Kagrol

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

Composition:

Active substance: ticagrelor (ticagrelor);

One film-coated tablet contains 60 mg or 90 mg of ticagrelor;

Excipients: mannite (E 421), calcium hydrogen phosphate dihydrate, corn starch, pregelatinized starch (corn), talc (E553b), sodium stearyl fumarate;

Film coating for 60 mg tablets: polyvinyl alcohol (E 1203), talc (E553b), titanium dioxide (E171), glycerol monocaprylocaprate, sodium lauryl sulfate, iron oxide red (E 172), iron oxide black (E 172);

Film coating for 90 mg tablets: polyvinyl alcohol (E 1203), talc (E553b), titanium dioxide (E171), glycerol monocaprylocaprate, sodium lauryl sulfate, iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

60 mg tablets: round, biconvex, pink tablets with "60" marked on one side and no markings on the other side;

90 mg tablets: round, biconvex, yellow tablets with "90" marked on one side and no markings on the other side.

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

Pharmacological Properties

Pharmacodynamics

Mechanism of action

The active substance of the medicinal product Kagrol ticagrelor belongs to the chemical class of cyclopentyltriazolopyrimidines (CPTP). It is an oral, direct-acting, selective P2Y12 receptor antagonist that reversibly binds to prevent adenosine diphosphate (ADP)-mediated platelet activation and aggregation. Ticagrelor does not prevent ADP binding, but by binding to the P2Y12 receptor, it interferes with ADP-induced signal transduction. Since platelets play a role in the initiation and/or progression of atherosclerotic thrombotic events, inhibition of platelet function has been shown to reduce the risk of cardiovascular (CV) events, including myocardial infarction (MI), stroke, or death.

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 whole human blood in vitro), and dyspnea. However, the relationship between the observed increase in adenosine levels and clinical outcomes (e.g., morbidity, mortality) has not been clearly established.

Pharmacodynamic effects

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

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

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 the efficacy and safety of ticagrelor was obtained from two Phase III studies:

the PLATO study [PLATelet Inhibition and Patient Outcomes], which compared ticagrelor with clopidogrel when used in combination with ASA and other standard therapies;

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 coronary artery bypass grafting (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 (PCEP), which included cardiovascular (CV) death, myocardial infarction (MI), or stroke, with differences in rates of CV death and MI. Patients received a loading dose of 300 mg clopidogrel (600 mg possible in case of PCI) or 180 mg ticagrelor.

The effect was rapid, 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 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 prevented one atherothrombotic event; treating 91 patients with ticagrelor prevented one CV death (see Figure 1 and Table 1).

The greater efficacy of ticagrelor compared to clopidogrel was independent of body weight, sex, presence of diabetes, history of transient ischemic attack (TIA) or non-hemorrhagic stroke, revascularization, or concomitant 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 hazard ratio (HR) for achieving the PCEP favored ticagrelor in various countries worldwide, except in North America, where participants 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 daily maintenance dose of ASA to be used concomitantly with ticagrelor should be 75–150 mg (see sections "Dosage and administration" and "Special precautions").

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

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

Ticagrelor reduced the frequency of events in the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI population and the STEMI population (Table 1). Thus, ticagrelor 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 event) N = 9,333	Clopidogrel, 75 mg once daily (% of patients with event) N = 9,291	ARRa (%/year)	RRRa (%) (95% CI [confidence interval])	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 MIs, major bleeding, RIs, TIA, or other ATEc	13.8	15.7	2.1	12 (5; 19)	0.0006
Death from any cause	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

aRRA — absolute risk reduction;

RRI — relative risk reduction. RRI = (1 – risk ratio) × 100%. A negative RRI value indicates an increase in relative risk.

b Except for silent myocardial infarction.

c SRI — severe recurrent ischemia;
RI — recurrent ischemia;
TIA — transient ischemic attack;
ATE — arterial thrombotic event.

