Gregorel

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

Composition:

Active substance: ticagrelor;

1 tablet contains 90 mg of ticagrelor;

Excipients: mannitol; microcrystalline cellulose 101; sodium starch glycolate; hypromellose, type 2910, 5 cp; magnesium stearate;

film coating "Opadry® 03F38056 yellow": hypromellose, talc, titanium dioxide (E 171), polyethylene glycol 8000, iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow, round, biconvex film-coated tablets, without embossing.

Pharmacotherapeutic group. Blood and blood-forming organs. Antithrombotic agents. Antiplatelet agents, excluding heparin. Ticagrelor.

ATC code B01AC24.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Ticagrelor belongs to the chemical class of cyclopentyltriazolopyrimidines (CPTPs) and is an oral, direct-acting, selective, and reversible antagonist of the P2Y12 receptor. It prevents adenosine diphosphate (ADP)-mediated P2Y12-dependent activation and aggregation of platelets. Ticagrelor does not prevent ADP binding but, by binding to the P2Y12 receptor, interferes with ADP-induced signal transduction. Since platelets play a key role in the initiation and/or progression of thrombotic complications of atherosclerosis, inhibition of platelet function has been shown to reduce the risk of such cardiovascular (CV) events as death, myocardial infarction (MI), or stroke.

Ticagrelor also increases local levels of endogenous adenosine by inhibiting the equilibrative nucleoside transporter subtype 1 (ENT-1).

In healthy volunteers and patients with acute coronary syndrome (ACS), ticagrelor enhanced adenosine-mediated effects such as vasodilation (as determined by increased coronary blood flow), 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 occurs rapidly, as evidenced by a mean platelet aggregation inhibition (PAI) of approximately 41% 0.5 hours after administration of a 180 mg loading dose, with maximum PAI reaching 89% within 2–4 hours after dosing, and maintained between 2–8 hours. In 90% of patients, the final PAI value 2 hours after dosing was >70%.

Offset of Action. In patients scheduled for coronary artery bypass grafting (CABG), the risk of bleeding is increased with ticagrelor compared to clopidogrel if therapy is discontinued less than 96 hours before the procedure.

Switching Between Agents. Switching from clopidogrel 75 mg to ticagrelor 90 mg twice daily results in an absolute increase in PAI of 26.4%, while switching from ticagrelor to clopidogrel results in an absolute decrease in PAI of 24.5%. Patients may be transitioned from clopidogrel to ticagrelor without a change in antiplatelet effect (see section "Dosage and Administration").

Clinical Efficacy and Safety

Clinical evidence of ticagrelor’s efficacy and safety was obtained from two Phase 3 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 ASA alone.

PLATO Study (Acute Coronary Syndrome)

The PLATO study included 18,624 patients with symptoms of unstable angina (UA), non-ST-elevation myocardial infarction (NSTEMI), or ST-elevation myocardial infarction (STEMI) within the past 24 hours, who were managed medically or with percutaneous coronary intervention (PCI) or CABG.

Clinical Efficacy. In combination with ASA, ticagrelor 90 mg twice daily was more effective than clopidogrel 75 mg once daily in preventing the primary composite endpoint (PCE), which included CV death, MI, or stroke, primarily due to differences in 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 benefit was achieved rapidly and sustained throughout the 12-month treatment period, with an absolute risk reduction (ARR) of 1.9% per year and a relative risk reduction (RRR) of 16%. Treatment with ticagrelor instead of clopidogrel prevented one atherothrombotic event in every 54 ACS patients and one CV death in every 91 patients.

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

The risk ratio (RR) for PCE events favored ticagrelor across various countries worldwide, except in North America, whose participants represented approximately 10% of the total study population (p for interaction = 0.045). A post hoc analysis suggests a possible interaction with ASA, 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 Warnings and Precautions for Use").

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

PLATO Genetic Study. Genotyping of 10,285 patients for CYP2C19 and ABCB1 in the PLATO study revealed associations between genotype groups and outcomes. The advantages of ticagrelor over clopidogrel in reducing the frequency of serious CV events were not significantly influenced by the CYP2C19 or ABCB1 genotype of patients. The overall frequency of major bleeding, as defined in the PLATO study, did not differ between ticagrelor and clopidogrel groups regardless of CYP2C19 or ABCB1 genotype. The frequency of non-CABG-related major bleeding, as defined in the PLATO study, was increased with ticagrelor compared to clopidogrel in patients lacking one or more functional CYP2C19 alleles, but similar to that observed with clopidogrel in patients without loss of functional alleles.

