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INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT HETIGLOR (HETIGLOR)

Composition:

Active substance: ticagrelor;

1 tablet contains 60 mg or 90 mg of ticagrelor;

Excipients: mannitol (E 421), sodium starch glycolate (type A), povidone, microcrystalline cellulose, magnesium stearate; «Instacoat Universal Brown A05E04420» [hypromellose (E 464), polyethylene glycol 400 (E 1521), polyethylene glycol 6000 (E 1521), talc (E 553b), titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172)] — for 60 mg tablets; «Instacoat Universal White A05R03281» [hypromellose (E 464), polyethylene glycol 400 (E 1521), polyethylene glycol 6000 (E 1521), talc (E 553b), titanium dioxide (E 171)] — for 90 mg tablets.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

60 mg tablets: film-coated tablets, from peach to light brown in color, round-shaped, biconvex, with the imprint «68» on one side and «V1» on the other;

90 mg tablets: film-coated tablets, white or almost white, round-shaped, biconvex, with the imprint «70» on one side and «V1» on the other.

Pharmacotherapeutic group. Antithrombotic agents. Antiplatelet agents, excluding heparin. ATC code B01AC24.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

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

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

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

Pharmacodynamic effects

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

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

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 leads to an absolute decrease in PAI of 24.5%. Patients may be switched from clopidogrel to ticagrelor without interruption of antiplatelet effect (see section "Dosage and administration").

Clinical efficacy and safety

Clinical evidence of efficacy and safety of ticagrelor was obtained in two phase 3 studies:

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

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

PLATO study (acute coronary syndrome)

The PLATO study included 18,624 patients with symptoms of unstable angina (UA), myocardial infarction without ST-segment elevation (NSTEMI), or myocardial infarction with ST-segment elevation (STEMI), who were initially treated medically or with PCI (percutaneous coronary intervention), or CABG.

Clinical efficacy. On a background of daily ASA use, ticagrelor 90 mg twice daily was more effective than clopidogrel 75 mg once daily in preventing the primary composite endpoint (PCE), which included CV death, myocardial infarction (MI), or stroke, 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 effect was rapid and sustained throughout the 12-month treatment period, with an absolute risk reduction (ARR) of 1.9% per year and a relative risk reduction (RRR) of 16%. Treatment of 54 ACS patients with ticagrelor instead of clopidogrel prevented one atherothrombotic event; treatment of 91 patients with ticagrelor prevented one CV death.

The greater efficacy of ticagrelor compared to clopidogrel was independent of body weight, sex, presence of diabetes, transient ischemic attack (TIA), non-hemorrhagic stroke, revascularization, or concomitant medications, including heparins, GpIIb/IIIa inhibitors, and proton pump inhibitors (see section "Interaction with other medicinal products and other forms of interaction"). Efficacy did not depend on the treatment strategy chosen at randomization (invasive or medical), in both UA/NSTEMI and STEMI patients.

The hazard ratio (HR) for PCE favored ticagrelor in countries outside North America, which represented approximately 10% of the total study population (p for interaction = 0.045). A post hoc analysis suggests a possible interaction with ASA dose, as higher ASA doses were associated with reduced efficacy of ticagrelor. ASA doses for continuous daily use in combination with the medicinal product Hetiglor should be 75–150 mg (see sections "Dosage and administration" and "Special precautions for use").

Ticagrelor treatment reduced the frequency of PCE compared to clopidogrel in all ACS patients (UA, NSTEMI, STEMI). Therefore, the medicinal product Hetiglor 90 mg twice daily in combination with low-dose ASA can be prescribed to ACS patients (UA, NSTEMI, STEMI), including those undergoing medical therapy, PCI, or CABG.

Genetic substudy of PLATO. Genotyping of 10,285 patients for CYP2C19 and ABCB1 in the PLATO study established associations between genotype groups and study outcomes. The advantages of ticagrelor over clopidogrel in reducing the frequency of serious CV events were not significantly dependent 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 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%, HR 0.92; p = 0.0257) over 12 months after ACS.

Clinical safety. Holter sub-study. According to Holter monitoring data from the PLATO study, more patients in the ticagrelor group had episodes of ventricular asystole ≥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 (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 at two doses (90 mg twice daily or 60 mg twice daily) in combination with low-dose ASA (75–150 mg) compared to ASA alone in patients with prior MI and additional risk factors for atherothrombosis.

