Tikarda

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

Composition:

Active substance: ticagrelor;

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

Excipients: hypromellose, mannitol (E 421), microcrystalline cellulose, sodium starch glycolate, magnesium stearate;

Film coating:

60 mg tablets: hypromellose, titanium dioxide (E 171), macrogol 400, talc, red iron oxide (E 172);

90 mg tablets: hypromellose, titanium dioxide (E 171), macrogol 400, talc, yellow iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

60 mg tablets: pink, round, biconvex, film-coated tablets with the imprint "60" on one side and smooth on the other;

90 mg tablets: yellow, round, biconvex, film-coated tablets with the imprint "90" on one side and smooth on the other.

Pharmacotherapeutic group. Antithrombotic agent. Inhibitors of platelet aggregation, excluding heparin.

ATC code B01AC24.

Pharmacological properties.

Mechanism of action

Ticarda contains ticagrelor, a member of the chemical class cyclopentyltriazolopyrimidines (CPTP), which is an oral, direct-acting, selective and reversibly binding P2Y12 receptor antagonist that prevents ADP-mediated activation and aggregation of P2Y12-dependent platelets. Ticagrelor does not prevent ADP binding, but upon binding to the P2Y12 receptor, it prevents ADP-induced signal transduction. Since platelets are involved in the initiation and/or progression of thrombotic complications of atherosclerotic disease, inhibition of platelet function has been shown to reduce the risk of cardiovascular events such as death, myocardial infarction (MI), or stroke.

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

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

Pharmacodynamics.

Onset of action

In patients with stable ischemic heart disease (IHD) receiving acetylsalicylic acid (ASA), ticagrelor demonstrates a rapid onset of pharmacological effect, as indicated by a mean platelet aggregation inhibition (PAI) of approximately 41% within 0.5 hours after administration of a 180 mg loading dose. Maximum PAI of 89% is achieved within 2–4 hours after dosing and is maintained for 2–8 hours. Ninety percent of patients achieved a final PAI > 70% within 2 hours after dosing.

Offset of action

If coronary artery bypass grafting (CABG) is planned, the risk of bleeding with ticagrelor is increased compared to clopidogrel if treatment is discontinued less than 96 hours before the procedure.

Switching between medicinal products

Switching from clopidogrel 75 mg to ticagrelor 90 mg twice daily results in an absolute increase in PAI of 26.4%, while switching from ticagrelor to clopidogrel results in an absolute decrease in PAI of 24.5%. Patients may be switched from clopidogrel to ticagrelor without loss of antiplatelet effect.

Clinical efficacy and safety

Clinical evidence of efficacy and safety of ticagrelor has been obtained from two Phase III studies:

• Study PLATO [PLATelet Inhibition and Patient Outcomes]: comparison of ticagrelor versus clopidogrel, both administered in combination with ASA and other standard therapy.
• Study PEGASUS TIMI-54 [PrEvention with TicaGrelor of SecondAry Thrombotic Events in High-RiSk AcUte Coronary Syndrome Patients]: comparison of ticagrelor in combination with ASA versus ASA monotherapy.

PLATO study (acute coronary syndromes)

The PLATO study included 18,624 patients who within 24 hours developed symptoms of unstable angina (UA), myocardial infarction without ST-segment elevation (NSTEMI), or myocardial infarction with ST-segment elevation (STEMI), and who were treated medically or underwent percutaneous coronary intervention (PCI) or CABG.

Clinical efficacy

Against a background of daily ASA use, ticagrelor 90 mg twice daily demonstrated superiority over clopidogrel 75 mg once daily in preventing the composite endpoint of cardiovascular death (CVD), MI, or stroke, driven by differences in CVD and MI rates. Patients received a loading dose of clopidogrel 300 mg (600 mg possible if PCI was performed) or ticagrelor 180 mg.

The benefit was achieved rapidly (absolute risk reduction [ARR] 0.6%, relative risk reduction [RRR] 12% at 30 days) and was maintained throughout the 12-month treatment period, with ARR of 1.9% per year and RRR of 16%. This supports the use of ticagrelor 90 mg twice daily for 12 months. Treatment of 54 ACS patients with ticagrelor instead of clopidogrel prevents one atherothrombotic event; treatment of 91 patients prevents one CVD death.

The therapeutic advantage of ticagrelor over clopidogrel was independent of patient body weight, sex, history of diabetes, transient ischemic attack or non-hemorrhagic stroke, revascularization; concomitant therapy, including heparins, GpIIb/IIIa inhibitors, and proton pump inhibitors; final diagnosis of the index event (STEMI, NSTEMI, or UA); and treatment strategy assigned at randomization (invasive or medical).