Net Clinical Benefit (CV death, MI, stroke, or total number of major bleeding events 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%, RR — 0.92; p = 0.0257) over 12 months following ACS.

Clinical Safety. Holter Monitoring in PLATO. According to Holter monitoring data from the PLATO study, more patients in the ticagrelor group experienced episodes of ventricular pauses ≥ 3 seconds during the acute phase of ACS compared to the clopidogrel group; such episodes were more frequently observed in patients with chronic heart failure (CHF) compared to the overall population; however, no statistically significant difference between ticagrelor and clopidogrel groups was observed at 1 month. No adverse clinical consequences (including syncope or need for pacemaker implantation) related to this 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, designed to evaluate the prevention of atherothrombotic events with ticagrelor at two doses (90 mg twice daily or 60 mg twice daily) in combination with low-dose ASA (75–150 mg), compared to ASA alone, in patients with a history of MI and additional risk factors for atherothrombosis.

Inclusion criteria included: 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, DM requiring medication, prior MI, evidence of multivessel IHD, or non-terminal 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. Treatment with ticagrelor 60 mg twice daily and 90 mg twice daily in combination with ASA was more effective than ASA alone in preventing atherothrombotic events (composite endpoint: CV death, MI, and stroke), with a consistent treatment effect throughout the study period, RRR of 16% and ARR of 1.27% with ticagrelor 60 mg, and RRR of 15% and ARR of 1.19% with ticagrelor 90 mg.

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

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

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

There was no evidence of benefit (no reduction in PCE [CV death, MI, and stroke] and increased frequency of major bleeding) with ticagrelor 60 mg twice daily in clinically stable patients more than 2 years after prior MI or more than 1 year after discontinuation of prior ADP receptor inhibitor therapy (see also section "Dosage and Administration").

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

Children

In a randomized, double-blind, Phase III, parallel-group 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% pre-dose and 56% two hours post-dose at steady state.

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

The European Medicines Agency has waived the obligation to submit results of ticagrelor studies in all pediatric subpopulations with acute coronary syndrome (ACS) and history of myocardial infarction (MI) (see section "Dosage and Administration" for use in children).

Pharmacokinetics

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

Absorption

Ticagrelor is rapidly absorbed, with a median tmax of approximately 1.5 hours. The formation of the main circulating metabolite of ticagrelor, AR-C124910XX (also active), occurs rapidly, with a median tmax of approximately 2.5 hours. After a single 90 mg oral dose of ticagrelor administered fasting to healthy volunteers, Cmax is 529 ng/mL and AUC is 3451 ng·h/mL. The metabolite-to-parent ratio is 0.28 for Cmax and 0.42 for AUC.

Pharmacokinetics of ticagrelor and AR-C124910XX in patients with a history of MI were generally similar to those observed in the ACS patient population. According to population pharmacokinetic analysis of the PEGASUS study, median Cmax of ticagrelor was 391 ng/mL and AUC was 3801 ng·h/mL at steady state with a 60 mg dose. Cmax of ticagrelor 90 mg was 627 ng/mL and AUC was 6255 ng·h/mL at steady state.

The mean absolute bioavailability of ticagrelor is estimated to be 36%. Consumption of a high-fat meal increased the AUC of ticagrelor by 21% and decreased the Cmax of the active metabolite by 22%, but had no effect on ticagrelor Cmax or AUC of the active metabolite. These changes are of minimal clinical significance; therefore, ticagrelor can be administered independently of food intake. Ticagrelor and its active metabolite are substrates of P-gp.

Crushed ticagrelor tablets mixed with water, when administered orally or via nasogastric tube into the stomach, have bioavailability comparable to that of intact tablets, based on AUC and Cmax values of ticagrelor and its active metabolite. Initial concentrations (0.5 and 1 hour after dosing) of crushed and water-mixed tablets were higher than those of intact tablets, but thereafter (2–48 hours) concentration profiles were predominantly similar.

Distribution

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

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 ADP P2Y12 receptors. Systemic exposure to the active metabolite is approximately 30–40% of systemic exposure to ticagrelor.

Elimination

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

Special Patient Populations

Elderly Patients. According to population pharmacokinetic analysis, elderly patients (≥75 years) with ACS had higher exposures to ticagrelor (approximately 25% higher for both Cmax and AUC) and the active metabolite compared to younger patients. These differences are not considered clinically significant (see section "Dosage and Administration").

