Catilorix^® (Tablets) Instructions for Use

ATC Code

B01AC24 (Ticagrelor)

Active Substance

Ticagrelor (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiplatelet agent

Pharmacotherapeutic Group

Antithrombotic agents; antiplatelet agents, other than heparin

Pharmacological Action

Mechanism of action

The drug Catilorix^® contains Ticagrelor, a representative of the chemical class cyclopentyltriazolopyrimidines, which is an oral, selective, and reversible direct-acting P2Y12 receptor antagonist and prevents adenosine diphosphate-mediated P2Y12-dependent activation and aggregation of platelets. Ticagrelor does not prevent the binding of adenosine diphosphate (ADP), but its interaction with the platelet P2Y12 receptor prevents ADP-induced signal transduction. Since platelets are involved in the initiation and/or development of thrombotic complications of atherosclerosis, inhibition of platelet function has been shown to reduce the risk of cardiovascular events such as cardiovascular death, MI, or stroke.

Ticagrelor has an additional mechanism of action by increasing local concentrations of endogenous adenosine by inhibiting the endogenous equilibrative nucleoside transporter type 1 (ENT-1).

Adenosine is formed locally at sites of hypoxia and tissue damage through the release from adenosine triphosphate and ADP. Since the breakdown of adenosine is essentially limited to the intracellular space, inhibition of ENT-1 by ticagrelor prolongs the T_1/2 of adenosine and thereby increases its local extracellular concentration, enhancing the local adenosine response.

Ticagrelor has no clinically significant direct effect on adenosine receptors (A₁, A_2A, A_2B, A₃) and is not metabolized to adenosine. Adenosine has several effects which include: vasodilation, cardioprotection, inhibition of platelet aggregation, modulation of inflammation, and induction of dyspnea, which may affect the clinical profile of ticagrelor.

It has been shown that in healthy volunteers and in patients with ACS, Ticagrelor enhanced the following effects of adenosine: vasodilation (assessed as an increase in coronary blood flow in healthy volunteers and in patients with ACS), inhibition of platelet function (in vitro in human whole blood), and dyspnea. However, the relationship between increased local adenosine concentrations and clinical outcomes (e.g., morbidity and mortality rates) has not been proven.

Pharmacodynamic effects

Onset of action. In patients with stable CAD on background ASA therapy, Ticagrelor begins to act rapidly, as confirmed by the results of determining the mean value of platelet aggregation inhibition (PAI): 0.5 hours after a loading dose of 180 mg of ticagrelor, the mean PAI value is approximately 41%, the maximum PAI value of 89% is reached 2-4 hours after administration and is maintained for 2-8 hours. In 90% of patients, a final PAI value of more than 70% is achieved 2 hours after administration.

Offset of action. When planning CABG, the risk of bleeding increases if Ticagrelor is discontinued less than 96 hours before the procedure.

Data on switching from one drug to another

Switching from clopidogrel 75 mg once daily to Ticagrelor twice daily leads to an increase in the absolute PAI value by 26.4%, and changing therapy from ticagrelor to clopidogrel leads to a decrease in the absolute PAI value by 24.5%. Therapy can be changed from clopidogrel to Ticagrelor without interruption of the antithrombotic effect (see section “Dosage Regimen”).

Clinical efficacy and safety

PLATO study (acute coronary syndrome)

The PLATO study included 18,624 patients who developed symptoms of unstable angina, NSTEMI, or STEMI within the last 24 hours and who were treated conservatively or with PCI or CABG. Against a background of daily ASA therapy, Ticagrelor at a dose of 90 mg twice daily was compared with clopidogrel at a dose of 75 mg/day in terms of efficacy in preventing the development of the composite endpoint, including cardiovascular death, MI, or stroke, by influencing the incidence of cardiovascular death and MI.

PEGASUS study (history of MI)

The PEGASUS TIMI-54 study involving 21,162 patients was conducted to evaluate the prevention of atherothrombotic complications with the use of ticagrelor at a dose of 90 mg twice daily or at a dose of 60 mg twice daily in combination with low-dose ASA compared with ASA monotherapy in patients with a history of MI.

Patients aged 50 years and older with a history of MI (within 1-3 years prior to randomization) and with at least one of the following risk factors for atherothrombosis were included: age ≥65 years, diabetes mellitus requiring drug therapy, a second prior MI, confirmed multivessel coronary artery disease, or chronic non-terminal stage renal impairment.

Ticagrelor at a dose of 60 mg twice daily and at a dose of 90 mg twice daily in combination with ASA was effective in preventing atherothrombotic complications (composite endpoint including cardiovascular death, MI, and stroke), with a sustained treatment effect throughout the study period, resulting in a relative risk reduction (RRR) of 16% and an absolute risk reduction (ARR) of 1.27% with ticagrelor 60 mg and an RRR of 15% and ARR of 1.19% with ticagrelor 90 mg.

With comparable efficacy of ticagrelor 90 mg and 60 mg doses, Ticagrelor at a dose of 60 mg showed better tolerability and safety profile regarding the risk of bleeding and dyspnea.

Ticagrelor at a dose of 60 mg twice daily significantly reduced the primary composite endpoint, including cardiovascular death, MI, and stroke, with a reduction in each of its components: RRR of cardiovascular death by 17%, RRR of MI by 16%, and RRR of stroke by 25%.

Ticagrelor at a dose of 60 mg in combination with ASA reduced the number of cases of cardiovascular death and all-cause death, although statistical significance was not achieved.

The efficacy of ticagrelor 60 mg twice daily was demonstrated in various patient subgroups, regardless of body weight, gender, medical history, region, and is independent of the use of other cardiovascular agents, including lipid-lowering drugs, beta-blockers, ACE inhibitors (ACEIs), angiotensin II receptor antagonists, slow calcium channel blockers, nitrates, and proton pump inhibitors (see section “Drug Interactions”).

THEMIS study (CAD and T2DM)

The THEMIS study involving 19,220 patients was conducted to evaluate the prevention of atherothrombotic events with the use of ticagrelor in combination with low-dose ASA compared with ASA monotherapy in patients with CAD and T2DM.