A minor treatment interaction by region was observed: the hazard ratio (HR) for the primary endpoint indicated benefit of ticagrelor in countries outside North America, which represented approximately 10% of the total study population (p-value for interaction 0.045). Subsequent analyses suggest a possible association with ASA dose, as reduced efficacy of ticagrelor was observed with increasing ASA doses. Daily ASA doses when co-administered with ticagrelor should be 75–150 mg.

Ticagrelor reduced the rate of the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI and STEMI populations. Thus, Ticarda 90 mg twice daily, in combination with low-dose ASA, can be used in patients with ACS (UA, STEMI), including those managed medically or undergoing PCI or CABG.

Genetic substudy of PLATO

Genotyping for CYP2C19 and ABCB1 in 10,285 patients in the PLATO study established associations between genotype groups and outcomes. The superiority of ticagrelor over clopidogrel in reducing major cardiovascular events did not significantly depend on CYP2C19 or ABCB1 genotype. Similar to the overall PLATO study, overall major bleeding in PLATO did not differ between ticagrelor and clopidogrel, regardless of CYP2C19 or ABCB1 genotype.

The rate of non-CABG-related major bleeding in the PLATO study was higher with ticagrelor compared to clopidogrel in patients lacking one or more functional CYP2C19 alleles, but similar to clopidogrel in patients with no loss of functional alleles.

Composite measure of efficacy and safety

The composite measure of efficacy and safety (CVD death, MI, stroke, or total number of major bleeds as defined by PLATO) indicates that the efficacy benefit of ticagrelor over clopidogrel is 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 monitoring substudy

To assess the occurrence of ventricular pauses and other arrhythmic episodes, Holter monitoring was performed in a subgroup of nearly 3000 patients in the PLATO study, of whom approximately 2000 had recordings during both the acute phase of ACS and at one month. The primary variable of interest was the occurrence of ventricular pauses ≥ 3 seconds. Ventricular pauses were observed more frequently with ticagrelor (6.0%) than with clopidogrel (3.5%) in the acute phase, and 2.2% vs. 1.6% at one month, respectively. The increase in ventricular pauses during the acute phase of ACS was more pronounced with ticagrelor in patients with a history of chronic heart failure (CHF) (9.2% vs. 5.4% in patients without CHF history; with clopidogrel: 4.0% in CHF patients vs. 3.6% in non-CHF patients). This imbalance was not evident at one month: 2.0% vs. 2.1% in ticagrelor-treated patients with and without CHF history, respectively, and 3.8% vs. 1.4% with clopidogrel. No adverse clinical consequences related to this imbalance (including pacemaker implantation) 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, designed to evaluate the prevention of atherothrombotic events with ticagrelor administered at two doses (either 90 mg twice daily or 60 mg twice daily) in combination with low-dose ASA (75–150 mg), compared to ASA monotherapy in patients with prior MI and additional risk factors for atherothrombosis.

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

Exclusion criteria included planned use of a P2Y12 receptor antagonist, dipyridamole, cilostazol, or anticoagulants during the study period; coagulation disorders or 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 at doses of 60 mg twice daily and 90 mg twice daily in combination with ASA was more effective than ASA monotherapy in preventing atherothrombotic events (composite endpoint: CVD death, MI, and stroke), with a consistent treatment effect throughout the study period, resulting in a 16% RRR and 1.27% ARR with ticagrelor 60 mg, and 15% RRR and 1.19% ARR with ticagrelor 90 mg.

Although the efficacy profiles of the 90 mg and 60 mg doses were similar, evidence suggests that the lower dose has better tolerability and a more favorable safety profile regarding bleeding risk and dyspnea. Therefore, the medicinal product Ticarda at a dose of 60 mg twice daily, in combination with ASA, is recommended for the prevention of atherothrombotic events (CVD death, MI, and stroke) in patients with prior MI and high risk of atherothrombotic events.

Compared to ASA monotherapy, ticagrelor 60 mg twice daily significantly reduced the primary composite endpoint of CVD death, MI, and stroke. Each component contributed to the reduction in the primary composite endpoint (CVD death: 17% RRR, MI: 16% RRR, stroke: 25% RRR).

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

No benefit was demonstrated (no reduction in the primary composite endpoint of CVD death, MI, and stroke, and increased incidence of major bleeding) with initiation of ticagrelor 60 mg twice daily in clinically stable patients more than 2 years after MI or more than 1 year after discontinuation of prior ADP receptor inhibitor therapy.

Clinical safety

The rate of 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 > 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 receive placebo or ticagrelor at doses ranging from 15 mg to 45 mg twice daily based on body weight. In the ticagrelor group, median platelet inhibition was 35% pre-dose and 56% 2 hours post-dose at steady state.

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

The European Medicines Agency (EMA) has waived the obligation to submit results of studies of Ticarda in all pediatric subpopulations for ACS and prior MI.

Pharmacokinetics.