Total number of MI cases includes cases of silent MI; the case reporting date was defined as the date of the event.

d Nominal level of significance; 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 an association between genotype groups and outcomes in the PLATO study. The advantages of ticagrelor over clopidogrel in reducing the frequency of major cardiovascular events did not substantially depend on the CYP2C19 or ABCB1 genotype of patients. The overall frequency of major bleeding in the PLATO study did not differ between ticagrelor and clopidogrel groups, regardless of CYP2C19 or ABCB1 genotype. The 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 (CV death, MI, stroke, or total number of major bleedings 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%, RRI 8%, HR 0.92; p = 0.0257) during 12 months after ACS.

Clinical safety. Holter substudy. To investigate the occurrence of ventricular asystole and other arrhythmia episodes within 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 than in the clopidogrel group in the acute phase of ACS: 6.0% vs. 3.5%, and 2.2% vs. 1.6% respectively at one month (see section "Particularities of use"); 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), however, no statistically significant difference between ticagrelor and clopidogrel groups was observed at one month (2.0% vs. 2.1% among 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 (prior myocardial infarction)

The PEGASUS TIMI-54 study was a randomized, double-blind, placebo-controlled, parallel-group, international, multicenter case-control study involving 21,162 patients, 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 ASA (75–150 mg), compared to ASA therapy alone in patients with prior MI and additional risk factors for atherothrombosis. Inclusion criteria: age ≥50 years, prior MI (1–3 years before randomization), and at least one of the following risk factors for atherothrombosis: age ≥65 years, diabetes requiring medication, second MI in history, signs of IHD with multivessel 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

Fig. 2. Analysis of the primary composite clinical endpoint of CV 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 = 7,045			ASA only N = 7,067		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%	-
Death from any cause	289 (4.1%)	4.7%	0.89 (0.76; 1.04)	326 (4.6%)	5.2%	-

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.

The Kaplan-Meier percentage was calculated at 36 months.

Note: The number of first events for the components of cardiovascular death, 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 method;
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 entire study period: RRR 16% and ARR 1.27% with ticagrelor 60 mg, and RRR 15% and ARR 1.19% with ticagrelor 90 mg, respectively.

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 Kagrul 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 high risk of atherothrombotic events.

Compared to aspirin monotherapy, ticagrelor 60 mg twice daily significantly reduced the rate of reaching the primary composite clinical endpoint (CV death, MI, and stroke). The reduction in the rate of reaching the primary composite endpoint was due to a reduction in the frequency of each component (HR for CV death reduced by 17%, HR for MI by 16%, and HR for stroke by 25%).

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

There was no evidence of benefit 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 previous P2Y12 inhibitor therapy (no reduction in the rate of reaching the primary composite clinical endpoint [CV death, MI, and stroke] and an increased incidence of major bleeding) (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, 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 advantage in reducing the frequency of vaso-occlusive crises.

The European Medicines Agency has waived the obligation to submit results of studies with a reference medicinal product containing ticagrelor in all pediatric subpopulations with acute coronary syndrome (ACS) and prior myocardial infarction (MI) (for use in children, see section "Dosage and administration").

Pharmacokinetics

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

Absorption

Ticagrelor is rapidly absorbed, with a median tmax of approximately 1.5 hours. 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 3,451 ng⁎h/mL. The metabolite-to-parent Cmax ratio was 0.28 and the AUC ratio was 0.42. The pharmacokinetics of ticagrelor and AR-C124910XX in patients with prior MI were generally similar to those observed in the ACS patient population. According to population pharmacokinetic analysis of the PEGASUS study, median Cmax of ticagrelor was 391 ng/mL and AUC was 3,801 ng⁎h/mL at steady state with a 60 mg dose. With a 90 mg dose, Cmax was 627 ng/mL and AUC was 6,255 ng⁎h/mL at steady state.