Children. Data on the use of ticagrelor in children with sickle cell anemia are limited (see sections "Dosage and Administration" and "Pharmacodynamics").

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

Sex. Women had higher exposures to ticagrelor and the 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 on hemodialysis, AUC and Cmax of 90 mg ticagrelor, when administered on a day without hemodialysis, were 38% and 51% higher, respectively, 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% and Cmax 17–36%). Platelet aggregation inhibition (PAI) by ticagrelor was independent of dialysis in patients with end-stage renal disease and was similar to that in patients with normal renal function (see section "Dosage and Administration").

Hepatic Impairment. Cmax and AUC of ticagrelor were 12% and 23% higher, respectively, in patients with mild hepatic impairment compared to healthy volunteers, but the PAI effect of ticagrelor was similar in both groups. Dose adjustment is not required in patients with mild hepatic impairment. The use of ticagrelor in patients with moderate or severe hepatic impairment has not been studied, and pharmacokinetic data in patients with moderate hepatic impairment are lacking. In patients with moderate or marked baseline elevations in one or more liver function tests, plasma concentrations of ticagrelor were on average similar or slightly higher compared to patients without baseline abnormalities. Dose adjustment is not required in patients with moderate hepatic impairment (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use").

Ethnicity. In patients of Asian origin, mean bioavailability is 39% higher than in Caucasian patients. In patients of Black origin, ticagrelor bioavailability 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 Caucasians. 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 Gregorel in combination with acetylsalicylic acid (ASA) is indicated for the prevention of atherothrombotic complications in adult patients with:

• acute coronary syndrome (ACS) or
• history of myocardial infarction (MI) and high risk of developing atherothrombotic complications (see sections "Dosage and administration" and "Pharmacodynamics").

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

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 primarily a substrate of CYP3A4 and a moderate inhibitor of CYP3A4. Ticagrelor is also a substrate of P-gp and a weak inhibitor of P-gp, and may increase exposure to P-gp substrates. Ticagrelor is an inhibitor of breast cancer resistance protein (BCRP).

Effects of medicinal products and other substances 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 may therefore 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 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 CYP3A)

Concomitant administration of cyclosporine (600 mg) and ticagrelor led to 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 inhibitors of P-gp and moderate inhibitors of CYP3A4 (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 pharmacology interaction studies showed that concomitant administration of ticagrelor with heparin, enoxaparin, ASA, or desmopressin did not affect the pharmacokinetics of ticagrelor or its active metabolite, or ADP-induced platelet aggregation compared to ticagrelor alone. When clinically indicated, medicinal products affecting haemostasis should be used with caution in combination with ticagrelor.

In patients with ACS receiving morphine, delayed and reduced exposure to oral P2Y12 inhibitors, including ticagrelor and its active metabolites (reduction in ticagrelor effect by 35%), was observed. This interaction may be related to reduced gastrointestinal (GI) motility and may also occur with other opioid agents. The clinical significance of this interaction is unknown, but data suggest a potential reduction in ticagrelor efficacy in patients receiving concomitant morphine. For patients with ACS in whom morphine administration cannot be delayed and rapid P2Y12 inhibition is considered critical, parenteral administration of a P2Y12 inhibitor should be considered.

Effects 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%, and increased Cmax of simvastatin acid by 64% and AUC by 52% (in some 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; therefore, the risk and expected benefit should be carefully considered. 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%. Similar increases in AUC and Cmax were observed for all metabolites of atorvastatin acid. However, this increase is not considered clinically significant.
• Other statins: a similar effect on other statins metabolized by CYP3A4 cannot be excluded. In the PLATO study, participants receiving ticagrelor were taking various statins, and no statin-related safety issues occurred in 93% of these patients.

Ticagrelor is a weak inhibitor of CYP3A4. Concomitant use of ticagrelor with CYP3A4 substrates 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 (e.g., digoxin and cyclosporine)

Concomitant administration of ticagrelor increased Cmax of digoxin by 75% and AUC by 28%. Mean trough levels of digoxin increased by approximately 30% with concomitant 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 is therefore unlikely to affect CYP2C9-mediated metabolism of drugs such as warfarin and tolbutamide.

Rosuvastatin (BCRP substrate)

It has been shown that concomitant use of ticagrelor increases plasma concentrations of rosuvastatin, which may increase the risk of myopathy, including rhabdomyolysis. When prescribing this combination, the benefits of preventing serious cardiovascular events with rosuvastatin should be weighed against the potential risks associated with increased plasma concentrations.