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

Absorption

Ticagrelor is rapidly absorbed, with a median tmax of approximately 1.5 hours. Formation of the main circulating metabolite of ticagrelor, AR-C124910XX (also active), occurs rapidly, with a median tmax of approximately 2.5 hours. After a single 90 mg oral dose administered fasting in healthy subjects, 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 in patients with ACS. According to population pharmacokinetic analysis from the PEGASUS study, median ticagrelor Cmax was 391 ng/mL and AUC was 3801 ng*h/mL at steady state with 60 mg dosing. 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 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 minor changes are considered to have minimal clinical significance; therefore, ticagrelor can be administered independently of food intake. Ticagrelor and its active metabolite are substrates of P-gp.

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

Distribution

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

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 based on in vitro assessment of 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 recovery of radioactivity was approximately 84% (57.8% in feces, 26.5% in urine). The amount of ticagrelor and active metabolite in urine is less than 1% of the dose. The main route of elimination of the active metabolite is likely biliary secretion. The mean t1/2 was approximately 7 hours for ticagrelor and 8.5 hours for the active metabolite.

Special patient groups

Elderly patients

Population pharmacokinetic analysis in elderly patients (≥ 75 years) with ACS showed higher exposure to ticagrelor (approximately 25% higher for both Cmax and AUC) and to the active metabolite compared to younger patients. These differences are not considered clinically significant.

Children

Limited data are available in children with sickle cell anemia.

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 dispersible pediatric tablets at doses of 15 mg, 30 mg, and 45 mg twice daily, respectively. According to population pharmacokinetic analysis, mean AUC ranged from 1095 ng*h/mL to 1458 ng*h/mL, and mean Cmax ranged from 143 ng/mL to 206 ng/mL at steady state.

Sex

Higher exposure to ticagrelor and its active metabolite was observed in women compared to men. These differences are not considered clinically significant.

Renal impairment

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

In patients with end-stage renal disease on hemodialysis, AUC and Cmax of 90 mg ticagrelor administered on a dialysis day when dialysis was not performed 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 by 13–14% and Cmax by 17–36%). The platelet aggregation inhibition effect of ticagrelor was independent of dialysis in patients with end-stage renal disease and was similar to that in patients with normal renal function.

Hepatic impairment

Cmax and AUC of ticagrelor were 12% and 23% higher, respectively, in patients with mild hepatic impairment compared to healthy subjects, but the PAI effect of ticagrelor was similar in both groups. Dose adjustment is not required for patients with mild hepatic impairment. Ticagrelor has not been studied in patients with severe hepatic impairment, and pharmacokinetic data in patients with moderate hepatic impairment are lacking. In patients with baseline moderate or marked elevation of one or more liver function tests, plasma concentrations of ticagrelor were on average similar or slightly higher than in those without baseline abnormalities. Dose adjustment is not required for patients with moderate hepatic impairment.

Ethnicity

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

Clinical characteristics.

Indications.

The use of the medicinal product Ticarda in combination with acetylsalicylic acid (ASA) is indicated for the prevention of atherothrombotic events in adult patients with:

• acute coronary syndrome (ACS) or
• history of myocardial infarction (MI) and high risk of developing atherothrombotic events.

Contraindications.

• Hypersensitivity to ticagrelor or to any of the excipients.
• Active pathological bleeding.
• History of intracranial hemorrhage.
• Severe hepatic impairment.
• Concomitant use of ticagrelor with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir), as such use may lead to a significant increase in ticagrelor exposure.

Interaction with other medicinal products and other forms of interaction.

Ticagrelor is primarily a substrate of CYP3A4 and a moderate inhibitor of CYP3A4. Ticagrelor is also a substrate of P-glycoprotein (P-gp) and a weak inhibitor of P-gp and may increase exposure to P-gp substrates.

Effect of medicinal products and other agents on ticagrelor

CYP3A4 inhibitors

• Strong CYP3A4 inhibitors. Concomitant use of ketoconazole with ticagrelor increased Cmax and AUC of ticagrelor by 2.4 and 7.3 times, 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 show a similar effect; therefore, concomitant use of strong CYP3A4 inhibitors with ticagrelor is contraindicated.
• Moderate CYP3A4 inhibitors. Concomitant use of diltiazem with ticagrelor increased Cmax of ticagrelor by 69% and AUC by 2.7 times, while decreasing Cmax of the active metabolite by 38%, with no change in AUC. No effect of ticagrelor on diltiazem plasma levels 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. Such an increase in exposure is not expected to be clinically significant for most patients.

CYP3A inducers

Concomitant use of rifampicin with ticagrelor decreased Cmax and AUC of ticagrelor by 73% and 86%, 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 reduce ticagrelor exposure and efficacy; therefore, such concomitant use is not recommended.