The mean absolute bioavailability of ticagrelor is estimated to be 36%. Consumption of a high-fat meal increased ticagrelor AUC by 21% and decreased the Cmax of the active metabolite by 22%, but did not affect ticagrelor Cmax 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.

Ticagrelor administered as crushed tablets mixed with water, either orally or via a nasogastric tube into the stomach, has bioavailability comparable to that of intact tablets, based on AUC and Cmax values of ticagrelor and its active metabolite. Initial exposure (at 0.5 and 1 hour after dosing) was higher with crushed tablets mixed with water compared to intact tablets, but the concentration profile thereafter (from 2 to 48 hours) was generally similar.

Distribution

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

Biotransformation

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

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

Elimination

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

Special patient groups

Elderly patients. Population pharmacokinetic analysis data show higher exposure to ticagrelor (approximately 25% higher for both Cmax and AUC) and its active metabolite in elderly patients (≥75 years) with ACS 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. Pharmacokinetic analysis showed that in this population, mean AUC of ticagrelor ranged from 1095 to 1458 ng⁎h/mL and mean Cmax ranged from 143 to 206 ng/mL at steady state.

Gender. Women had higher exposure to ticagrelor and its active metabolite than men. These differences are not considered clinically significant.

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

In patients with end-stage renal disease undergoing hemodialysis, AUC and Cmax of 90 mg ticagrelor, when administered on a non-dialysis day, were 38% and 51% higher, respectively, compared to patients with normal renal function. A similar increase in exposure was observed when ticagrelor was administered immediately before dialysis (49% and 61%, respectively), indicating that ticagrelor is not removed by dialysis. Exposure to the active metabolite increased to a lesser extent (AUC 13–14%, 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 in patients with mild hepatic impairment. The use of ticagrelor in patients with severe hepatic impairment has not been studied; pharmacokinetic data in patients with moderate hepatic impairment are lacking. In patients with moderate or marked elevation of one or more baseline liver function laboratory parameters, plasma concentrations of ticagrelor were on average similar or slightly higher compared to patients without baseline abnormalities. Dose adjustment is not required in 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% 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 Kagrul 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 haemorrhage (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 this may lead to a significant increase in ticagrelor exposure (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction

Ticagrelor is an inhibitor of the breast cancer resistance protein (BCRP). 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 thus may be used concomitantly with ticagrelor.
• Daily consumption of large quantities of grapefruit juice (3×200 ml) resulted in a doubling of ticagrelor exposure. Such an increase in exposure is not expected to be clinically significant for most patients.

Inducers of CYP3A4

Concomitant administration of rifampicin with ticagrelor led to 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 is therefore not recommended.

Cyclosporine (inhibitor of P-gp and CYP3A4)

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%.

There are no 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. 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, ASA, or desmopressin did not affect the pharmacokinetics of ticagrelor or its active metabolite, nor did it affect 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 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 both ticagrelor and morphine. For patients with ACS in whom morphine cannot be delayed and rapid P2Y12 inhibition is considered life-saving, the use of 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 daily 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.

P-gp substrates (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 P-gp-dependent medicinal products with a narrow therapeutic index, such as digoxin, are used concomitantly with ticagrelor, appropriate clinical and/or laboratory monitoring is recommended.

No effect of ticagrelor on blood concentrations 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 thus it is unlikely that the medicinal product will affect CYP2C9-mediated metabolism of drugs 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 adverse cardiovascular events should be weighed against the risks associated with increased plasma concentrations of rosuvastatin.

Oral contraceptives

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

MEDICINAL PRODUCTS THAT MAY CAUSE BRADYCARDIA

Since cases of predominantly asymptomatic ventricular asystole and bradycardia have been observed, ticagrelor should be used with caution when administered concomitantly with medicinal products that may cause 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% calcium channel blockers diltiazem and verapamil, 4% digoxin).