Patients aged 50 years and older with CAD, defined as a history of PCI (58% of the study population) or a history of CABG (29%), or without a history of coronary revascularization but with angiographically confirmed lumen stenosis ≥50% of at least one coronary artery (20%), and with T2DM receiving therapy with a hypoglycemic drug for at least 6 months prior to study initiation were included. Patients with a history of MI or stroke were not included in the study. In the overall THEMIS study population, Ticagrelor twice daily in combination with ASA was effective in preventing atherothrombotic events (composite endpoint: cardiovascular death, MI, and stroke) compared with ASA: hazard ratio (HR) 0.90 (95% confidence interval (CI): 0.81, 0.99, p=0.0378), corresponding to an RRR of 10% and an ARR of 0.73%. The effect was driven by a reduction in the individual components of the composite endpoint, MI and stroke, with no difference in cardiovascular death.

In THEMIS study patients who had undergone PCI (n=11,154), therapy with ticagrelor in combination with ASA compared with ASA monotherapy led to the prevention of atherothrombotic events (composite endpoint: cardiovascular death, MI, and stroke): HR 0.85 (95% CI: 0.74, 0.97; nominal p=0.0133), corresponding to an RRR of 15%, ARR of 1.19% with a more favorable benefit-risk ratio than in the overall THEMIS study population. With ticagrelor therapy in combination with ASA compared with ASA monotherapy, fewer events were recorded for each component of the composite endpoint (cardiovascular death: 174 (3.1%) vs. 183 (3.3%), HR 0.96 (95% CI 0.78, 1.18); MI: 171 (3.1%) vs. 216 (3.9%), HR 0.80 (95% CI 0.65, 0.97); stroke: 96 (1.7%) vs. 131 (2.3%), HR 0.74 (95% CI 0.57, 0.96)).

The effect of ticagrelor therapy was comparable in patient subgroups formed based on patient characteristics, including body weight, gender, medical history, and geographic region.

Children

In a randomized, double-blind, placebo-controlled Phase III study, the primary objective of reducing the frequency of vaso-occlusive crises in children aged 2 to 18 years with sickle cell anemia was not achieved.

Pharmacokinetics

Absorption

Ticagrelor is rapidly absorbed, with a median T_max of approximately 1.5 hours. The formation of the main circulating metabolite AR-C124910XX (also active) from ticagrelor occurs rapidly, with a median T_max of approximately 2.5 hours. After administration of a 90 mg dose of ticagrelor on an empty stomach, the C_max is 529 ng/ml and AUC is 3451 ng×h/ml. The ratio of the metabolite’s C_max and AUC to ticagrelor is 0.28 and 0.42, respectively.

The mean absolute bioavailability of ticagrelor is 36%. Intake of a high-fat meal leads to a 21% increase in the AUC of ticagrelor and a 22% decrease in the C_max of the active metabolite, but does not affect the C_max of ticagrelor or the AUC of the active metabolite. These small changes have minimal clinical significance; therefore, Ticagrelor can be administered regardless of food intake.

Ticagrelor as a suspension of crushed tablets in drinking water, taken orally or administered into the stomach via a nasogastric tube, is bioequivalent to ticagrelor taken orally as ticagrelor tablets (AUC and C_max of ticagrelor and the active metabolite within the 80-125% range). When taking the suspension, the initial exposure (at 0.5 and 1 hour after administration) was higher than when taking ticagrelor as tablets, but subsequently (from 2 to 48 hours) the concentration profile was almost identical.

Distribution

The V_d of ticagrelor at steady state is 87.5 L. Ticagrelor and the active metabolite are highly bound to plasma proteins (>99%).

Metabolism

CYP3A4 is the main isoenzyme responsible for the metabolism of ticagrelor and the formation of the active metabolite, and their interactions with other CYP3A4 substrates vary from activation to inhibition. Ticagrelor and the active metabolite are weak inhibitors of P-glycoprotein (Pgp).

The main metabolite of ticagrelor is AR-C124910XX, which is also active, as confirmed by the results of in vitro assessment of binding to the platelet ADP P2Y12 receptor. The systemic exposure of the active metabolite is approximately 30-40% of the exposure of ticagrelor.

Excretion

The main route of elimination of ticagrelor is hepatic metabolism. After administration of radiolabeled ticagrelor, an average of approximately 84% of the radioactivity is excreted (57.8% in feces, 26.5% in urine). The excretion of ticagrelor and the active metabolite in urine is less than 1% of the dose. The active metabolite is mainly excreted in the bile. The mean T_1/2 of ticagrelor and the active metabolite was 7 and 8.5 hours, respectively.

Linearity (non-linearity)

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

Pharmacokinetic-pharmacodynamic relationship

Renal impairment. The exposure of ticagrelor is approximately 20% lower, and that of its active metabolite is approximately 17% higher in patients with severe renal impairment (CrCl <30 ml/min) compared to patients with normal renal function.

In patients with end-stage renal disease on hemodialysis, the AUC and C_max of a 90 mg dose of ticagrelor obtained on a non-dialysis day were 38% and 51% higher, respectively, compared to patients with normal renal function. A similar increase in exposure was noted when ticagrelor was administered immediately before dialysis, showing that Ticagrelor is not dialyzable. The exposure of the active metabolite increased to a lesser extent. In patients with end-stage renal disease, the effect of ticagrelor on PAI was independent of dialysis and was similar to that observed in patients with normal renal function (see section “Dosage Regimen”).

Hepatic impairment. The C_max and AUC of ticagrelor were 12% and 23% higher in patients with mild hepatic impairment compared to healthy volunteers. Studies of ticagrelor have not been conducted in patients with severe hepatic impairment, and its use in these patients is contraindicated (see sections “Dosage Regimen” and “Contraindications”).

The pharmacokinetic parameters of ticagrelor in patients with moderate hepatic impairment have not been studied (see sections “Dosage Regimen”, “Contraindications” and “Special Instructions”).

Elderly. In elderly patients (aged 75 years and older), higher exposure of ticagrelor (C_max and AUC approximately 25% higher) and the active metabolite was noted compared to young patients. These differences are not considered clinically significant (see section “Dosage Regimen”).

Gender. Women have higher exposure to ticagrelor and the active metabolite compared to men. These differences are not considered clinically significant.

Ethnic groups. The mean bioavailability of the drug in Asian patients is 39% higher than in Caucasian patients. The bioavailability of ticagrelor was 18% lower in Black patients compared to Caucasian patients. In clinical pharmacology studies, the exposure (C_max and AUC) of ticagrelor in Japanese subjects was approximately 40% (20% after body weight correction) higher than in Caucasians. Exposure in Hispanic or Latino patients was similar to that in Caucasians.