Cyclosporine (P-gp and CYP3A inhibitor)

Concomitant use of cyclosporine (600 mg) with ticagrelor increased Cmax and AUC of ticagrelor by 2.3 and 2.8 times, respectively. AUC of the active metabolite increased by 32%, while Cmax decreased by 15% in the presence of cyclosporine.

There are no data on concomitant use of ticagrelor with other active substances that are strong P-gp inhibitors and moderate CYP3A4 inhibitors (such as verapamil, quinidine), which may increase ticagrelor exposure. If such combination cannot be avoided, concomitant use should be performed with caution.

Others

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

Delayed and reduced exposure of oral P2Y12 inhibitors, including ticagrelor and its active metabolite, was observed in patients with ACS who received morphine (a 35% reduction in ticagrelor exposure). This interaction may be related to decreased gastrointestinal motility and may also apply to other opioids. The clinical significance is unknown, but data suggest a potential reduction in ticagrelor efficacy in patients who received ticagrelor and morphine concomitantly. For patients with ACS in whom morphine cannot be discontinued and rapid P2Y12 inhibition is considered life-critical, parenteral administration of a P2Y12 inhibitor may be considered.

Effect of ticagrelor on other medicinal products

Medicinal products metabolized by CYP3A4

• Simvastatin. Concomitant use 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/day may cause simvastatin-related adverse effects, which should be weighed against potential benefits. No effect of simvastatin on ticagrelor plasma levels 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 use 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. These increases are 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 were reported in 93% of the PLATO cohort who used these medicinal products.

Ticagrelor is a weak inhibitor of CYP3A4. Concomitant use of ticagrelor with CYP3A4 substrates having 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, cyclosporine)

Concomitant use 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 individual cases, maximum increases up to 2 times were observed. The presence of digoxin did not affect Cmax and AUC of ticagrelor and its active metabolite. Therefore, when ticagrelor is used concomitantly with P-gp-dependent medicinal products with a narrow therapeutic index, such as digoxin, appropriate clinical and/or laboratory monitoring is recommended.

No effect of ticagrelor on blood levels of cyclosporine was observed. The effect of ticagrelor on other P-gp substrates has not been studied.

Medicinal products metabolized by CYP2C9

Concomitant use of ticagrelor with tolbutamide did not result in changes in plasma levels of these medicinal products, indicating that ticagrelor is not an inhibitor of CYP2C9 and is unlikely to alter CYP2C9-mediated metabolism of medicinal products such as warfarin and tolbutamide.

Rosuvastatin

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

Oral contraceptives

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

Medicinal products capable of causing bradycardia

Since cases of predominantly asymptomatic ventricular asystole and bradycardia have been observed, ticagrelor should be used with caution when administered concomitantly with medicinal products capable of causing bradycardia. 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, 4% received digoxin).

Other concomitant therapies

In clinical studies, ticagrelor was usually administered with ASA, proton pump inhibitors, statins, beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs), which were used long-term as needed due to patients' comorbidities, as well as with heparin, low-molecular-weight heparin, and intravenous GpIIb/IIIa inhibitors, used for short periods. No evidence of clinically significant adverse interactions with these medicinal products has been found.

Concomitant use of ticagrelor with heparin, enoxaparin, or desmopressin did not affect activated partial thromboplastin time (aPTT), activated clotting time (ACT), or factor Xa assay. However, due to potential 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 with the use of selective serotonin reuptake inhibitors (SSRIs) (e.g., paroxetine, sertraline, citalopram), SSRIs should be used with caution in combination 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 events. In the presence of clinical indications, ticagrelor should be used with caution in the following patient groups:

• Patients with a tendency to bleed (e.g., due to recent trauma, recent surgical intervention, coagulation disorders, active or recently experienced gastrointestinal bleeding) or with an increased risk of injury. Ticagrelor is contraindicated in patients with active pathological bleeding, history of intracranial hemorrhage (ICH), or severe hepatic impairment.
• Patients receiving medicinal products that may increase the risk of bleeding (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, and/or fibrinolytics) within 24 hours after ticagrelor administration.

Platelet transfusion did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is unlikely to be effective in treating patients with bleeding. Since co-administration of ticagrelor with desmopressin did not reduce template bleeding time, it is unlikely that desmopressin will be effective in managing clinical bleeding.

Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or treatment with recombinant factor VIIa may enhance hemostasis. Ticagrelor therapy may be resumed after identification and control of the cause of bleeding.

Surgical procedures

Patients should inform physicians, including dentists, that they are taking ticagrelor prior to any planned surgical procedure and before initiating any new medicinal product.

In the PLATO study, among patients undergoing coronary artery bypass grafting (CABG), bleeding events were more frequent in the ticagrelor group compared to the clopidogrel group when therapy was discontinued one day before surgery. However, the rate of major bleeding was similar between ticagrelor and clopidogrel when therapy was stopped at least two or more days prior to surgery (see section "Adverse reactions"). If a patient requires elective surgery and antiplatelet effect is undesirable, ticagrelor should be discontinued five days before the procedure.

