates that the efficacy benefits of ticagrelor compared to clopidogrel are not offset by major bleeding events (ARR – 1.4%, RRR – 8%, HR 0.92; p = 0.0257) over 12 months 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, the proportion of patients with episodes of ventricular asystole ≥ 3 seconds was higher in the ticagrelor group (6.0%) than in the clopidogrel group (3.5%) during the acute phase of ACS, and 2.2% vs. 1.6% respectively at one month (see section "Dosage and Administration"); such episodes were more frequently observed in the ticagrelor group among patients with chronic heart failure (CHF) (9.2% vs. 5.4% in patients without CHF history; in the clopidogrel group – 4.0% vs. 3.6%, respectively), although no statistically significant difference between ticagrelor and clopidogrel groups was observed at one 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 difference 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 myocardial infarction 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 requiring medication, prior history of second MI, evidence of multivessel coronary artery disease, or non-end-stage chronic kidney disease (CKD).

Exclusion criteria included planned use of P2Y12 receptor antagonists, 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 abnormalities; 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)

Characteristic	Ticagrelor, 60 mg twice daily + ASA N = 7045			ASA alone N = 7067		p-value
	Patients with events	% KM	HR (95 % CI)	Patients with events	% KM
Primary endpoint
Composite endpoint of CV death/MI/stroke	487 (6.9 %)	7.8 %	0.84 (0.74; 0.95)	578 (8.2 %)	9.0 %	0.0043 (c)
CV death	174 (2.5 %)	2.9 %	0.83 (0.68; 1.01)	210 (3.0 %)	3.4 %	0.0676
MI	285 (4.0 %)	4.5 %	0.84 (0.72; 0.98)	338 (4.8 %)	5.2 %	0.0314
Stroke	91 (1.3 %)	1.5 %	0.75 (0.57; 0.98)	122 (1.7 %)	1.9 %	0.0337
Secondary endpoint
CV death	174 (2.5 %)	2.9 %	0.83 (0.68; 1.01)	210 (3.0 %)	3.4 %	-
All-cause mortality	289 (4.1 %)	4.7 %	0.89 (0.76; 1.04)	326 (4.6 %)	5.2 %	-

The hazard 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 at 36 months.

Note: The number of first events for the components of cardiovascular (CV) 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 combined 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, resulting in 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.

Despite similar efficacy profiles between the 90 mg and 60 mg doses, the lower dose demonstrated a better safety profile regarding the risk of bleeding and dyspnea. Therefore, only Brilinta 60 mg twice daily in combination with aspirin 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 aspirin monotherapy, ticagrelor 60 mg twice daily significantly reduced the rate of primary composite clinical endpoint (CV death, MI, and stroke). The reduction in the primary composite endpoint was driven by a reduction in each component (17% RRR in CV death, 16% RRR in MI, and 25% RRR in stroke).

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

There was no evidence of benefit (lack of reduction in the primary composite endpoint [CV death, MI, and stroke] and increased incidence of major bleeding) with ticagrelor 60 mg twice daily in clinically stable patients more than 2 years after prior MI or more than 1 year after discontinuation of prior P2Y12 inhibitor therapy (see also section "Dosage and administration").

Clinical safety

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

Children

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

No benefit of ticagrelor over placebo was observed in terms of reducing the frequency of vaso-occlusive crises.

The European Medicines Agency has waived the obligation to submit results of Brilinta 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. 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 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 the population pharmacokinetic analysis of the PEGASUS study, median Cmax of ticagrelor was 391 ng/mL and AUC was 3801 ng*hour/mL at steady state with the 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 the AUC of ticagrelor 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 post-dose) after administration of crushed and water-mixed tablets was higher than after 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 induction to inhibition.

The main metabolite of ticagrelor is AR-C124910XX, which is also pharmacologically active, as evidenced by in vitro binding to platelet P2Y12 ADP 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 likely biliary secretion. The mean t1/2 of ticagrelor is approximately 7 hours, and that of the active metabolite is 8.5 hours.