Oral contraceptives

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

MEDICINAL PRODUCTS THAT MAY CAUSE BRADYCARDIA

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

Other concomitant therapy

In the PLATO study, ticagrelor was frequently used concomitantly with ASA, PPIs, statins, beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) for prolonged periods, as required by patients' comorbidities; as well as with heparin, low molecular weight heparin, and intravenous 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 potential pharmacodynamic interactions, ticagrelor should be used with caution concomitantly with medicinal products capable of affecting haemostasis.

Due to reports of pathological skin bleeding associated with use of selective serotonin reuptake inhibitors (SSRIs) (e.g., paroxetine, sertraline, and citalopram), SSRIs should be used with caution concomitantly with ticagrelor, as this may increase the risk of bleeding.

Special precautions for use

Bleeding risk

The use of ticagrelor in patients with known increased risk of bleeding should be carefully considered, weighing the benefit of the medicinal product in preventing atherothrombotic complications (see sections "Side effects" and "Pharmacodynamics"). When clinically indicated, ticagrelor should be used with caution in the following patient groups:

• Patients with a tendency to bleed (e.g., due to recent trauma or surgical procedures, coagulation disorders, active or recent gastrointestinal bleeding) or with an increased risk of trauma. Ticagrelor is contraindicated in patients with active pathological bleeding, history of intracranial hemorrhage (ICH), and patients with moderate to 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., nonsteroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, and/or fibrinolytic agents).

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

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

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

Surgical procedures

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

In the PLATO study, among patients undergoing coronary artery bypass grafting (CABG), bleeding events were more frequent with ticagrelor than with clopidogrel when therapy was discontinued one day before surgery. However, when therapy was stopped at least two days before surgery, the frequency of major bleeding was similar between the ticagrelor and clopidogrel treatment groups (see section "Side effects"). If a patient requires elective surgery and an antiplatelet effect is undesirable, ticagrelor should be discontinued at least 5 days before the procedure (see section "Pharmacodynamics").

Patients who have experienced ischemic stroke

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

Patients with a history of myocardial infarction (MI) who have experienced an ischemic stroke were not included in the PEGASUS study. Therefore, due to lack of data, treatment beyond 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, caution is recommended when administering the medicinal product to these patients (see sections "Dosage and administration" and "Pharmacokinetics").

Patients at risk of bradycardia

Holter ECG monitoring revealed an increased frequency of predominantly asymptomatic ventricular pauses during ticagrelor treatment compared to clopidogrel. Patients at high risk of bradycardia (e.g., 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 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 the Holter substudy of 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 ventricular asystole episodes with ticagrelor was more pronounced in patients with heart failure (HF) compared to the overall study population during the acute phase of ACS, but this difference was no longer observed after one month of treatment with ticagrelor or compared to clopidogrel. No adverse clinical consequences related to this discrepancy (including syncope or pacemaker implantation) were observed in this patient population (see section "Pharmacodynamics").

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

Dyspnea

Dyspnea has been observed in patients receiving ticagrelor. Dyspnea is usually mild or moderate in severity and often resolves without discontinuation of treatment. The absolute risk of developing dyspnea with ticagrelor is increased in patients with asthma (BA) and/or chronic obstructive pulmonary disease (COPD). 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 the 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. See section "Side effects" for details.

Central sleep apnea

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

Increase in creatinine levels

Creatinine levels may increase during treatment with ticagrelor. The mechanism of this phenomenon is not fully understood. Renal function should be monitored according to routine clinical practice. In patients with ACS, renal function should also be assessed one month after initiation of ticagrelor therapy, with particular attention to patients aged ≥75 years, patients with moderate to severe renal impairment, and patients receiving concomitant treatment with ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs).

Increase in uric acid levels

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

Thrombotic thrombocytopenic purpura

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

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 taking ticagrelor, falsely negative results in platelet function tests (including the HIPA test) for the diagnosis of HIT have been obtained. This is due to the inhibition of P2Y12 receptors on donor platelets by ticagrelor in the patient serum/plasma test. The concomitant use of ticagrelor must be taken into account when interpreting platelet function test results for the diagnosis of HIT.

In patients who develop HIT, the benefit-risk balance 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 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").

Early discontinuation of treatment

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

The medicinal product Gregorel contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially sodium-free.

This medicinal product contains mannitol, which may have a mild laxative effect.

Use during pregnancy and breastfeeding

Women of childbearing potential

Women of childbearing 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 has been observed in animal studies. Ticagrelor is not recommended for use during pregnancy.