OTHER CONCOMITANT THERAPY

In clinical trials, ticagrelor was frequently used concomitantly with ASA, proton pump inhibitors (PPIs), statins, beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) for prolonged periods as required by patients' comorbidities, as well as with heparin, low molecular weight heparin, and intravenous administration of GpIIb/IIIa inhibitors for short periods (see section "Pharmacodynamics"). No signs of clinically significant adverse interactions with these medicinal products were observed.

Concomitant use of ticagrelor with heparin, enoxaparin, or desmopressin did not affect activated partial thromboplastin time (aPTT), activated clotting time (ACT), or quantitative factor Xa determination. However, due to possible pharmacodynamic interactions, ticagrelor should be used with caution when administered 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 together with ticagrelor, as this may increase the risk of bleeding.

Special precautions for use

Bleeding risk

Ticagrelor should be prescribed cautiously in patients with known increased risk of bleeding, taking into account the benefit of the medicinal product in preventing atherothrombotic events (see sections "Adverse reactions" and "Pharmacodynamics"). Ticagrelor should be used with caution in the following patient groups when clinically indicated:

• patients with a tendency 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, with a history of intracranial haemorrhage (ICH), and in patients with severe hepatic impairment (see section "Contraindications");
• patients who are concurrently using (within 24 hours after ticagrelor administration) medicinal products capable of increasing bleeding risk (e.g., nonsteroidal anti-inflammatory drugs, 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 and continuation of therapy with ticagrelor alone for 9 or 12 months, respectively, reduced the risk of bleeding. No increase in the risk of serious cardiovascular events was observed compared to continuation of dual antiplatelet therapy (ticagrelor + aspirin). The decision to discontinue aspirin after 3 months and continue antiplatelet therapy with ticagrelor alone for 9 months in patients at increased risk of bleeding should be based on clinical assessment, weighing the risk of bleeding against the risk of thrombotic events (see section "Dosage and administration").

Platelet transfusion did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is unlikely to be effective in treating patients with bleeding. Since co-administration of ticagrelor with desmopressin did not reduce bleeding time measured by template method, it is unlikely that desmopressin will 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 haemostasis. 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 planning any surgical procedure and before taking any new medicinal product.

In the PLATO study, in patients undergoing CABG, bleeding events were more frequent in the ticagrelor group than in the clopidogrel group when therapy was discontinued one day before surgery, but major bleeding occurred with similar frequency in both groups when therapy was discontinued at least two days before surgery (see section "Adverse reactions"). If a patient requires elective surgery and antiplatelet effect is undesirable, ticagrelor should be discontinued 5 days prior to surgery (see section "Pharmacodynamics").

Patients with prior ischaemic stroke

Patients with ACS who have had an ischaemic stroke may be treated with ticagrelor for up to 12 months (PLATO study).

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

Hepatic impairment

Ticagrelor is contraindicated in patients with severe hepatic impairment (see sections "Dosage and administration" and "Contraindications"). Experience with ticagrelor in patients with moderate hepatic impairment is limited; therefore, the medicinal product should be used with caution in 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., those without a pacemaker and with 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 medicinal products capable of causing bradycardia (e.g., 96% of patients received beta-blockers, 33% received calcium channel blockers diltiazem and verapamil, and 4% received digoxin) (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Dyspnoea

Dyspnoea has been observed in patients receiving ticagrelor. Dyspnoea 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 dyspnoea 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 new, prolonged, or worsening dyspnoea, a full evaluation should be performed and, if intolerance to the medicinal product is suspected, treatment with ticagrelor should be discontinued. See section "Adverse reactions" for details.

Central sleep apnoea

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

Increased creatinine levels

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

Increased uric acid levels

Hyperuricaemia may occur during treatment with ticagrelor (see section "Adverse reactions"). Caution should be exercised when treating patients with a history of hyperuricaemia or gouty arthritis. Ticagrelor is not recommended for patients with urate nephropathy.