Children

Ticagrelor is not indicated for children (see sections “Pharmacological Action” and “Contraindications”).

Indications

The drug Catilorix^®, used concomitantly with acetylsalicylic acid (ASA), is indicated for use in adult patients over 18 years of age with relevant conditions

• For the prevention of atherothrombotic complications in adult patients with a history of myocardial infarction (MI) (MI occurred one year or more ago) and at high risk of atherothrombotic complications;
• For the prevention of atherothrombotic complications in patients aged 50 years and older with coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM), without a history of MI and/or stroke, who have undergone percutaneous coronary intervention (PCI).

ICD codes

Dosage Regimen

Tablets

Before starting treatment with the drug Catilorix^® (in combination with ASA), patients should discontinue current antiplatelet therapy.

Patients taking the drug Catilorix^® should take a low maintenance dose of ASA (75-150 mg) daily, unless there are specific contraindications.

History of MI

Patients with a history of MI (MI occurred one year or more ago) do not require a loading dose of the drug Catilorix^®, the recommended dose is 60 mg twice daily.

Long-term therapy with the drug Catilorix^® is recommended, except in cases of clinical necessity for premature discontinuation of the drug (see section “Pharmacological Action”). There is no experience with the use of the drug Catilorix^® 60 mg for more than three years in patients with a history of MI.

Patients can start therapy with the drug Catilorix^® 60 mg twice daily one year after MI, regardless of prior antiplatelet therapy and the presence of therapy interruptions.

Patients who started taking the drug Catilorix^® 90 mg twice daily during an acute coronary syndrome (ACS) period can continue therapy with the drug Catilorix^® 60 mg twice daily after one year without interruption.

CAD and T2DM in patients who have undergone PCI

Patients aged 50 years and older with CAD and T2DM, without a history of MI and/or stroke, who have undergone PCI, do not require a loading dose, the recommended dose is 60 mg twice daily. Long-term therapy with the drug Catilorix^® is recommended, except in cases of clinical necessity for premature discontinuation of the drug (see section “Pharmacological Action”).

Missed dose

Interruptions in therapy should be avoided. A patient who misses a dose of the drug Catilorix^® should take only one 60 mg tablet (the next dose) at the scheduled time.

Premature discontinuation of therapy

Premature discontinuation of any antiplatelet therapy, including the drug Catilorix^®, may increase the risk of cardiovascular death, MI, or stroke due to the underlying disease (see section “Special Instructions”).

Premature discontinuation of the drug should be avoided.

Switching therapy

When switching patients to the drug Catilorix^®, the first dose should be administered 24 hours after the last dose of another antiplatelet drug.

Special patient groups

Elderly patients

No dose adjustment is required (see section “Pharmacokinetics”).

Patients with renal impairment

No dose adjustment of the drug is required in patients with renal impairment (see section “Pharmacokinetics”).

Patients with hepatic impairment

No dose adjustment of the drug is required for patients with mild or moderate hepatic impairment (see sections “Pharmacokinetics” and “Special Instructions”).

Studies of ticagrelor have not been conducted in patients with severe hepatic impairment, therefore the use of ticagrelor in these patients is contraindicated (see sections “Pharmacokinetics”, “Contraindications” and “Special Instructions”).

Children

The safety and efficacy of the drug in children under 18 years of age have not been established. Data are not available.

Method of administration

For oral use. The drug Catilorix^® can be taken regardless of meals.

For patients with swallowing difficulties, the Catilorix^® 60 mg tablet should be crushed into a fine powder, stirred in 1/2 glass of drinking water, and the resulting suspension should be drunk immediately. The residue should be mixed with an additional 1/2 glass of drinking water and the resulting suspension should be drunk. The suspension can also be administered via a nasogastric tube (size CH8 or larger). After administration of the suspension, the nasogastric tube must be flushed with water to ensure the full dose of the drug enters the patient’s stomach.

Adverse Reactions

Summary of the safety profile

The safety profile of ticagrelor was studied in a large-scale clinical program in which more than 58,000 patients and healthy volunteers received Ticagrelor. Below is data on adverse drug reactions (ADRs) noted in clinical studies or during post-marketing use of ticagrelor, including information from clinical studies related to the approved indications (PLATO, PEGASUS, and THEMIS). Information about these studies is provided in the “Pharmacological Properties” section.

In the PLATO study, patients receiving Ticagrelor discontinued therapy due to the development of ADRs more often than patients receiving clopidogrel (7.4% compared to 5.4%). In the PEGASUS study, the frequency of therapy discontinuation due to ADRs was higher in patients receiving Ticagrelor than in patients receiving ASA monotherapy (16.1% in the ticagrelor 60 mg plus ASA group and 8.5% in the ASA monotherapy group). In the THEMIS study, in patients who underwent PCI, the frequency of therapy discontinuation due to the development of ADRs was 21.3% with ticagrelor in combination with ASA compared to 13% with ASA monotherapy.

The most frequently reported ADRs in patients taking Ticagrelor were bleeding and dyspnea (see the “Special Instructions” section).

Tabulated summary of adverse reactions

ADRs noted in clinical studies or during post-marketing use of ticagrelor are categorized by system organ class and frequency of occurrence and listed in descending order of severity. The frequency of ADRs is determined using the following categories: very common (≥1/10), common (≥1/100 but <1/10), uncommon (≥1/1000 but <1/100), rare (≥1/10000 but <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

^aFor example, bleeding from bladder tumor, gastric tumor, colon tumor.

^bFor example, increased tendency to bruise, spontaneous hematoma, hemorrhagic diathesis.

^cNoted during post-marketing use.

^dThe frequency of laboratory parameter deviations is given (increase in uric acid concentration above the upper limit of normal from a baseline value that was within normal limits or below the lower limit of normal. Increase in creatinine concentration >50% from baseline), not the frequency of ADR reports.

^eFor example, conjunctival, retinal, intraocular hemorrhage.

^fFor example, epistaxis (nosebleed), hemoptysis.

^gFor example, gingival bleeding, rectal bleeding, gastric ulcer bleeding.

^hFor example, ecchymosis, skin hemorrhage, petechiae.

ⁱFor example, hemarthrosis, muscle hemorrhage.

^jFor example, hematuria, hemorrhagic cystitis.

^kFor example, vaginal bleeding, hematospermia, postmenopausal bleeding.