Patients with prior ischemic stroke

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

Patients with prior ischemic stroke were excluded from the PEGASUS study. Therefore, due to lack of data, treatment beyond one year is not recommended for these patients.

Patients with hepatic impairment

Ticagrelor is contraindicated in patients with severe hepatic impairment. Experience with ticagrelor use in patients with moderate hepatic impairment is limited; therefore, the drug should be used with caution in such patients (see sections "Dosage and administration").

Patients at risk of bradycardia

Holter ECG monitoring revealed an increased incidence 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 AV block, or syncope due to bradycardia) were excluded from 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.

Additionally, ticagrelor should be used with caution when co-administered with medicinal products that may cause bradycardia. However, in the PLATO study, no signs of clinically significant adverse reactions were observed after concomitant use with one or more drugs capable of causing bradycardia (e.g., 96% of patients received beta-blockers, 33% received calcium channel blockers diltiazem or verapamil, and 4% received digoxin).

During Holter sub-study within PLATO, ventricular pauses lasting ≥ 3 seconds occurred more frequently during the acute phase of ACS with ticagrelor than with clopidogrel. The increased frequency of Holter-detected ventricular pauses with ticagrelor was more pronounced in patients with heart failure (HF) compared to the overall study population during the acute phase of ACS, but this difference was no longer observed after one month of treatment with ticagrelor or compared to clopidogrel. No adverse clinical consequences related to this discrepancy (including syncope or need for pacemaker implantation) were observed in this patient population.

In the post-marketing period, cases of bradyarrhythmia and AV block have been reported in patients receiving ticagrelor, primarily in patients with ACS, where myocardial ischemia and concomitant medications that reduce heart rate or affect cardiac conduction are potential contributing factors. Before modifying 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 discontinuation of treatment. Patients with asthma and/or chronic obstructive pulmonary disease (COPD) may have an increased absolute risk of developing dyspnea when receiving ticagrelor. Ticagrelor should be used with caution in patients with a history of asthma and/or COPD. The mechanism of dyspnea development is not fully understood. If a patient reports new, persistent, or worsening dyspnea, a full evaluation should be performed, and if intolerance to the medicinal product is suspected, treatment with ticagrelor should be discontinued.

Central sleep apnea

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

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 assessed one month after initiation of ticagrelor therapy, with special attention to patients aged ≥ 75 years, those with moderate/severe renal impairment, and those receiving concomitant treatment with ACE inhibitors (ACEIs) or ARBs.

Increase in uric acid

Hyperuricemia may occur during treatment with ticagrelor. The drug should be used with caution in patients with a history of hyperuricemia or gouty arthritis. As a precaution, ticagrelor is not recommended for patients with uric acid nephropathy.

Thrombotic thrombocytopenic purpura (TTP)

TTP has been reported very rarely with ticagrelor use. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia, often associated with neurological symptoms, renal dysfunction, or fever. TTP is a potentially life-threatening condition requiring immediate treatment, including plasma exchange.

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

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

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

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

Other

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

Early discontinuation of treatment

Premature discontinuation of any antiplatelet therapy, including ticagrelor, may increase the risk of cardiovascular death, myocardial infarction, or stroke due to the patient’s underlying condition. Therefore, premature discontinuation of treatment should be avoided.

Precautions regarding excipients

Ticagrelor contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding

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. Animal studies have shown reproductive toxicity. Ticagrelor is not recommended during pregnancy.

Breastfeeding

Pharmacodynamic/toxicological studies have shown excretion of ticagrelor and its active metabolite into animal milk. Risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from ticagrelor therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

Ticagrelor did not affect fertility in male or female animals.

Ability to drive and use machines

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

Method of Administration and Dosage

Dosage

Patients taking the medicinal product TICARDIA should also take low-dose acetylsalicylic acid (ASA) daily at a maintenance dose of 75–150 mg, unless contraindicated.

Acute Coronary Syndrome (ACS)

Treatment with TICARDIA should be initiated with a single loading dose of 180 mg (two 90 mg tablets), followed by a maintenance dose of 90 mg twice daily. The recommended duration of treatment (90 mg twice daily) for patients with ACS is 12 months, unless there are clinical reasons for discontinuation.

History of Myocardial Infarction

For long-term treatment in patients with a history of myocardial infarction (MI) occurring at least one year prior and at high risk of atherothrombotic events, the recommended dose of TICARDIA is 60 mg twice daily. Treatment may be initiated without interruption as a continuation of therapy following the initial 12-month treatment with TICARDIA 90 mg twice daily, or with other adenosine diphosphate (ADP) receptor inhibitors in patients with ACS at high risk of atherothrombotic events. Treatment may also be initiated two years after MI or within one year after discontinuation of prior ADP receptor inhibitor therapy. Data on the efficacy and safety of ticagrelor use beyond 3 years are limited.