Breastfeeding

Available pharmacodynamic/toxicological data 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/forego ticagrelor therapy should be made, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Reproductive function

Ticagrelor did not affect fertility in male and female animals.

Ability to affect reaction speed when driving or operating machinery

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

Dosage and Administration

Dosage

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

Acute Coronary Syndrome

Treatment should begin with a single loading dose of Gregorel 180 mg (two 90 mg tablets), followed by 90 mg twice daily. The recommended duration of treatment with Gregorel 90 mg in patients with ACS is 12 months, unless there are clinical reasons for earlier discontinuation (see section "Pharmacodynamics").

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

History of Myocardial Infarction

The recommended dose of Gregorel for patients with a history of myocardial infarction (MI) occurring at least one year prior and who are at high risk of atherothrombotic complications requiring long-term treatment is 60 mg twice daily (see section "Pharmacodynamics"). Treatment of ACS patients at high risk of atherothrombotic complications may be initiated without interruption as a continuation of therapy following initial treatment with Gregorel 90 mg or another adenosine diphosphate (ADP) receptor inhibitor that 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 use beyond 3 years of continued treatment are limited.

When switching from another agent to Gregorel, the first dose of Gregorel should be taken 24 hours after the last dose of the previous antithrombotic agent.

Missed Dose

Missed doses should be avoided. If a patient misses a dose of Gregorel, 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 effect of ticagrelor in patients with severe hepatic impairment has not been studied; therefore, its use is contraindicated in such patients (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 Warnings and Precautions for Use" and "Pharmacokinetics"). Dose adjustment is not required in patients with mild hepatic impairment (see section "Pharmacokinetics").

Administration

Gregorel is intended for oral administration. It may be taken independently of food.

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 water 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.

Children

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

Ticagrelor is not recommended for use in children with sickle cell anemia (see section "Pharmacological Properties").

Overdose

Ticagrelor has been well tolerated at single doses up to 900 mg. Gastrointestinal toxicity was the dose-limiting factor in dose-escalation studies. Other clinically significant manifestations of overdose include dyspnea and episodes of ventricular pauses (see section "Adverse Reactions"). Therefore, ECG monitoring should be considered in cases of overdose.

There is currently no known antidote for ticagrelor; ticagrelor is not removed 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 for patients experiencing bleeding (see section "Special Warnings and Precautions for Use"). Appropriate supportive measures should be taken in the event of bleeding.

Adverse reactions

The safety profile of ticagrelor was evaluated in two large-scale phase 3 clinical outcome 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 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 adverse reactions 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 adverse reactions in patients receiving ticagrelor treatment were bleeding and dyspnea (see section "Special precautions for use").

The adverse reactions listed below were identified during clinical trials or reported during post-marketing use of ticagrelor (see Table 1).

Adverse reactions are listed by system organ class according to MedDRA (Medical Dictionary for Regulatory Activities). The frequency of adverse reactions is defined according to the following criteria: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

Table 1

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

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

c Identified during the post-marketing period.

d Frequency established based on laboratory data (increase in uric acid levels above the upper limit of normal from baseline levels that were below or within the normal range; creatinine level increase >50% from baseline) and does not reflect the reporting rate 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

General data on the frequency of bleeding events in the PLATO study are presented in Table 2.

Table 2. Analysis of total bleeding events: Kaplan-Meier estimate at 12 months (PLATO)

Definition of Bleeding Types

Major fatal/life-threatening 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 drugs 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 permanent disability.

Minor bleeds: require 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, presented for the treatment group as an exploratory measure only.

There was no difference between ticagrelor and clopidogrel in the rate of major fatal/life-threatening bleeds according to PLATO criteria, total number of major bleeds, or frequency 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 few patients in the PLATO study experienced fatal bleeds: 20 (0.2%) in the ticagrelor group and 23 (0.3%) in the clopidogrel group (see section "Special Warnings and Precautions for Use").

Age, sex, body weight, race, geographic region, concomitant conditions, concomitant 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 1584 patients (12% of the cohort) who underwent coronary artery bypass grafting (CABG) experienced a major fatal/life-threatening bleed according to PLATO study criteria, with no statistically significant difference between treatment groups. Fatal bleeding related to CABG occurred in 6 patients in each treatment group (see section "Special Warnings and Precautions for Use").