^lFor example, contusion, traumatic hematoma, traumatic bleeding.

^mI.e., spontaneous, procedure-related, or traumatic intracranial hemorrhage.

Description of selected adverse reactions

Bleeding

The following bleeding definitions were used in the PLATO, PEGASUS, and THEMIS studies.

PLATO-defined major fatal/life-threatening bleeding fatal, or any intracranial hemorrhage, or intrapericardial hemorrhage with cardiac tamponade; or with hypovolemic shock or severe arterial hypotension requiring vasoconstrictors/inotropic drugs or surgical intervention, or clinically overt bleeding accompanied by a decrease in hemoglobin concentration of more than 50 g/L, or transfusion of 4 or more units of red blood cells.

For the THEMIS study only. In the case of CABG-related bleeding: fatal bleeding or perioperative intracranial bleeding, or re-operation after sternotomy wound closure to control bleeding, or transfusion of ≥5 units of whole blood or packed red blood cells within 48 hours (transfusion via Cell Saver system will not be counted in the blood product calculation), or chest tube drainage >2 L within 24 hours.

PLATO-defined major other bleeding causing significant patient disability, or clinically overt bleeding accompanied by a decrease in hemoglobin concentration of 30-50 g/L, or transfusion of 2-3 units of red blood cells.

PLATO-defined minor bleeding requires medical intervention to stop or treat the bleeding.

TIMI-defined major bleeding fatal, or any intracranial hemorrhage, or clinically overt signs of bleeding associated with a decrease in hemoglobin concentration of 50 g/L or more, or, if hemoglobin data are unavailable, a decrease in hematocrit of ≥15%.

For the THEMIS study only. In the case of CABG-related bleeding: fatal bleeding or perioperative intracranial bleeding, or re-operation after sternotomy wound closure to control bleeding, or transfusion of ≥5 units of whole blood or packed red blood cells within 48 hours (transfusion via Cell Saver system will not be counted in the blood product calculation), or chest tube drainage >2 L within 24 hours.

TIMI-defined major other bleeding non-fatal, non-intracranial TIMI-defined major bleeding.

TIMI-defined minor bleeding clinically overt bleeding accompanied by a decrease in hemoglobin level of 30-50 g/L.

For the THEMIS study only

TIMI-defined minor bleeding clinically overt bleeding accompanied by a decrease in hemoglobin level of 30-50 g/L or a decrease in hematocrit of ≥10% to <15%, or in the absence of observed blood loss, a decrease in hemoglobin concentration of ≥40 g/L or a decrease in hematocrit of ≥12%.

TIMI-defined bleeding requiring medical attention requires medical intervention or leads to hospitalization, or urgent examination.

Fatal bleeding leads to patient death within 7 days.

Data on bleeding events in the PLATO study (Kaplan-Meier estimate (%) at 12 months)

Ticagrelor and clopidogrel did not differ in the frequency of total major bleeding by PLATO criteria (11.6% and 11.2%, respectively), PLATO-defined fatal/life-threatening bleeding (5.8% in both groups). However, the frequency of the composite of major and minor bleeding by PLATO criteria was higher in the ticagrelor group (16.1%) compared to clopidogrel (14.6%, p=0.0084). A few fatal bleeding events were noted: 20 (0.2% of patients) in the ticagrelor group and 23 (0.3% of patients) in the clopidogrel group.

Age, sex, body weight, ethnicity, geographic region, comorbidities, concomitant therapy, medical history, including prior stroke and TIA, did not affect the frequency of total major and non-procedure-related bleeding by PLATO criteria. No groups with an increased risk of bleeding were identified.

CABG-related bleeding in the PLATO study, in 42% of patients out of 1584 (12% of the cohort) who underwent CABG, major fatal/life-threatening bleeding developed without differences between both treatment groups. Fatal CABG-related bleeding was noted in 6 patients in each treatment group (see the “Special Instructions” section).

Non-CABG-related bleeding and non-procedure-related bleeding Ticagrelor and clopidogrel did not differ in the frequency of PLATO-defined major fatal/life-threatening non-CABG bleeding, but with ticagrelor use, total major bleeding by PLATO criteria developed more often (4.5% compared to 3.8%; p=0.0264). If procedure-related bleeding events were removed, more bleeding was noted in the ticagrelor group (3.1%) than in the clopidogrel group (2.3%; p=0.0058). Treatment discontinuation due to non-procedure-related bleeding was more frequent with ticagrelor (2.9%) compared to clopidogrel (1.2%, p<0.001).

Intracranial hemorrhage: more non-procedure-related intracranial hemorrhages developed in the ticagrelor group (n=27 hemorrhages in 26 patients, 0.3%) than in the clopidogrel group (n=14 hemorrhages, 0.2%), of which 11 hemorrhages with ticagrelor use and 1 with clopidogrel use were fatal. However, there were no significant differences in the total number of fatal bleeding events. The percentage of intracranial hemorrhages was low in both treatment groups, considering the significant comorbidities and cardiovascular risk factors in the study population.

Data on bleeding events in the PEGASUS study (Kaplan-Meier estimate (%) at 36 months)

In the PEGASUS study, TIMI-defined major bleeding with ticagrelor 60 mg twice daily occurred more frequently (2.3%) than with ASA monotherapy (1.1%). No increase in the risk of fatal bleeding was observed; only a slight increase in the frequency of intracranial hemorrhage (0.6%) compared to ASA monotherapy (0.5%). A few fatal bleeding events were noted: 11 (0.3%) in the ticagrelor 60 mg group and 12 (0.3%) in the ASA monotherapy group. The increased risk of TIMI-defined major bleeding with ticagrelor 60 mg was mainly due to a higher frequency of TIMI-defined other major bleeding, driven by gastrointestinal events.

With ticagrelor 60 mg, an increase in the frequency of TIMI-defined major or minor bleeding was noted (3.4% with ticagrelor 60 mg compared to 1.4% with ASA monotherapy), PLATO-defined major bleeding (3.5% compared to 1.4%) and PLATO-defined major or minor bleeding (15.2% compared to 6.2%). Treatment discontinuation due to bleeding was more frequent with ticagrelor 60 mg than with ASA monotherapy (6.2% and 1.5%, respectively). Most of these bleedings were less severe (classified as TIMI-defined bleeding requiring medical attention), for example, nosebleed, bruising, hematomas.