If switching from another medicinal product, the first dose of TICARDIA should be taken 24 hours after the last dose of the previous antiplatelet agent.

Missed Dose

Missed doses should be avoided. If a patient misses a dose of TICARDIA, they should take only one tablet (the next scheduled dose) at the usual time.

Special Patient Groups

Elderly Patients

Dose adjustment in elderly patients is not required.

Patients with Renal Impairment

Dose adjustment is not required in patients with renal impairment.

Patients with Hepatic Impairment

The use of ticagrelor in patients with severe hepatic impairment has not been studied and is therefore contraindicated. Limited data are available on the use of ticagrelor in patients with moderate hepatic impairment. Dose adjustment is not recommended, but ticagrelor should be used with caution. In patients with mild hepatic impairment, no dose adjustment is necessary.

Method of Administration

For oral use.

TICARDIA may be administered independently of food intake.

For patients unable to swallow the tablet(s) whole, the tablet can be crushed into a fine powder, mixed with half a glass of water, and taken immediately. The glass should then be rinsed with an additional half glass of water, which should also be consumed. The mixture can also be administered via a nasogastric tube (CH8 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.

Data on the use of ticagrelor in children with sickle cell anemia are lacking.

Overdose

Symptoms. Ticagrelor is well tolerated at single doses up to 900 mg. Gastrointestinal toxicity was dose-limiting in a single ascending dose study. Other clinically significant adverse reactions that may occur in overdose include dyspnea and episodes of ventricular asystole.

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

Treatment. There is currently no known antidote to reverse the effects of ticagrelor. Ticagrelor is not dialyzable. Management of overdose should follow local standards of medical practice. The expected effect of ticagrelor overdose is prolonged bleeding risk due to platelet inhibition. Platelet transfusion is unlikely to provide clinical benefit in patients experiencing bleeding. Appropriate supportive measures should be initiated in case of bleeding.

Adverse Reactions

The safety profile of ticagrelor was evaluated in two large Phase III studies (PLATO and PEGASUS), which included over 39,000 patients.

In the PLATO study, the rate of drug discontinuation due to adverse reactions was higher in patients receiving ticagrelor compared to those receiving clopidogrel (7.4% vs. 5.4%). In the PEGASUS study, the rate of drug discontinuation due to adverse reactions was higher in patients receiving ticagrelor compared to those receiving aspirin monotherapy (16.1% with ticagrelor 60 mg plus aspirin vs. 8.5% with aspirin alone). The most commonly reported adverse reactions in patients receiving ticagrelor were bleeding and dyspnea.

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

Adverse reactions are listed by organ system classes according to MedDRA. Within each organ system class, adverse reactions are categorized by frequency. The frequency category is defined according to the following conventional notation: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon: Bleeding from tumor^a