Thrombotic thrombocytopenic purpura

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

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

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

In patients receiving ticagrelor, false-negative results in platelet function tests (including the HIPA test) for the diagnosis of HIT have been observed. This is due to ticagrelor's inhibition of P2Y12 receptors on donor platelets in the patient's 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 treatment should be assessed, considering both the prothrombotic state of HIT and the increased risk of bleeding with concomitant anticoagulant and ticagrelor therapy.

Other

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

Early discontinuation of treatment

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

Sodium content

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

Use during pregnancy or breastfeeding

Women of reproductive potential

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

Pregnancy

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

Breastfeeding

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

Fertility

Ticagrelor had no effect on fertility in male and female animals.

Ability to affect reaction speed when driving or operating machinery

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

Method of Administration and Dosage

Dosage

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

Acute Coronary Syndrome (ACS)

Treatment with the medicinal product Kagról 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 Kagról 90 mg in patients with ACS is 12 months, unless there are clinical reasons 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 have an increased bleeding risk. In such cases, ticagrelor as sole antiplatelet therapy should be continued for 9 months (see section "Special Warnings and Precautions for Use").

History of Myocardial Infarction

The recommended dose of Kagról 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"). In patients with ACS at high risk of atherothrombotic events, treatment may be initiated without interruption, as a continuation of therapy following initial treatment with Kagról 90 mg or another adenosine diphosphate (ADP) receptor inhibitor, which has lasted for one year. Treatment may also be initiated within a period of up to 2 years after the MI or within one year after completion of prior ADP receptor inhibitor therapy. Data on the efficacy and safety of ticagrelor for treatment continuation beyond 3 years are limited.

If switching from another medicinal product to Kagról, the first dose of Kagról 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 Kagról, they should take only one tablet (the next scheduled dose) at the usual time.

Special Patient Populations

Elderly Patients

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

Renal Impairment

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

Hepatic Impairment

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

Method of Administration

Kagról should be administered orally. It can be taken with or without food.

For patients unable to swallow the tablet whole, it may be crushed into a powder, mixed with half a glass of water, and taken immediately. The glass should then be rinsed with an additional half glass of water, and the rinse solution should be consumed.

The mixture may also be administered via a nasogastric tube (size 8 French or larger). It is important to flush the nasogastric tube with water after administration.

Children

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

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

Overdose

Ticagrelor is well tolerated at single doses up to 900 mg. Gastrointestinal toxicity was dose-limiting in ascending single-dose studies. Other clinically significant adverse reactions that may occur in overdose include dyspnea and episodes of ventricular asystole (see section "Adverse Reactions").

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

There is currently no known antidote for ticagrelor; ticagrelor is not eliminated by dialysis (see section "Pharmacokinetics"). Management of overdose should follow current standards of medical practice. The expected consequence of ticagrelor overdose is prolonged bleeding risk due to platelet inhibition. Platelet transfusion is unlikely to be an effective treatment method in patients with bleeding (see section "Special Warnings and Precautions for Use"). In 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 trials (the PLATO and PEGASUS studies), involving over 39,000 patients (see section "Pharmacodynamics").

In the PLATO study, the rate of premature discontinuation of treatment due to adverse reactions (ARs) was higher 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 alone (16.1% with ticagrelor 60 mg plus aspirin vs. 8.5% with aspirin 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 classes according to MedDRA (Medical Dictionary for Regulatory Activities). Within each system organ class, ARs are listed in order of frequency. The frequency of ARs is defined according to the following criteria: 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); frequency not known (cannot be estimated from available data).