The profile of TIMI-defined major bleeding, TIMI-defined major or minor bleeding, and PLATO-defined major bleeding with ticagrelor 60 mg was comparable across several predefined subgroups (e.g., based on age, sex, body weight, race, geographic region, comorbidities, concomitant therapy, and medical history).

Intracranial hemorrhage spontaneous intracranial hemorrhage was noted with similar frequency with ticagrelor 60 mg and ASA monotherapy (13 cases each, 0.2% in each treatment group). The frequency of intracranial hemorrhages due to trauma or procedure was slightly higher with ticagrelor 60 mg therapy (15 cases, 0.2%) compared to ASA monotherapy (10 cases, 0.1%). There were 6 fatal intracranial hemorrhages with ticagrelor 60 mg and 5 fatal intracranial hemorrhages with ASA monotherapy. The frequency of intracranial hemorrhages was low in both treatment groups, considering the significant comorbidities and cardiovascular risk factors in the study population.

Data on bleeding events in the THEMIS study in patients who underwent PCI

Data on bleeding in the THEMIS study in patients who underwent PCI are presented below.

Analysis of bleeding events: frequency of bleeding in therapy groups at 36 months, Kaplan-Meier estimate (patients with PCI, THEMIS study)

A few fatal bleeding events were noted: 6 in the ticagrelor plus ASA group and 6 in the ASA monotherapy group. The number of patients with intracranial hemorrhage in the ticagrelor plus ASA group was 33, and in the ASA monotherapy group – 31.

Treatment discontinuation due to bleeding in patients who underwent PCI was more frequent with ticagrelor in combination with ASA therapy compared to ASA monotherapy (4.7% and 1.3%, respectively). The most frequent types of bleeding leading to discontinuation of ticagrelor were nosebleed and tendency to bruise.

Dyspnea

In the PLATO study, adverse reactions in the form of dyspnea (dyspnea, dyspnea at rest, exertional dyspnea, paroxysmal nocturnal dyspnea, and nocturnal dyspnea) developed in 13.8% of patients receiving Ticagrelor 90 mg twice daily, and in 7.8% of patients taking clopidogrel 75 mg once daily. According to the investigators’ assessment, dyspnea was associated with therapy in 2.2% of patients in the ticagrelor group. Most cases of dyspnea were mild and moderate in intensity and often resolved without discontinuation of therapy. Typically, dyspnea developed at the start of therapy and in 87% of patients occurred as a single episode. Dyspnea as a serious ADR was noted in 0.7% of patients receiving Ticagrelor and in 0.4% of patients taking clopidogrel.

Patients who experienced dyspnea were older, often had dyspnea noted prior to starting ticagrelor therapy, chronic heart failure, COPD or asthma. Data from the PLATO study do not indicate that the higher frequency of dyspnea with ticagrelor is associated with the development of new or worsening of existing heart or lung disease. Ticagrelor does not affect pulmonary function parameters (see the “Special Instructions” section).

In the PEGASUS study, dyspnea was noted in 14.2% of patients receiving Ticagrelor 60 mg twice daily, and in 5.5% of patients receiving ASA monotherapy. As in the PLATO study, most cases of dyspnea were mild or moderate in intensity (see the “Special Instructions” section).

In the THEMIS study, among patients who underwent PCI, dyspnea was noted in 22% of patients taking Ticagrelor twice daily in combination with ASA, and in 7.5% of patients receiving ASA monotherapy. Most cases of dyspnea were mild and moderate in intensity (see the “Special Instructions” section).

Laboratory and Instrumental Data

Increase in Uric Acid Concentration

In the PLATO study, serum uric acid concentration increased above the upper limit of normal in 22% of patients receiving Ticagrelor compared to 13% of patients receiving clopidogrel. The corresponding numbers in the PEGASUS study were 9.1%, 8.8%, and 5.5% in the ticagrelor 90 mg, 60 mg, and placebo groups, respectively. The mean serum uric acid concentration increased by approximately 15% with ticagrelor compared to approximately 7.5% with clopidogrel, and after discontinuation of therapy, it decreased to approximately 7% in the ticagrelor group, with no decrease in the clopidogrel group. In the PEGASUS study, a reversible increase in mean serum uric acid concentration of 6.3% and 5.6% was observed with ticagrelor 90 mg and 60 mg, respectively, compared to a decrease of 1.5% in the placebo group. In the PLATO study, the incidence of gouty arthritis was 0.2% with ticagrelor versus 0.1% with clopidogrel. The incidence of gout/gouty arthritis in the PEGASUS study was 1.6%, 1.5%, and 1.1% in the ticagrelor 90 mg, 60 mg, and placebo groups, respectively.

Reporting of Suspected Adverse Reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the drug’s benefit-risk balance. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to ticagrelor or to any of the excipients of the drug;
• Active pathological bleeding;
• History of intracranial hemorrhage;
• Severe hepatic impairment;
• Concomitant use of ticagrelor with potent inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir);
• Pregnancy;
• Breastfeeding period.

With Caution

• Predisposition to bleeding (e.g., due to recent trauma, recent surgery, coagulation disorders, moderate hepatic impairment, active or recent gastrointestinal bleeding) or increased risk of injury;
• Concomitant therapy with drugs that increase the risk of bleeding (i.e., NSAIDs, oral anticoagulants and/or fibrinolytics) within 24 hours prior to taking Catilorix^®;
• Prior ischemic stroke with therapy duration of more than one year (for patients with a history of MI);
• Patients with moderate hepatic impairment;
• Patients at risk of bradycardia (e.g., patients without a pacemaker with sick sinus syndrome (SSS), with second- or third-degree atrioventricular block; syncope associated with bradycardia); concomitant use with drugs that can cause bradycardia;
• Patients with bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD);
• Patients aged 75 years and older;
• Patients with moderate or severe renal impairment;
• Patients receiving therapy with angiotensin II receptor antagonists;
• Patients with hyperuricemia or gouty arthritis;
• Concomitant therapy with digoxin; potent P-glycoprotein inhibitors and moderate inhibitors of the CYP3A4 isoenzyme (e.g., verapamil and quinidine); selective serotonin reuptake inhibitors (e.g., paroxetine, sertraline, and citalopram); drugs affecting hemostasis (see section “Drug Interactions”).