Blood and lymphatic system disorders

Very common: Bleeding due to coagulation disorder^b

Frequency not known: Thrombotic thrombocytopenic purpura^c

Immune system disorders

Uncommon: Hypersensitivity, including angioedema^c

Metabolism and nutrition disorders

Very common: Hyperuricemia^d

Common: Gout/gouty arthritis

Psychiatric disorders

Uncommon: Confusion

Nervous system disorders

Common: Dizziness, syncope, headache

Uncommon: Intracranial hemorrhage^m

Eye disorders

Uncommon: Eye hemorrhage^e

Ear and labyrinth disorders

Common: Dizziness

Uncommon: Ear hemorrhage

Cardiac disorders

Frequency not known: Bradycardia, AV block^c

Vascular disorders

Common: Arterial hypotension

Respiratory, thoracic and mediastinal disorders

Very common: Dyspnea

Common: Bleeding from respiratory organs^f

Gastrointestinal disorders

Common: Gastrointestinal hemorrhage^g, diarrhea, nausea, dyspepsia, constipation

Uncommon: Retroperitoneal hemorrhage

Skin and subcutaneous tissue disorders

Common: Subcutaneous or skin hemorrhage^h, rash, pruritus

Musculoskeletal and connective tissue disorders

Uncommon: Muscle hemorrhageⁱ

Renal and urinary disorders

Common: Bleeding from urinary tract^j

Reproductive system and breast disorders

Uncommon: Genital bleeding^k

Investigations

Common: Increased blood creatinine^d

Injury, poisoning and procedural complications

Common: Bleeding after procedure, traumatic hemorrhage^l

^a e.g., bleeding from a malignant bladder, stomach, or colon tumor
^b e.g., increased tendency to bruising, spontaneous hematoma, hemorrhagic diathesis
^c Identified during post-marketing period
^d Frequency determined based on laboratory observations (increase in uric acid levels > upper limit of normal from baseline levels below or within the control range; increase in creatinine > 50% from baseline). This does not reflect the frequency of adverse event reporting.
^e e.g., conjunctival, retinal, intraocular hemorrhage
^f e.g., epistaxis, hemoptysis
^g e.g., gingival bleeding, rectal bleeding, bleeding from gastric ulcer
^h e.g., ecchymoses, skin hemorrhages, petechiae
ⁱ e.g., hemarthrosis, muscle hemorrhage
^j e.g., hematuria, hemorrhagic cystitis
^k e.g., vaginal bleeding, hemospermia, postmenopausal bleeding
^l e.g., contusion, traumatic hematoma, traumatic hemorrhage
^m i.e., spontaneous, procedure-related, or traumatic intracranial hemorrhage

Description of selected adverse reactions

Bleeding

Cases of bleeding in the PLATO study

The overall results for bleeding frequency in the PLATO study are presented in Table 1.

Table 1. Analysis of total bleeding events, Kaplan-Meier estimate at 12 months (PLATO)

Definition of types of bleeding

Major fatal/life-threatening bleeds: clinically overt, with a decrease in hemoglobin level of > 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 hypotension requiring use of vasopressor drugs or surgical intervention.

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

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

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

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

* p-value calculated based on Cox proportional hazards model, with treatment group as an exploratory endpoint.

Ticagrelor and clopidogrel did not differ in the incidence of major fatal/life-threatening bleeds according to PLATO criteria, total number of major bleeds according to PLATO criteria, or major or minor bleeds according to TIMI criteria (see Table 2). However, there were more combined major and minor bleeds according to PLATO criteria with ticagrelor compared to clopidogrel. A small number of patients in the PLATO study experienced fatal bleeds: 20 (0.2%) with ticagrelor and 23 (0.3%) with clopidogrel.

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

Bleeding associated with CABG

In the PLATO study, 42% of 1584 patients (12% of the cohort) who underwent CABG procedure experienced major fatal/life-threatening bleeding according to study criteria, with no difference between treatment groups. Fatal bleeding associated with CABG was observed in 6 patients in each treatment group.

Bleeding not associated with CABG and bleeding not associated with procedure

Ticagrelor and clopidogrel did not differ in the rate of non-CABG-related fatal/life-threatening major bleeds according to PLATO criteria. However, the overall rate of major bleeds according to PLATO criteria, the rate of major bleeds according to TIMI criteria, and the overall rate of major and minor bleeds according to TIMI criteria were higher in the ticagrelor treatment group. Similarly, when all procedure-related bleeds were excluded, more bleeds occurred with ticagrelor than with clopidogrel (see Table 2). Discontinuation of treatment due to non-procedural bleeding was more frequent with ticagrelor (2.9%) than with clopidogrel (1.2%; p < 0.001).

Intracranial hemorrhage (ICH)

Non-procedure-related ICH was more frequent with ticagrelor (27 bleeds in 26 patients, 0.3%) than with clopidogrel (14 bleeds, 0.2%), of which 11 bleeds in the ticagrelor group and 1 bleed in the clopidogrel group were fatal. No difference was observed in the overall rate of fatal bleeds.

Bleeding events in the PEGASUS study

The overall assessment of bleeding frequency in the PEGASUS study is presented in Table 2.

Table 2. 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 clinically overt signs of hemorrhage associated with a decrease in hemoglobin (Hgb) level by ≥ 50 g/L, or, when Hgb levels are unavailable, a decrease in hematocrit (Hct) by 15%.

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

ICH: intracranial hemorrhage.

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

Minor TIMI bleeding: clinically overt bleeding associated with a decrease in Hgb level by 30–50 g/L.

Bleeding requiring medical attention according to TIMI criteria: requires intervention OR leads to hospitalization OR requires investigation.

Major fatal/life-threatening bleeding according to PLATO criteria: fatal bleeding OR any ICH OR intracardiac bleeding with cardiac tamponade OR hypovolemic shock or severe hypotension requiring vasopressor/inotropic drugs or surgical intervention OR clinically overt bleeding associated with a decrease in Hgb level by > 50 g/L or transfusion of ≥ 4 units of packed red blood cells.

Other major bleeding according to PLATO criteria: leading to significant disability OR clinically overt bleeding associated with a decrease in Hgb level by 30–50 g/L OR transfusion of 2–3 units of packed red blood cells.

Minor bleeding according to PLATO criteria: requires medical intervention to stop or treat bleeding.

In the PEGASUS trial, the incidence of major bleeding (TIMI) with ticagrelor 60 mg twice daily was higher than with aspirin alone. There was no increase in the risk of fatal bleeding; however, there was only a slight increase in the incidence of ICH compared to aspirin monotherapy. There were several cases of fatal bleeding in the study: 11 (0.3%) in the ticagrelor 60 mg group and 12 (0.3%) in the aspirin-only group. The observed increase in risk of major bleeding (TIMI) with ticagrelor 60 mg was primarily due to a higher incidence of other major bleeding (TIMI), predominantly gastrointestinal events.