Special patient populations

Elderly patients

Population pharmacokinetic analysis in 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 disease are limited (see sections "Dosage and administration" and "Pharmacodynamics").

In the HESTIA 3 study, patients aged 2 to 18 years with body weights ≥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 mg, 30 mg, and 45 mg twice daily, respectively. Pharmacokinetic analysis in this population showed that 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 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 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. Similar increases in exposure were observed when ticagrelor was administered immediately before dialysis (49% and 61%, respectively), indicating that ticagrelor is not removed by dialysis. Exposure to the active metabolite increased to a lesser extent (AUC 13–14%, Cmax 17–36%). Platelet aggregation inhibition (PAI) by ticagrelor was independent of dialysis in patients with end-stage renal disease and was similar to that in patients with normal renal function (see section "Dosage and administration").

Hepatic impairment

Cmax and AUC of ticagrelor were 12% and 23% higher, respectively, in patients with mild hepatic impairment compared to healthy volunteers, but the pharmacodynamic 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; there is no pharmacokinetic data available for patients with moderate hepatic impairment. In patients with moderate or marked baseline elevations in one or more liver function tests, plasma concentrations of ticagrelor were on average similar or slightly higher 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 is 39% higher than in Caucasian patients. In patients of Black/African origin, bioavailability of ticagrelor is 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 Caucasian subjects. Drug exposure in patients of Hispanic or Latino origin was similar to that in Caucasian patients.

Clinical characteristics.

Indications.

The use of the medicinal product Brilinta 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 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.

Effect of medicinal products and other agents on ticagrelor

Inhibitors of CYP3A4

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

Inducers of CYP3A4

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

Cyclosporine (inhibitor of P-gp and CYP3A)

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

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

Others

Clinical pharmacological interaction studies 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 who received morphine, delayed and reduced exposure to oral P2Y12 inhibitors, including ticagrelor and its active metabolites (35% reduction in the effect of ticagrelor), 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 potential 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-critical, the possibility of using a parenterally administered 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 in doses exceeding 40 mg per day may cause adverse effects of simvastatin, 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 in doses exceeding 40 mg is not recommended.
• Atorvastatin: concomitant administration of atorvastatin and ticagrelor increased Cmax of atorvastatin acid by 23% and AUC by 36%. A similar increase in AUC and Cmax was observed for all metabolites of atorvastatin acid. This increase is not considered clinically significant.
• A similar effect on other statins metabolized by CYP3A4 cannot be excluded. Participants in the PLATO study who received ticagrelor were taking various statins, and no safety issues with statin use occurred in 93% of such patients.

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

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, 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 that the medicinal product will affect CYP2C9-mediated metabolism of drugs such as warfarin and tolbutamide.

Rosuvastatin

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

Oral contraceptives

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

Medicinal products capable of causing bradycardia

Since cases of predominantly asymptomatic ventricular 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 therapies

In clinical studies, 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 use of ticagrelor with heparin, enoxaparin, or desmopressin did not affect activated partial thromboplastin time (aPTT), activated clotting time (ACT), or quantitative factor Xa assay results. However, due to possible pharmacodynamic interactions, ticagrelor should be used with caution 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), caution is recommended when using SSRIs 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 relation to 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 predisposition to bleeding (e.g., due to recent trauma or surgical procedures, coagulation disorders, active or recent gastrointestinal bleeding) or with an increased risk of trauma. Ticagrelor is contraindicated in patients with active pathological bleeding, history of intracranial hemorrhage (ICH), and patients with severe hepatic impairment (see section "Contraindications").
• Patients who are concurrently using (within 24 hours after ticagrelor administration) medicinal products that may increase the risk of bleeding (e.g., non-steroidal 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 an 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, weighing the risk of bleeding against the risk of thrombotic complications (see section "Dosage and administration").

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

The use of antifibrinolytic agents (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa may enhance hemostasis. Ticagrelor administration 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 taking any new medicinal product.