Use in Pregnancy and Lactation

Women of Reproductive Age

Women of reproductive age should use appropriate contraceptive methods to avoid pregnancy during therapy with Catilorix^®.

Pregnancy

Data on the use of ticagrelor in pregnant women are absent or limited.

In animal studies, Ticagrelor caused a slight decrease in body weight gain in females, a decrease in the viability of newborn animals and their body weight, and delayed growth. Catilorix^® is contraindicated during pregnancy.

Breastfeeding Period

Available pharmacodynamic and toxicological data in animals have shown that Ticagrelor and its active metabolites are excreted in milk. A risk to the newborn/infant cannot be excluded. The decision to discontinue breastfeeding or to discontinue Catilorix^® therapy should be made taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother. Catilorix^® is contraindicated during breastfeeding.

Fertility

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

Use in Hepatic Impairment

No studies of ticagrelor have been conducted in patients with severe hepatic impairment, therefore the use of ticagrelor in these patients is contraindicated. No dose adjustment of the drug is required for patients with mild or moderate hepatic impairment.

Use in Renal Impairment

No dose adjustment of the drug is required for patients with renal impairment. Use with caution in patients with moderate or severe renal impairment.

Pediatric Use

The safety and efficacy of the drug in children under 18 years of age have not been established. Data are not available.

Geriatric Use

Use with caution in patients aged 75 years and older.

Special Precautions

Risk of Bleeding

When prescribing Catilorix^® to patients at increased risk of bleeding, the benefit of preventing atherothrombotic complications should be weighed against the risk of bleeding.

If clinically indicated, Catilorix^® should be used with caution in the following groups of patients

• Patients predisposed to bleeding (e.g., due to recent trauma, recent surgery, coagulation disorders, moderate hepatic impairment, active or recent gastrointestinal bleeding) or patients with an increased risk of injury. The use of Catilorix^® is contraindicated in patients with active pathological bleeding, a history of intracranial hemorrhage, severe hepatic impairment (see section “Contraindications”);
• Concomitant use of drugs that may increase the risk of bleeding (e.g., NSAIDs, oral anticoagulants and/or fibrinolytics, taken within 24 hours prior to taking Catilorix^®).

In a study involving healthy volunteers, platelet transfusion did not reverse the antiplatelet effect of Catilorix^® and is unlikely to have a clinical effect in patients with bleeding. Since concomitant use of Catilorix^® and desmopressin did not reduce the standardized bleeding time, it is unlikely that desmopressin will effectively stop bleeding (see section “Drug Interactions”).

Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or therapy with recombinant factor VIIa may enhance hemostasis. After the cause of bleeding has been identified and the bleeding has been controlled, therapy with Catilorix^® can be resumed.

Surgical Interventions

Before planned surgery or starting new medications, the patient should inform the doctor that he/she is taking Catilorix^®.

In the PLATO study, in patients undergoing coronary artery bypass graft (CABG) surgery, there were more bleedings with ticagrelor compared to clopidogrel when therapy was discontinued 1 day before surgery, but the incidence of major bleedings after discontinuation of therapy 2 or more days before surgery was similar compared to clopidogrel (see section “Adverse Reactions”). If a patient is undergoing elective surgery and the antithrombotic effect is undesirable, Catilorix^® therapy should be discontinued 5 days before surgery.

Patients with a History of Ischemic Stroke

Patients with ACS with a prior ischemic stroke can take Catilorix^® for up to 12 months (PLATO study).

The PEGASUS (history of MI) and THEMIS (CAD and T2DM) studies did not include patients with a prior ischemic stroke. Therefore, in the absence of data, therapy lasting more than 1 year should be used with caution (for patients with a history of MI).

Patients with Moderate Hepatic Impairment

The use of Catilorix^® is contraindicated in patients with severe hepatic impairment (see sections “Dosage Regimen” and “Contraindications”). Caution should be exercised in patients with moderate hepatic impairment, given the limited experience with the drug in this patient group (see sections “Dosage Regimen” and “Pharmacokinetics”).

Bradyarrhythmia

During 24-hour Holter electrocardiogram (ECG) monitoring, an increase in the frequency of mainly asymptomatic ventricular pauses was observed during therapy with ticagrelor compared to clopidogrel. In phase 3 studies evaluating the safety and efficacy of ticagrelor, bradyarrhythmia events were reported with similar frequency for ticagrelor and comparator drugs (placebo, clopidogrel, and ASA). Patients at increased risk of bradycardia (e.g., patients without a pacemaker diagnosed with SSS, second- or third-degree atrioventricular block, syncope associated with bradycardia) were excluded from the ticagrelor outcome studies. Therefore, due to limited clinical experience in these patients, it is recommended to prescribe Catilorix^® to them with caution (see section “Pharmacological Action”).

Caution should also be exercised when co-administering Catilorix^® with drugs that can cause bradycardia. However, in the PLATO study, no clinically significant ADRs were observed with concomitant use with one or more drugs that can cause bradycardia (e.g., 96% of patients concomitantly took beta-blockers, 33% took slow calcium channel blockers, diltiazem and verapamil, and 4% took digoxin) (see section “Drug Interactions”). In a substudy using 24-hour Holter ECG monitoring, more patients in the ticagrelor group compared to the clopidogrel group had ventricular pauses ≥3 seconds in the acute phase of ACS. The increase in the number of ventricular pauses recorded by Holter monitoring while taking ticagrelor was more frequent in patients with chronic heart failure compared to the general population in the acute phase of ACS, but not in the first month of therapy and not compared to clopidogrel. These pauses in these patients were not accompanied by subsequent adverse clinical consequences (syncope and pacemaker implantation).

During post-marketing use of ticagrelor, cases of bradyarrhythmia and atrioventricular block have been reported (see section “Adverse Reactions”), mainly in patients with ACS, in which myocardial ischemia and concomitant use of drugs that reduce heart rate or affect conduction could potentially have an influence. The patient’s clinical condition and concomitant medications should be assessed as potential causes before adjusting therapy.

Dyspnea

Dyspnea has been reported in patients taking Ticagrelor. Dyspnea is usually mild or moderate in intensity and often resolves without discontinuing therapy. Patients with BA/COPD may have an increased absolute risk of dyspnea while taking Catilorix^® (see section “Adverse Reactions”). Ticagrelor should be used with caution in patients with a history of BA and/or COPD. The mechanism of dyspnea with ticagrelor is not understood. If a patient develops a new episode of dyspnea, or if dyspnea persists or worsens during the use of Catilorix^®, a full examination should be performed, and in case of intolerance, the drug should be discontinued.