Inclusion criteria were: age ≥ 50 years, prior MI (1–3 years before randomization), and at least one of the following risk factors for atherothrombosis: age ≥ 65 years, diabetes requiring medication, second prior MI, evidence of multivessel coronary artery disease, or non-terminal stage chronic kidney disease (CKD).

Exclusion criteria included planned use of a P2Y12 receptor antagonist, dipyridamole, cilostazol, or anticoagulant therapy during the study period; coagulation disorders, history of ischemic stroke or intracranial hemorrhage (ICH), central nervous system tumor or intracranial vascular anomaly; gastrointestinal bleeding within the previous 6 months or major surgery within the previous 30 days.

Clinical efficacy. Ticagrelor 60 mg twice daily and 90 mg twice daily in combination with ASA were more effective than ASA alone in preventing atherothrombotic events (composite endpoint: CV death, MI, and stroke), with a consistent treatment effect throughout the study period, RRR of 16% and ARR of 1.27% 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 bleeding risk and dyspnea. Therefore, only ticagrelor 60 mg twice daily in combination with ASA is recommended for the prevention of atherothrombotic events (CV death, MI, and stroke) in patients with prior MI and high risk of atherothrombotic events.

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

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

No evidence of benefit (no reduction in PCE frequency [CV death, MI, and stroke] and increased frequency of major bleeding) was observed 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 ADP receptor inhibitor therapy (see also section "Dosage and administration").

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

Children

In a randomized, double-blind, phase III, 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% before dosing and 56% two hours after dosing at steady state.

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

Pharmacokinetics

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

Absorption

Ticagrelor is rapidly absorbed, with a median tmax of approximately 1.5 hours. The formation of the main circulating metabolite of ticagrelor, AR-C124910XX (also active), occurs rapidly, with a median tmax of approximately 2.5 hours. After a single 90 mg oral dose of ticagrelor administered fasting to healthy volunteers, Cmax was 529 ng/mL and AUC was 3451 ng•h/mL. The metabolite-to-parent ratio was 0.28 for Cmax and 0.42 for AUC. The pharmacokinetics of ticagrelor and AR-C124910XX in patients with prior MI were generally similar to those observed in the ACS patient population. According to population pharmacokinetic analysis of the PEGASUS study, median Cmax of ticagrelor was 391 ng/mL and AUC was 3801 ng•h/mL at steady state with the 60 mg dose. For ticagrelor 90 mg, Cmax was 627 ng/mL and AUC was 6255 ng•h/mL at steady state.

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

The bioavailability of ticagrelor in the form of crushed tablets mixed with water, when administered orally or via nasogastric tube into the stomach, is comparable to that of whole tablets with regard to AUC and Cmax of ticagrelor and its active metabolite. Initial exposure (0.5 and 1 hour after dosing) of crushed and water-mixed ticagrelor tablets was higher than that of whole tablets, but generally with a similar concentration profile thereafter (2–48 hours).

Distribution

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

Biotransformation

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

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

Elimination

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

Special patient groups

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

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

In the HESTIA 3 study, patients aged 2 to 18 years with body weight ≥ 12 to ≤ 24 kg, > 24 to ≤ 48 kg, and > 48 kg received ticagrelor in the form of 15 mg chewable pediatric tablets at doses of 15, 30, and 45 mg twice daily, respectively. According to pharmacokinetic analysis 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.

Sex. Women had higher exposure to ticagrelor and 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 values in 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 by 13–14%, Cmax by 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 in patients with mild hepatic impairment is not required. 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 tests, plasma concentrations of ticagrelor were on average similar or slightly higher compared to patients without baseline abnormalities. Dose adjustment in patients with moderate hepatic impairment is not required (see sections "Dosage and administration" and "Special precautions for use").

Ethnicity. In patients of Asian origin, mean bioavailability of ticagrelor is 39% higher than in Caucasian patients. In patients of African descent, 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 medicinal product Getiglor should be used in combination with acetylsalicylic acid (ASA) for the prevention of atherothrombotic events in adult patients with:

• acute coronary syndrome (ACS), or
• history of myocardial infarction (MI) and high risk of atherothrombotic events (see sections "Dosage and Administration" and "Pharmacodynamics").

Contraindications

Hypersensitivity to the active substance or to any of the excipients (see section "Adverse Reactions").