Table 3. Adverse reactions by frequency and system organ classes

System Organ Classes	Very common	Common	Uncommon	Frequency not known
Benign, malignant and unspecified neoplasms (including cysts and polyps)			Bleeding from tumora
Blood and lymphatic system disorders	Bleeding due to coagulation disorderb			Thrombotic thrombocytopenic purpurav
Immune system disorders			Hypersensitivity, including angioneurotic edemav
Metabolism and nutrition disorders	Hyperuricemiag	Gout / gouty arthritish
Psychiatric disorders			Confusion
Nervous system disorders		Dizziness, syncope, headache	Intracranial hemorrhagej
Eye disorders			Eye hemorrhagek
Ear and labyrinth disorders		Vertigo	Ear hemorrhage
Cardiac disorders				Bradyarrhythmia, atrioventricular blockv
Vascular disorders		Arterial hypotension
Respiratory, thoracic and mediastinal disorders	Dyspnea	Bleeding from respiratory tractd
Gastrointestinal disorders		Gastrointestinal hemorrhagee, diarrhea, nausea, dyspepsia, constipation	Retroperitoneal hemorrhage
Skin and subcutaneous tissue disorders		Subcutaneous or skin hemorrhagesz, rash, pruritus
Musculoskeletal and connective tissue disorders			Muscle hemorrhagesy
Renal and urinary disorders		Bleeding from urinary tractz
Reproductive system and breast disorders			Bleeding from genital organsi
Investigation parameter abnormalities		Increased blood creatinine levelg
Injury, poisoning and procedural complications		Bleeding after procedure, traumatic hemorrhagesi

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; increase in creatinine levels by > 50 % from baseline). This does not reflect the reporting frequency of the adverse event.

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

f For example, epistaxis, haemoptysis.

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

h For example, ecchymosis, skin haemorrhage, petechiae.

i For example, haemarthrosis, muscle haemorrhage.

j For example, haematuria, haemorrhagic cystitis.

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

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

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

Description of selected adverse reactions

Bleeding

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 number of bleeding events — Kaplan-Meier estimate over 12 months (PLATO)

Bleeding events	Ticagrelor, 90 mg, twice daily N = 9,235	Clopidogrel N = 9,186	p-value*
PLATO-defined major bleeds	11.6	11.2	0.4336
PLATO-defined major fatal / life-threatening bleeds	5.8	5.8	0.6988
Non-CABG-related PLATO-defined major bleeds	4.5	3.8	0.0264
Non-procedure-related PLATO-defined major bleeds	3.1	2.3	0.0058
PLATO-defined major + minor bleeds	16.1	14.6	0.0084
Non-procedure-related PLATO-defined major + minor bleeds	5.9	4.3	<0.0001
TIMI-defined major bleeds [eng. Thrombolysis In Myocardial Infarction]	7.9	7.7	0.5669
TIMI-defined major + minor bleeds	11.4	10.9	0.3272

Definition of bleeding types:

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

Other major bleeds: Clinically significant bleeds associated with a decrease in hemoglobin level of 30–50 g/L or transfusion of 2–3 units of packed red blood cells, or bleeds leading to permanent loss of function.

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

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

Minor bleeds according to TIMI criteria: Clinically significant bleeds associated with a decrease in hemoglobin level of 30–50 g/L.

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

There were no differences between ticagrelor and clopidogrel in the rate of major life-threatening/fatal bleeds according to PLATO criteria, total number of major bleeds according to PLATO criteria, or in the rate of major or minor bleeds according to TIMI criteria. However, the rate of combined major and minor bleeds according to PLATO criteria was higher in the ticagrelor group compared to the clopidogrel group. A small number of patients in the PLATO study experienced fatal 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 major bleeding rate unrelated to procedures in the PLATO study. 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 1,584 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. Six patients in each treatment group experienced a fatal bleed related to CABG (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 non-CABG-related 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 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 on bleeding rates in the PEGASUS study are presented in Table 5.

Table 5. Analysis of total number of bleeding events — Kaplan-Meier estimate over 36 months (PEGASUS)

	Ticagrelor 60 mg, twice daily + ASA N = 6,958		ASA alone N = 6,996
	% CV	Risk ratio (95% CI)	% CV	p-value
Bleeding types 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
Intracranial hemorrhage (ICH)	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 those requiring medical attention	16.6	2.64 (2.35; 2.97)	7.0	< 0.0001
Bleeding types 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 bleeds or any type of ICH, or hemorrhages associated with clinical manifestations related to a drop in hemoglobin (Hb) level ≥ 50 g/L; or, if Hb levels are unavailable, a decrease in hematocrit (Hct) by 15%.