Central Sleep Apnea

Cases of central sleep apnea, including Cheyne-Stokes respiration, have been reported during post-marketing use of ticagrelor. If central sleep apnea is suspected, the need for further clinical investigation should be assessed.

Increase in Creatinine Concentration

During therapy with ticagrelor, creatinine concentration may increase. The mechanism of this effect is unknown (see section “Adverse Reactions”). Assessment of renal function should be performed according to routine clinical practice. In patients with ACS, assessment of renal function is also recommended one month after starting ticagrelor therapy, paying particular attention to patients aged 75 years and older, patients with moderate or severe renal impairment, and those receiving therapy with angiotensin II receptor antagonists.

Increase in Uric Acid Concentration

During therapy with ticagrelor, uric acid concentration may increase (see section “Adverse Reactions”). Caution is necessary in patients with a history of hyperuricemia or gouty arthritis. As a preventive measure, the use of ticagrelor should be avoided in patients with hyperuricemic nephropathy.

Thrombotic Thrombocytopenic Purpura

TTP during the use of ticagrelor has been reported very rarely. TTP is a serious condition and requires immediate treatment.

Effect on Laboratory Test Results

Platelet Function Analysis in the Diagnosis of Heparin-Induced Thrombocytopenia

In patients taking Ticagrelor, false-negative results of platelet function analysis in the diagnosis of HIT were obtained. This is due to the inhibition of P2Y12 receptors of donor platelets by ticagrelor when the test is performed in the patient’s serum/plasma. Information on concomitant ticagrelor therapy should be taken into account when interpreting the results of platelet function analysis in the diagnosis of HIT.

Before considering the possibility of discontinuing ticagrelor, the benefit and risk of continuing therapy should be assessed, taking into account both the prothrombotic state due to HIT and the increased risk of bleeding with the concomitant use of an anticoagulant and ticagrelor.

Others

Based on the observed relationship in the PLATO study between the maintenance dose of ASA and the efficacy of ticagrelor compared to clopidogrel, concomitant use of a high maintenance dose of ASA (more than 300 mg) with ticagrelor is not recommended.

Concomitant use of ticagrelor with potent CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir) is contraindicated (see section “Contraindications”), as it may lead to a significant increase in ticagrelor exposure (see section “Drug Interactions”).

Concomitant use of ticagrelor with potent CYP3A4 inducers (e.g., rifampicin, phenytoin, carbamazepine, and phenobarbital) is not recommended, as their concomitant use may reduce the exposure and efficacy of ticagrelor (see section “Drug Interactions”).

Concomitant use of ticagrelor and CYP3A4 substrates with a narrow therapeutic index (e.g., cisapride and ergot alkaloids) is not recommended, as Ticagrelor may increase the exposure of these drugs. Concomitant use of ticagrelor with simvastatin or lovastatin at doses greater than 40 mg is not recommended (see section “Drug Interactions”).

When digoxin and ticagrelor are used concomitantly, careful clinical and laboratory monitoring (heart rate and, if clinically indicated, also ECG and blood digoxin concentrations) is recommended.

There are no data on the concomitant use of ticagrelor with potent P-glycoprotein inhibitors and moderate inhibitors of the CYP3A4 isoenzyme (e.g., verapamil and quinidine), which may increase the exposure of ticagrelor. If their concomitant use cannot be avoided, it should be done with caution (see section “Drug Interactions”).

Discontinuation of Therapy

Premature discontinuation of any antiplatelet therapy, including Catilorix^®, may increase the risk of cardiovascular death, MI, or stroke due to the underlying disease. Premature discontinuation of the drug should be avoided.

Effect on Ability to Drive and Operate Machinery

Ticagrelor has no or negligible influence on the ability to drive and use machines. Cases of dizziness and confusion have been reported during therapy with ticagrelor. Therefore, patients experiencing such symptoms should exercise caution when driving vehicles and operating machinery.

Overdose

Symptoms

Ticagrelor is well tolerated in a single dose of up to 900 mg. In a single dose-escalation study, adverse effects on the gastrointestinal tract were dose-limiting. Other clinically significant adverse reactions that could be observed with overdose were dyspnea and ventricular pauses. In case of overdose, monitoring for these ADRs and ECG monitoring are recommended.

Treatment

Currently, no antidote to reverse the effects of ticagrelor is known, and Ticagrelor is not removed by hemodialysis (see section “Pharmacokinetics”). In case of overdose, symptomatic therapy should be administered according to local standards. Due to platelet inhibition, an increase in bleeding duration is an expected pharmacological effect of an overdose of Catilorix^®. If bleeding occurs, appropriate supportive measures should be taken.

Drug Interactions

Ticagrelor is primarily a substrate of the CYP3A4 isoenzyme and a weak inhibitor of the CYP3A4 isoenzyme. Ticagrelor is also a substrate of P-glycoprotein (Pgp) and a weak inhibitor of Pgp, and may increase the exposure of Pgp substrates.

Effect of Other Drugs on Ticagrelor

Drugs Metabolized by the CYP3A4 Isoenzyme

CYP3A4 Inhibitors

Potent CYP3A4 Inhibitors concomitant use of ketoconazole with ticagrelor increases the C_max and AUC of ticagrelor by 2.4 and 7.3 times, respectively. The C_max and AUC of the active metabolite decrease by 89% and 56%, respectively. Other potent CYP3A4 inhibitors (clarithromycin, nefazodone, ritonavir, and atazanavir) will have similar effects, so their concomitant use with ticagrelor is contraindicated (see section “Contraindications” and “Special Precautions”).

Moderate CYP3A4 inhibitors Concomitant use of diltiazem with ticagrelor increases the C_max of ticagrelor by 69% and the AUC by 2.7 times, and reduces the C_max of the active metabolite by 38%, while the AUC does not change. Ticagrelor does not affect the plasma concentrations of diltiazem. Other moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, erythromycin, fluconazole) will have similar effects and can also be co-administered with ticagrelor.

CYP3A inducers

Concomitant use of rifampicin with ticagrelor reduces the C_max and AUC of ticagrelor by 73% and 86%, respectively. The C_max of the active metabolite does not change, while the AUC decreases by 46%. Other CYP3A4 inducers (e.g., phenytoin, carbamazepine, and phenobarbital) are expected to reduce the exposure to ticagrelor. Potent CYP3A4 inducers may reduce the exposure and efficacy of ticagrelor; therefore, their concomitant use with ticagrelor should be avoided.