A similar trend of increased bleeding frequency, as seen for major bleeding (TIMI), was observed for major or minor bleeding (TIMI) and major bleeding (PLATO), as well as for major or minor bleeding (PLATO) (see Table 2). Premature discontinuation of treatment due to bleeding occurred more frequently with ticagrelor 60 mg compared to aspirin monotherapy (6.2% vs. 1.5%, respectively). Most of these bleeding events were less severe (classified as requiring medical attention according to TIMI), including epistaxis, bruising, and hematomas.

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

Intracranial hemorrhage (ICH)

Spontaneous ICH occurred with similar frequency in patients treated with ticagrelor 60 mg and those treated with aspirin alone (n = 13, 0.2% in both treatment groups). Traumatic and procedure-related ICH occurred slightly more frequently with ticagrelor 60 mg (n = 15, 0.2%) compared to aspirin monotherapy (n = 10, 0.1%). There were 6 fatal ICH events in the ticagrelor 60 mg group and 5 in the aspirin group. The incidence of ICH was low in both treatment groups, considering the significant comorbidities and cardiovascular risk factors in the studied population.

Dyspnea

Dyspnea or sensation of shortness of breath has been reported in patients treated with ticagrelor. In the PLATO study, adverse events of dyspnea (dyspnea, dyspnea at rest, exertional dyspnea, paroxysmal nocturnal dyspnea, and nocturnal dyspnea) were reported in 13.8% of patients receiving ticagrelor and in 7.8% of patients receiving clopidogrel. In the PLATO study, treatment was considered the cause of dyspnea in 2.2% of patients taking ticagrelor and 0.6% of those taking clopidogrel, with some of these cases being serious (0.14% in the ticagrelor group; 0.02% in the clopidogrel group). Most dyspnea symptoms were mild to moderate in intensity and occurred as transient episodes early in treatment.

Compared to patients treated with clopidogrel, patients with asthma/COPD receiving ticagrelor may have an increased risk of non-serious dyspnea (3.29% with ticagrelor vs. 0.53% with clopidogrel) and serious dyspnea (0.38% with ticagrelor vs. 0.00% with clopidogrel). This risk was higher in absolute terms than in the overall population of the PLATO study. Ticagrelor should be used with caution in patients with a history of asthma and/or COPD.

Approximately 30% of dyspnea episodes resolved within 7 days. The PLATO study included patients with congestive heart failure, COPD, or asthma; these patients and elderly patients reported dyspnea more frequently. Premature discontinuation of the study due to dyspnea occurred in 0.9% of patients receiving ticagrelor compared to 0.1% of those taking clopidogrel. The higher incidence of dyspnea with ticagrelor is not associated with new onset or worsening of pre-existing cardiac or pulmonary conditions. Ticagrelor does not affect pulmonary function test results.

In the PEGASUS study, dyspnea was reported in 14.2% of patients receiving ticagrelor 60 mg twice daily and in 5.5% of patients receiving aspirin alone. As in the PLATO study, most reported cases of dyspnea were mild to moderate in severity. Patients reporting dyspnea were typically elderly and more likely to have baseline dyspnea, COPD, or asthma.

Laboratory findings

Increased uric acid levels: In the PLATO study, serum uric acid levels increased above the upper normal limit in 22% of patients receiving ticagrelor compared to 13% of those receiving clopidogrel. Corresponding values in the PEGASUS study were 9.1%, 8.8%, and 5.5% for ticagrelor 90 mg, 60 mg, and placebo, respectively. Mean serum uric acid levels increased by approximately 15% with ticagrelor compared to approximately 7.5% with clopidogrel; after discontinuation of treatment, levels decreased by approximately 7% with ticagrelor, but no decrease was observed with clopidogrel. In the PEGASUS study, reversible increases in mean serum uric acid levels of 6.3% and 5.6% were observed with ticagrelor 90 mg and 60 mg, respectively, compared to a 1.5% decrease in the placebo group. In the PLATO study, the incidence of gouty arthritis was 0.2% with ticagrelor compared to 0.1% with clopidogrel. Corresponding rates of gout/gouty arthritis in the PEGASUS study were 1.6%, 1.5%, and 1.1% with ticagrelor 90 mg, 60 mg, and placebo, respectively.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Keep out of reach of children.

This medicinal product does not require special storage temperature conditions; store in the original packaging to protect from light.

Packaging.

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

Prescription status. Prescription only.

Manufacturer.

Jenepharm S.A.

Manufacturer's address and location of its business operations.

18th km Marathon Avenue, Pallini, 15 351, Greece.