In the PLATO study, among patients undergoing CABG, the incidence of bleeding was higher in the ticagrelor group than in the clopidogrel group when therapy was discontinued 1 day before surgery, but major bleeding occurred with similar frequency in both groups when therapy was discontinued 2 or more days before surgery (see section "Side effects"). If a patient requires elective surgery and the antiplatelet effect is undesirable, ticagrelor should be discontinued 5 days before 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 study).

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

Hepatic impairment

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

Concomitant use of ticagrelor with medicinal products capable of causing bradycardia requires caution. However, in the PLATO study, no signs of clinically significant adverse reactions (ARs) were observed after concomitant use of one or more bradycardia-inducing medicinal products (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 in the PLATO study, 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) than in the overall study population during the acute phase of ACS, but this difference was no longer observed after one month of ticagrelor treatment 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").

During 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 medications should be evaluated as potential causes.

Dyspnea

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

Central sleep apnea

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

Increase in creatinine levels

Ticagrelor treatment may lead to increased creatinine levels. 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, patients with moderate to severe renal impairment, and those concurrently using ARBs.

Increase in uric acid levels

Hyperuricemia may occur during treatment with ticagrelor (see section "Side effects"). Caution should be exercised when treating patients with a history of hyperuricemia or gouty arthritis. Use of ticagrelor 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 donor platelets in the patient serum/plasma test. Information on concomitant ticagrelor treatment is required for the 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

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

The medicinal product Brilinta 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 Brilinta, may increase the risk of cardiovascular death, myocardial infarction, or stroke due to the patient's underlying condition. Therefore, premature discontinuation of treatment 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. Risk to the newborn/infant cannot be excluded. The decision to discontinue breastfeeding or to discontinue/abandon 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 or negligible influence on the ability to drive or operate machinery. Cases of dizziness and confusion have been reported during ticagrelor treatment. Therefore, patients experiencing these symptoms should be cautious when driving or operating machinery.

Method of Administration and Dosage

Dosage

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

Acute Coronary Syndrome

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

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

History of Myocardial Infarction

The recommended dose of Brilinta for patients with a history of MI (occurring at least 1 year prior) and at high risk of atherothrombotic events, when long-term treatment is required, is 60 mg twice daily (see section "Pharmacodynamics"). For patients with ACS at high risk of atherothrombotic events, treatment may be initiated without interruption—as continuation therapy following initial treatment with Brilinta 90 mg or another adenosine diphosphate (ADP) receptor inhibitor that has been administered for 1 year. Treatment may also be initiated within 2 years following the MI or within 1 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.

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

Missed Dose

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

Special Patient Groups

Elderly Patients

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

Method of Administration

For oral use.

Brilinta may be administered independently of food intake.

For patients unable to swallow the tablet whole, the tablet may be crushed into a powder, mixed with half a glass of water, and taken immediately. The glass should then be rinsed with another half glass of water, and the rinse solution consumed. The mixture may also be administered via a nasogastric tube (size ≥8 French). 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 single ascending dose studies. Other clinically significant adverse reactions (ADRs) that may occur in overdose include dyspnea and episodes of ventricular pause (see section "Adverse Reactions").

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

An antidote for ticagrelor is currently unknown; ticagrelor is not eliminated 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 Instructions"). In the event of bleeding, other appropriate supportive measures should be implemented.

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 compared to 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 Warnings and 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 system organ class, ARs are categorized by frequency. Frequency groups 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).