Bleeding not related to CABG and bleeding not related to procedures. Ticagrelor and clopidogrel did not differ in the rate of CABG-unrelated fatal/life-threatening major bleeds according to PLATO criteria. However, the overall rate of major bleeds according to PLATO criteria, the rate of major bleeds according to TIMI criteria, and the total rate of major + 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 2). 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). There were more non-procedure-related ICH events with ticagrelor (n = 27 bleeds in 26 patients, 0.3%) compared to clopidogrel (n = 27 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 data on bleeding rates in the PEGASUS study are presented in Table 3.

Table 3. Analysis of total bleeding events: Kaplan-Meier (KM) estimate over 36 months (PEGASUS)

Definition of types of bleeding

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

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

ICH: intracranial hemorrhage.

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

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

Bleeding requiring medical attention according to TIMI criteria: bleeding requiring intervention or hospitalization, or investigation.

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

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

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

In the PEGASUS study, the incidence of major bleeding according to TIMI criteria in the group treated with ticagrelor 60 mg twice daily was higher than in the group treated with aspirin (ASA) alone. Compared with ASA-only therapy, no increase in the risk of fatal bleeding was observed, and only a slight increase in the risk of ICH was noted. During the study, there were few fatal bleeding events: 11 (0.3%) in the ticagrelor 60 mg treatment group and 12 (0.3%) in the ASA-only group. The increased risk of major bleeding according to TIMI criteria observed in the ticagrelor 60 mg group was primarily due to a higher incidence of other major bleeding events according to TIMI criteria, most of which were gastrointestinal disorders.

A similar trend of increased bleeding frequency, as seen with major bleeding according to TIMI criteria, was observed for the following types of bleeding: major or minor bleeding according to TIMI criteria, major bleeding according to PLATO criteria, and major or minor bleeding according to PLATO criteria (see Table 3). Discontinuation of treatment due to bleeding occurred more frequently in the ticagrelor 60 mg group than in the ASA-only group (6.2% vs. 1.5%, respectively). Most of these bleeding events were of lower severity (classified as requiring medical attention according to TIMI criteria), such as epistaxis, bruises, and hematomas.

The bleeding profile in the ticagrelor 60 mg group was consistent across many predefined subgroups (i.e., by age, sex, weight, race, geographic region, comorbidities, and medical history) for cases of major bleeding according to TIMI criteria, major or minor bleeding according to TIMI criteria, and major bleeding according to PLATO criteria.

Intracranial hemorrhage

Spontaneous ICH was reported with similar frequency in both the ticagrelor 60 mg treatment group and the ASA-only group (n=13, 0.2% in both treatment groups). The incidence of ICH due to trauma or procedure was slightly higher in the ticagrelor 60 mg group (n=15, 0.2%) compared to the ASA-only group (n=10, 0.1%). During the study, there were 6 fatal ICH events in the ticagrelor 60 mg group and 5 in the ASA-only group. The incidence of ICH was low in both treatment groups, considering the significant number of comorbidities and cardiovascular risk factors in the study population.

Dyspnea

Dyspnea and the sensation of shortness of breath were observed in patients taking ticagrelor. 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, investigators considered dyspnea to be treatment-related in 2.2% of patients in the ticagrelor group and 0.6% in the clopidogrel group, 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; single episodes occurring soon after initiation of treatment were most commonly reported.

Compared with clopidogrel, patients with asthma/COPD receiving ticagrelor have an increased risk of non-serious dyspnea events (3.29% with ticagrelor vs. 0.53% with clopidogrel) and serious dyspnea events (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 asthma; these patients, as well as elderly patients, were more prone to developing dyspnea. 0.9% of patients receiving ticagrelor discontinued treatment prematurely due to dyspnea compared to 0.1% of patients receiving clopidogrel. The higher incidence of dyspnea with ticagrelor is not associated with the development of new or worsening pre-existing heart or lung disease (see section "Special precautions"). Ticagrelor does not affect pulmonary function test results.

Laboratory findings

Increased uric acid levels: In the PLATO study, uric acid concentration exceeded the upper limit of normal in 22% of patients in the ticagrelor group compared to 13% in the clopidogrel group. 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 about 7.5% with clopidogrel, and decreased by approximately 7% after discontinuation of 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 in the ticagrelor 90 mg and 60 mg groups, respectively, compared to a 1.5% decrease in the placebo group. In the PLATO study, the incidence of gouty arthritis was 0.2% in the ticagrelor group and 0.1% in the clopidogrel group. 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 enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach and sight of children.

Packaging. 14 tablets in a blister; 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Atlantik Pharma Produtos Farmaceuticos S.A.

Manufacturer's location and address of business premises. Rua Tapada Grande 2, Abrunheira, Sintra, 2710-228, Portugal.