Active pathological bleeding.

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

Severe hepatic impairment (see sections "Dosage and Administration", "Special Warnings and 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-glycoprotein (P-gp) and a weak inhibitor of P-gp, and may increase exposure to P-gp substrates.

Effect 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 and ticagrelor led to a 69% increase in Cmax and a 2.7-fold increase in AUC of ticagrelor, as well as a 38% decrease in Cmax of the active metabolite, while its AUC remained unchanged. No effect of ticagrelor on plasma levels of diltiazem was observed. Other moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, erythromycin, and fluconazole) are expected to have a similar effect; therefore, they may be used concomitantly with ticagrelor.
• Daily consumption of large amounts of grapefruit juice (3 × 200 ml) resulted in a doubling of ticagrelor exposure. Such an increase in exposure is not expected to be clinically significant for most patients.

Inducers of CYP3A4

Concomitant administration of rifampicin and ticagrelor resulted in a 73% and 86% decrease in Cmax and AUC of ticagrelor, respectively. Cmax of the active metabolite remained unchanged, while AUC decreased by 46%. Other CYP3A4 inducers (e.g., phenytoin, carbamazepine, and phenobarbital) are also expected to reduce ticagrelor exposure. Concomitant use of ticagrelor with strong CYP3A inducers may lead to reduced exposure and efficacy of ticagrelor; therefore, such concomitant use is not recommended.

Cyclosporine (inhibitor of P-gp and CYP3A)

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

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 undertaken with caution.

Others

Clinical pharmacology interaction studies showed that concomitant administration of ticagrelor with heparin, enoxaparin, ASA, or desmopressin had no effect on the pharmacokinetics of ticagrelor or its active metabolite, or on ADP-induced platelet aggregation compared to ticagrelor alone. When clinically indicated, medicinal products affecting hemostasis should be used with caution in combination with ticagrelor.

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

Effect of Ticagrelor on Other Medicinal Products

Medicinal Products Metabolized by CYP3A4

• Simvastatin — Concomitant administration of ticagrelor and 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 doses exceeding 40 mg daily may cause adverse effects of simvastatin, which should be weighed against potential benefit. No effect of simvastatin on plasma levels of ticagrelor was observed. Ticagrelor may have a similar effect on lovastatin. Concomitant use of ticagrelor with simvastatin or lovastatin at doses exceeding 40 mg is not recommended.
• Atorvastatin — Concomitant administration of atorvastatin and ticagrelor increased Cmax of atorvastatin acid by 23% and AUC by 36%. A similar increase in AUC and Cmax was observed for all metabolites of atorvastatin acid. This increase is not considered clinically significant.
• A similar effect on other statins metabolized by CYP3A4 cannot be excluded. Participants in the PLATO study who received ticagrelor were taking various statins, and no safety issues with statins occurred in 93% of 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 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 concentration of cyclosporine was observed. The effect of ticagrelor on other P-gp substrates has not been studied.

Medicinal Products Metabolized by CYP2C9

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

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

Oral Contraceptives

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

Medicinal Products Capable of Causing 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 capable of causing bradycardia (see section "Special Warnings and Precautions for Use"). However, in the PLATO study, no clinically significant adverse reactions (ARs) were observed after concomitant use of one or more medicinal products capable of causing bradycardia (e.g., 96% of patients received beta-blockers, 33% received calcium channel blockers diltiazem and verapamil, and 4% received digoxin).

Other Concomitant Therapy

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

Concomitant administration of ticagrelor with heparin, enoxaparin, or desmopressin had no effect on activated partial thromboplastin time (aPTT), activated clotting time (ACT), or quantitative anti-factor Xa assay results. However, due to possible pharmacodynamic interactions, ticagrelor should be used with caution when administered concomitantly with medicinal products capable of affecting hemostasis.

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

Special precautions for use

Bleeding risk

The decision to use ticagrelor in patients with an increased risk of bleeding should be based on a careful assessment of the benefit of the medicinal product in preventing atherothrombotic events (see sections "Side effects" and "Pharmacodynamics"). Ticagrelor should be used with caution in the following patient groups when clinically indicated:

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

Platelet transfusion did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is therefore unlikely to be effective in treating patients with bleeding. Since coadministration of ticagrelor with desmopressin did not reduce template bleeding time, 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 hemostasis. Ticagrelor therapy may be resumed once the cause of bleeding has been identified and controlled.