Table 3. Adverse reactions by frequency and system organ class

System Organ Classes	Very Common	Common	Uncommon	Frequency not known
Benedign, malignant and unspecified neoplasms (including cysts and polyps)			Tumour bleedinga
Blood and lymphatic system disorders	Bleeding due to coagulation disorderb			Thrombotic thrombocytopenic purpurav
Immune system disorders			Hypersensitivity, including angioedemav
Metabolism and nutrition disorders	Hyperuricemiag	Gout / gouty arthritis
Psychiatric disorders			Confusion
Nervous system disorders		Dizziness, syncope, headache	Intracranial haemorrhagej
Eye disorders			Eye haemorrhagek
Ear and labyrinth disorders		Vertigo	Ear haemorrhage
Cardiac disorders				Bradyarrhythmia, atrioventricular blockd
Vascular disorders		Arterial hypotension
Respiratory, thoracic and mediastinal disorders	Dyspnoea	Bleeding from respiratory tractd
Gastrointestinal disorders		Gastrointestinal haemorrhagee, diarrhoea, nausea, dyspepsia, constipation	Retroperitoneal haemorrhage
Skin and subcutaneous tissue disorders		Subcutaneous or skin haemorrhages, rash, pruritus
Musculoskeletal and connective tissue disorders			Haemorrhage into muscle tissue
Renal and urinary disorders		Bleeding from urinary tractz
Reproductive system and breast disorders			Bleeding from genital organsi
Investigations		Elevated blood creatinine levelg
Injury, poisoning and procedural complications		Bleeding after procedure, traumatic haemorrhagei

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

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

c Identified during the post-marketing period.

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

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.

ye For example, ecchymosis, skin haemorrhage, petechiae.

zh For example, haemarthrosis, muscle haemorrhage.

z For example, haematuria, haemorrhagic cystitis.

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

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

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

Description of selected adverse reactions

• Bleeding *

• Bleeding events in the PLATO study *

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

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

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

Definition of bleeding types:

Major life-threatening/fatal bleeds: clinically evident, with a hemoglobin decrease > 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 hemoglobin decrease of 30–50 g/L or transfusion of 2–3 units of packed red blood cells, or resulting in persistent loss of functional capacity.

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

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

Minor bleeds according to TIMI criteria: clinically evident, with a hemoglobin decrease 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 life-threatening/fatal 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 significantly 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.

Bleeds 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 life-threatening/fatal bleed according to PLATO study criteria, with no statistically significant difference between treatment groups. Fatal bleeds related to CABG occurred in 6 patients in each treatment group (see section "Special warnings and precautions for use").

Bleeds not related to CABG and bleeds not related to procedures: Ticagrelor and clopidogrel did not differ in the rate of CABG-unrelated life-threatening/fatal major bleeds according to PLATO study criteria. However, the overall rate of major bleeds according to PLATO criteria, the rate of major bleeds according to TIMI criteria, and the overall rate of 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 bleeds 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 ICHs occurred with ticagrelor (n = 27 bleeds in 26 patients, 0.3%) than with clopidogrel (n = 14 bleeds, 0.2%), of which 11 bleeds in the ticagrelor group and 1 bleed in the clopidogrel group were fatal. There was no difference in the overall rate of fatal bleeds.

Bleeding events in the PEGASUS study

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

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

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

Definition of bleeding types:

Major bleeds according to TIMI criteria: fatal bleeding or any intracranial hemorrhage (ICH), or hemorrhage associated with clinical signs and linked to a decrease in hemoglobin (Hb) level ≥ 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 according to TIMI criteria.

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

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

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

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

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

In the PEGASUS study, major bleeds (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; furthermore, 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 bleeds (TIMI) with ticagrelor 60 mg was primarily due to a higher frequency of other major bleeds (TIMI), predominantly 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-only (6.2% vs. 1.5%, respectively). Most of these bleeds were less severe (classified as TIMI medically attended), for example: epistaxis, bruising, and hematomas.

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

Intracranial hemorrhage (ICH): spontaneous ICH occurred at similar frequencies with ticagrelor 60 mg and 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 cases with ticagrelor 60 mg and 5 fatal ICH cases 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 Brilinta reported dyspnea and shortness of breath. 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 treatment-related by investigators 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 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 frequency 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 occurred 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, dyspnea was mostly mild or moderate in most cases (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 concentrations 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, 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 frequency 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 and pharmacists, as well as patients or 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 pack, 4 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

AstraZeneca AB/AstraZeneca AB.

Manufacturer's location and address of place of business.

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