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

ICH: intracranial hemorrhage.

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

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

Medically significant bleeds according to TIMI criteria: requiring intervention, leading to hospitalization, or requiring investigation.

Major fatal/life-threatening bleeds according to PLATO criteria: fatal bleeds or any type of ICH, or intracardiac hemorrhages with cardiac tamponade or hypovolemic shock or acute arterial hypotension requiring use of vasopressor/inotropic drugs or surgical intervention, or clinically significant 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 persistent loss of function, or clinically significant 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: requiring 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 treatment group. No increase in risk of fatal bleeds was observed; additionally, only a slight increase in the frequency of ICH was observed compared to aspirin-only treatment. There were several cases of fatal bleeds 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), among which gastrointestinal disorders were predominant.

A similar trend toward increased bleeding frequency, as seen for major bleeds according to TIMI criteria, was also observed for major or minor bleeds according to TIMI criteria and major bleeds according to PLATO criteria, as well as for major or minor bleeds according to 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 serious (classified according to TIMI as requiring medical attention), for example: epistaxis, bruising, and hematomas.

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

Intracranial hemorrhage: spontaneous ICH occurred at a similar frequency with ticagrelor 60 mg and with aspirin-only (n = 13, 0.2% in both treatment groups). Traumatic and procedure-related ICH occurred slightly more frequently with ticagrelor 60 mg (n = 15, 0.2%) than with aspirin-only (n = 10, 0.1%). There were 6 fatal ICH 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 ticagrelor reported dyspnea and shortness of breath. In the PLATO study, this AE, defined as dyspnea (dyspnea, dyspnea at rest, exertional dyspnea, paroxysmal nocturnal dyspnea, and nocturnal dyspnea), was observed overall in 13.8% of patients treated with ticagrelor and in 7.8% of patients treated with clopidogrel. In the PLATO study, dyspnea was considered by investigators to be treatment-related in 2.2% of patients receiving ticagrelor and in 0.6% of patients receiving clopidogrel, with some of these cases being serious (0.14% in the ticagrelor group; 0.02% in the clopidogrel group) (see section "Special precautions"). Symptoms of dyspnea were mostly mild or moderate; in most cases, a single episode was reported shortly after initiation of treatment.

Compared to patients receiving clopidogrel, patients with asthma/COPD receiving ticagrelor 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 general population of the PLATO study. Ticagrelor should be used with caution in patients with a history of asthma and/or COPD (see section "Special precautions").

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"). 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-only. As in the PLATO study, dyspnea was mostly mild or moderate (see section "Special precautions"). Patients who experienced dyspnea were predominantly elderly and had baseline dyspnea, COPD, or bronchial asthma.

Laboratory test data

Increased uric acid levels: in the PLATO study, uric acid concentration increased above the upper limit of normal in 22% of patients receiving ticagrelor versus 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, and after discontinuation of treatment 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 drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions

No special storage conditions required. Keep out of reach of children.

Packaging

60 mg: 10, 14, or 56 film-coated tablets in a blister; 3 blisters of 56 tablets, or 4 blisters of 14 tablets, or 6 blisters of 10 tablets in a cardboard box;

90 mg: 10, 14, or 56 film-coated tablets in a blister; 3 blisters of 56 tablets, or 4 blisters of 14 tablets, or 6 blisters of 10 tablets, or 12 blisters of 14 tablets in a cardboard box.

Prescription category. Prescription only.

Manufacturer

Lek Pharmaceuticals d.d.

or

Pharos MT Limited

Manufacturer's location and address of business operations

Verovskova 57, Ljubljana 1526, Slovenia

HF62x, Hal Far Industrial Estate, Hal Far, Birzebbugia, BBG 3000, Malta