Cyclosporine (Pgp and CYP3A inhibitor)

Concomitant use of cyclosporine (600 mg) with ticagrelor increases the C_max and AUC of ticagrelor by 2.3 and 2.8 times, respectively. There is an increase in the AUC of the active metabolite by 32% and a decrease in C_max by 15% in the presence of cyclosporine. Ticagrelor does not affect the plasma concentration of cyclosporine.

Others

Based on the results of pharmacological interaction studies, concomitant use of ticagrelor with heparin, enoxaparin, and acetylsalicylic acid or desmopressin does not affect the pharmacokinetics of ticagrelor, its active metabolite, or ADP-dependent platelet aggregation. If there is a clinical indication for the use of drugs affecting hemostasis, they should be used with caution in combination with ticagrelor (see the “Special Instructions” section).

There are no data on the concomitant use of ticagrelor with potent P-glycoprotein inhibitors and moderate CYP3A4 inhibitors (e.g., verapamil and quinidine), which may increase the exposure to ticagrelor. If their concomitant use cannot be avoided, it should be done with caution (see the “Special Instructions” section).

A delay and reduction in the exposure of oral P2Y12 inhibitors, including Ticagrelor and its active metabolite, has been observed in patients receiving morphine therapy (approximately 35% reduction in ticagrelor exposure). This interaction may be associated with reduced gastrointestinal motility and is therefore applicable to other opioids. The clinical significance is unknown, but the data indicate a possible reduction in the efficacy of ticagrelor in patients simultaneously receiving Ticagrelor and morphine. In patients with ACS for whom morphine use cannot be delayed and rapid P2Y12 inhibition is considered critical, the use of a parenteral P2Y12 inhibitor may be considered.

Effect of ticagrelor on other medicinal products

Medicinal products metabolized by the CYP3A4 isoenzyme

Simvastatin Concomitant use of ticagrelor and simvastatin increases the C_max and AUC of simvastatin by 81% and 56%, respectively, and increases the C_max and AUC of simvastatin acid by 64% and 52%, respectively; in some cases, these parameters increase by 2-3 times. Concomitant use of simvastatin at a dose greater than 40 mg/day with ticagrelor may lead to the development of simvastatin side effects, and the risk-benefit ratio should be assessed. Simvastatin did not affect the plasma concentration of ticagrelor. Ticagrelor is expected to have a similar effect on lovastatin. Concomitant use of ticagrelor with simvastatin or lovastatin at doses greater than 40 mg is not recommended.

Atorvastatin Concomitant use of atorvastatin and ticagrelor increases the Cmax and AUC of atorvastatin acid by 23% and 36%, respectively. A similar increase in C_max and AUC values is observed for all metabolites of atorvastatin acid. These changes are considered clinically insignificant.

A similar effect on other statins metabolized by the CYP3A4 isoenzyme cannot be excluded. In the PLATO study, patients receiving Ticagrelor took various statins without any safety concerns in 93% of patients taking this group of drugs.

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

Pgp substrates (including digoxin, cyclosporine)

Concomitant use of ticagrelor with digoxin increased the C_max and AUC of digoxin by 75% and 28%, respectively. When used concomitantly with ticagrelor, the mean minimum concentration of digoxin increased by approximately 30%, and in some individual cases by 2 times. The C_max and AUC of ticagrelor and its active metabolite did not change when digoxin was used. Therefore, appropriate clinical and/or laboratory monitoring (heart rate, and, if clinically indicated, also ECG and blood digoxin concentrations) is recommended when ticagrelor is used concomitantly with Pgp-dependent drugs with a narrow therapeutic index, such as digoxin. No effect of ticagrelor on blood cyclosporine concentration was noted. The effect of ticagrelor on other Pgp substrates has not been studied.

Medicinal products metabolized by the CYP2C9 isoenzyme

Concomitant use of ticagrelor and tolbutamide did not change the plasma concentrations of either drug, indicating that Ticagrelor is not an inhibitor of the CYP2C9 isoenzyme, and it is unlikely to affect CYP2C9-mediated metabolism of drugs such as warfarin and tolbutamide.

Oral contraceptives

Concomitant use of ticagrelor, levonorgestrel, and ethinyl estradiol increases the exposure of ethinyl estradiol by approximately 20% but does not affect the pharmacokinetics of levonorgestrel. No clinically significant impact on contraceptive efficacy is expected with the concomitant use of levonorgestrel, ethinyl estradiol, and ticagrelor.

Medicinal products that can cause bradycardia

Due to the identification of mainly asymptomatic ventricular pauses and bradycardia, Ticagrelor should be used with caution concomitantly with medicinal products that can cause bradycardia (see the “Special Instructions” section). However, in the PLATO study, no clinically significant adverse drug reactions were observed with concomitant use with one or more drugs that can cause bradycardia (e.g., 96% of patients concomitantly took beta-blockers, 33% took slow calcium channel blockers, diltiazem and verapamil, and 4% took digoxin).

Other concomitant therapy

In clinical studies, Ticagrelor was predominantly administered concomitantly with acetylsalicylic acid, proton pump inhibitors, statins, beta-blockers, ACE inhibitors, and angiotensin II receptor antagonists for long-term treatment of concomitant diseases, as well as with heparin, low molecular weight heparins, intravenous glycoprotein IIb/IIIa receptor inhibitors for short-term therapy. Based on the results of these studies, no clinically significant undesirable interactions were identified. Concomitant use of ticagrelor with heparin, enoxaparin, or desmopressin did not affect aPTT, activated clotting time (ACT), or factor Xa testing; however, due to potential pharmacodynamic interaction, caution is required when used concomitantly with drugs affecting hemostasis.

Due to reports of subcutaneous hemorrhages with the use of SSRIs (e.g., paroxetine, sertraline, and citalopram), caution is recommended when they are used concomitantly with ticagrelor, as the risk of bleeding may be increased.

Grapefruit juice

When large volumes of grapefruit juice were consumed daily (200 ml 3 times a day), a 2-fold increase in ticagrelor exposure was noted. This increase in ticagrelor exposure is not expected to be of clinical significance for most patients.

Storage Conditions

The drug should be stored at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.