Surgical procedures

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

In the PLATO study, in patients undergoing CABG, bleeding events were more frequent in the ticagrelor group compared to the clopidogrel group when therapy was discontinued one day before surgery. However, major bleeding occurred with similar frequency in both groups when therapy was discontinued at least two days before surgery (see section "Side effects"). If a patient requires elective surgery and the antiplatelet effect is undesirable, ticagrelor should be discontinued five days prior to surgery (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 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, the medicinal product should be used with caution in these patients (see sections "Dosage and administration" and "Pharmacokinetics").

Patients at risk of bradycardia

Holter ECG monitoring revealed an increased frequency of predominantly asymptomatic ventricular pauses during ticagrelor treatment compared to clopidogrel. Patients at increased risk of bradycardia (e.g., patients without pacemakers 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").

Coadministration of ticagrelor with medicinal products capable of causing bradycardia requires caution. However, in the PLATO study, no signs of clinically significant interactions were observed after coadministration 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 interactions").

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

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

Dyspnea

Dyspnea has been observed in patients receiving ticagrelor. Dyspnea was usually mild or moderate in severity and often resolved without the need to discontinue treatment. The absolute risk of developing dyspnea with ticagrelor may be 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 new onset, prolonged duration, or worsening of dyspnea, a full clinical 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

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

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 standard medical practice. In patients with ACS, renal function should also be evaluated one month after initiation of ticagrelor therapy, with particular attention to patients aged ≥ 75 years, patients with moderate to severe renal impairment, and those receiving concomitant ARBs.

Increase in uric acid levels

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

Thrombotic thrombocytopenic purpura (TTP)

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

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

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

In patients receiving ticagrelor, false-negative results have been observed in platelet function tests (including the HIPA test) for the diagnosis of HIT. This is due to ticagrelor's inhibition of P2Y12 receptors on the platelets of healthy donors in the patient serum/plasma test. Information on concomitant ticagrelor therapy is required for the interpretation of platelet function test results for HIT diagnosis.

In patients who develop HIT, the benefit-risk balance of continuing ticagrelor therapy should be evaluated, considering both the prothrombotic state of HIT and the increased risk of bleeding associated with concomitant anticoagulant and ticagrelor therapy.

Other

Due to the observed relationship between maintenance 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").

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

Early discontinuation of treatment

Early discontinuation of any antiplatelet agent, including the medicinal product Hetiglor, increases the risk of cardiovascular death, myocardial infarction (MI), or stroke due to the patient's underlying condition. Therefore, early discontinuation of treatment should be avoided.

Use during pregnancy or breastfeeding

Women of reproductive potential

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

Pregnancy

Data on the use of ticagrelor in pregnant women are lacking or limited. Reproductive toxicity has been 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. A risk to the newborn/infant cannot be excluded. The decision to discontinue breastfeeding or to discontinue/forego ticagrelor therapy should be made, taking into account the 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. Cases of dizziness and confusion have been reported during treatment with ticagrelor. Therefore, patients experiencing these symptoms should exercise caution when driving or operating machinery.

Method of Administration and Dosage

Dosage

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

Acute Coronary Syndrome

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

History of Myocardial Infarction

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

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

Missed Dose

Patients should avoid missing doses of the medicinal product. If a patient misses a dose of Getiglor, they should take only 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"). 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").

Method of Administration

For oral use.

The medicinal product Getiglor can be administered independently of food intake.

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

Children

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

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

Overdose

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

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

There is currently no known antidote for ticagrelor; ticagrelor is not removed by dialysis (see section "Pharmacokinetics"). Management of overdose should follow current standards of medical practice. The expected consequence of ticagrelor overdose is prolonged bleeding time 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 implemented.

Adverse reactions

The safety profile of ticagrelor was evaluated in two large-scale phase 3 clinical outcome studies (the PLATO and PEGASUS trials), which included over 39,000 patients (see section "Pharmacodynamics").

In the PLATO study, the rate of premature discontinuation of treatment due to adverse reactions (ARs) was higher in patients receiving ticagrelor than in those receiving clopidogrel (7.4% vs. 5.4%). In the PEGASUS study, the rate of premature discontinuation due to ARs was higher among patients receiving ticagrelor compared to those receiving aspirin alone (16.1% with ticagrelor 60 mg plus aspirin vs. 8.5% with aspirin alone). The most common ARs in patients receiving ticagrelor were bleeding and dyspnea (see section "Special precautions").

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

Adverse reactions are listed by organ systems according to MedDRA [Medical Dictionary for Regulatory Activities]. Within each organ system, adverse reactions are categorized by frequency: 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), and frequency not known (cannot be estimated from available data).

Table 1. Adverse reactions by organ system and frequency

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

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 on bleeding frequency in the PLATO study are presented in Table 2.

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

Definition of bleeding types:

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

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

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

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

Minor bleeds according to TIMI criteria: clinically significant 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.

The rates of major life-threatening/fatal bleeds according to PLATO criteria, total number of major bleeds, and rates of major or minor bleeds according to TIMI criteria did not differ significantly between ticagrelor and clopidogrel. However, the rate of combined major and minor bleeds was higher in the ticagrelor group compared to the clopidogrel group. A small number of patients in the PLATO study experienced fatal bleeds: 20 (0.2%) in the ticagrelor group and 23 (0.3%) in the clopidogrel group (see section "Special precautions").

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

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

Bleeds not related to CABG and bleeds 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 total 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 remained 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): More non-procedure-related ICH events occurred with ticagrelor (n = 27 bleeds in 26 patients, 0.3%) than with clopidogrel (n = 14 bleeds, 0.2%), of which 11 bleeds in the ticagrelor group and 1 bleed in the clopidogrel group were fatal. There was no difference in the overall rate of fatal bleeds.

Bleeding events in the PEGASUS study

General results regarding bleeding rates in the PEGASUS study are presented in Table 3.

Table 3. Analysis of total number of bleeding events, assessed by Kaplan-Meier method over 36 months (PEGASUS)

Definition of bleeding types:

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

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

ICH: intracranial hemorrhage.

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

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

Bleeding requiring medical attention according to TIMI criteria: bleeding requiring intervention or hospitalization, or necessitating diagnostic evaluation.

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 drugs or surgical intervention, or clinically evident bleeding with a hemoglobin decrease ≥ 50 g/L or transfusion of ≥4 units of packed red blood cells.

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

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

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

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

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

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

Dyspnea

Patients treated with ticagrelor reported dyspnea and shortness of breath. In the PLATO trial, dyspnea-related adverse reactions (dyspnea, dyspnea at rest, exertional dyspnea, paroxysmal nocturnal dyspnea, and nocturnal dyspnea) occurred in 13.8% of patients treated with ticagrelor and in 7.8% of patients treated with clopidogrel. In the PLATO trial, dyspnea was considered treatment-related by investigators in 2.2% of patients receiving ticagrelor and in 0.6% of those receiving clopidogrel, with some cases being serious (0.14% in the ticagrelor group; 0.02% in the clopidogrel group) (see section "Special precautions"). Most dyspnea symptoms were mild or moderate; typically, single episodes occurred 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 overall population of the PLATO trial. 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 trial 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 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.

In the PEGASUS trial, dyspnea was reported in 14.2% of patients receiving ticagrelor 60 mg twice daily and in 5.5% of patients receiving aspirin-only treatment. As in the PLATO trial, most cases of dyspnea were mild or moderate (see section "Special precautions"). Patients who experienced dyspnea were typically elderly and had baseline dyspnea, COPD, or bronchial asthma.

Laboratory findings

Increased uric acid levels: In the PLATO trial, serum uric acid concentrations increased above the upper limit of normal in 22% of patients receiving ticagrelor compared to 13% of patients receiving clopidogrel. Corresponding values in the PEGASUS trial 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, levels decreased by approximately 7% with ticagrelor but did not decrease with clopidogrel. In the PEGASUS trial, 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 trial, the incidence of gouty arthritis was 0.2% with ticagrelor and 0.1% with clopidogrel. Corresponding rates for gout/gouty arthritis in the PEGASUS trial 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 highly important. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 30 °C, in a place inaccessible to children.

Packaging. 10 tablets per blister, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Annora Pharma Private Limited / Annora Pharma Private Limited.

Manufacturer's address and location of business operations

Sy. No. 261, Annaram Village, Gummadidala Mandal, Sangareddy District, Telangana State - 502313, India / Sy. No. 261, Annaram Village, Gummadidala Mandal, Sangareddy District, Telangana State - 502313, India.