Decagrel

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEKA GREL (DEKAGREL)

Composition:

Active substance: ticagrelor;

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

Excipients: mannite (E 421), calcium hydrogen phosphate, hypromellose 2910 (5mPa.s), sodium starch glycolate (type A), magnesium stearate.

Coating Pink 03F240069 for 60 mg tablets: hypromellose 2910 (6mPa.s), titanium dioxide (E 171), talc, macrogol 8000, yellow iron oxide (E 172), red iron oxide (E 172);
Coating Yellow 03F12967 for 90 mg tablets: hypromellose 2910 (6mPa.s), titanium dioxide (E 171), talc, macrogol 8000, yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

60 mg tablets: round, biconvex, film-coated tablets, pink in color, engraved with "60" on one side; core color after breaking ranges from white to light pink; diameter 7.9–8.4 mm.

90 mg tablets: round, biconvex, film-coated tablets, light yellow with a possible orange tint, core color after breaking ranges from white to light pink; diameter 8.9–9.4 mm.

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

Pharmacological Properties

Pharmacodynamics.

Mechanism of action

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

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

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

Pharmacodynamic effects

Onset of action

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

Offset of action

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

Data on switching between medicinal products

Switching from clopidogrel 75 mg to ticagrelor 90 mg twice daily results in an absolute increase in PAI of 26.4%, while switching from ticagrelor to clopidogrel results in an absolute decrease in PAI of 24.5%. Patients may be switched from clopidogrel to ticagrelor without interruption of antiplatelet effect (see section "Posology and method of administration").

Clinical efficacy and safety

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

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

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

PLATO study (acute coronary syndrome)

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

Clinical efficacy

With background daily ASA use, ticagrelor 90 mg twice daily was more effective than clopidogrel 75 mg once daily in preventing the primary composite endpoint (PCE), which included CV death, myocardial infarction (MI), or stroke, due to differences in rates of CV death and MI. Patients received a loading dose of 300 mg clopidogrel (600 mg possible in case of PCI) or 180 mg ticagrelor.

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

A post-hoc analysis suggests a possible interaction with ASA dose, as higher ASA doses were associated with reduced efficacy of ticagrelor. Doses of ASA for continuous daily use in combination with ticagrelor should be 75–150 mg (see sections "Posology and method of administration" and "Special warnings and precautions for use").

Treatment with ticagrelor reduced the incidence of PCE compared to clopidogrel in all patients with ACS (UA, NSTEMI, STEMI). Therefore, ticagrelor 90 mg twice daily in combination with low-dose ASA may be prescribed to patients with ACS (UA, NSTEMI, STEMI), including those receiving medical therapy, PCI, or CABG.

Genetic substudy of PLATO

Genotyping of patients for CYP2C19 and ABCB1 in the PLATO study established associations between genotype groups and outcomes in the PLATO study. The advantages of ticagrelor over clopidogrel in reducing the frequency of serious CV events were not significantly dependent on the CYP2C19 or ABCB1 genotype of patients. The overall frequency of major bleeding in the PLATO study did not differ between ticagrelor and clopidogrel groups, regardless of CYP2C19 or ABCB1 genotype. The frequency of non-CABG-related major bleeding as defined in the PLATO study was increased with ticagrelor compared to clopidogrel in patients lacking one or more functional CYP2C19 alleles, but was similar to that observed with clopidogrel in patients with no loss of functional alleles.

Composite measure of efficacy and safety

The composite measure of efficacy and safety (CV death, MI, stroke, or total number of major bleeds as defined in the PLATO study) indicates that the efficacy benefits of ticagrelor compared to clopidogrel are not offset by cases of major bleeding during the 12 months following ACS.

Clinical safety

Holter sub-study

According to Holter monitoring data from the PLATO study, more patients in the ticagrelor group than in the clopidogrel group had episodes of ventricular asystole ≥3 seconds during the acute phase of ACS; such episodes were more frequent in patients with chronic heart failure (CHF) compared to the overall population; however, no statistically significant difference between ticagrelor and clopidogrel groups was observed at 1 month. No adverse clinical consequences (including syncope or need for pacemaker implantation) related to this difference were observed in this patient population.

PEGASUS study (prior myocardial infarction)

The PEGASUS TIMI-54 study was a randomized, double-blind, placebo-controlled, parallel-group, international, multicenter case-control study conducted to evaluate the prevention of atherothrombotic events with ticagrelor at two doses (90 mg twice daily or 60 mg twice daily) in combination with low-dose ASA (75–150 mg) compared to ASA alone in patients with prior MI and additional risk factors for atherothrombosis.

Clinical efficacy

Ticagrelor 60 mg twice daily and 90 mg twice daily in combination with ASA were more effective in preventing atherothrombotic events compared to ASA alone (composite endpoint: CV death, MI, and stroke), with a stable treatment effect throughout the study period.

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

Compared to ASA alone, ticagrelor 60 mg twice daily significantly reduced the frequency of PCE (CV death, MI, and stroke), with reduction in the frequency of each component.

Data on the efficacy and safety of ticagrelor with treatment continuation beyond 3 years are limited.

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

Clinical safety

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

Children

In a randomized, double-blind, parallel-group phase III study (HESTIA 3), pediatric patients (aged 2 to 18 years) with sickle cell anemia were randomized to placebo or ticagrelor at doses ranging from 15 mg to 45 mg twice daily depending on body weight. In the ticagrelor group, median platelet inhibition was 35% before dosing and 56% two hours after dosing at steady state.

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

Pharmacokinetics.

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

Absorption

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

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

Ticagrelor administered as crushed tablets mixed with water, either orally or via nasogastric tube into the stomach, has comparable bioavailability to intact tablets with respect to AUC and C_max of ticagrelor and its active metabolite. Initial exposure (0.5 and 1 hour after dosing) of crushed and water-mixed tablets was higher than that of intact tablets, with generally similar concentration profiles thereafter (2–48 hours).

Distribution

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

Biological transformation

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

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

Elimination

The main route of elimination of ticagrelor is hepatic metabolism. After administration of radiolabeled ticagrelor, the mean amount of radioactivity recovered was approximately 84% (57.8% in feces and 26.5% in urine). The amount of ticagrelor and active metabolite in urine was less than 1% of the dose. The main route of elimination of the active metabolite is likely biliary secretion. The mean t_1/2 of ticagrelor is approximately 7 hours, and that of the active metabolite is 8.5 hours.

Special patient groups

Elderly patients

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

Children

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

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

Sex

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

Renal impairment

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

In patients with end-stage renal disease undergoing hemodialysis, AUC and C_max values of 90 mg ticagrelor, when administered on a day without hemodialysis, were 38% and 51% higher, respectively, compared to patients with normal renal function. A similar increase in exposure was observed when ticagrelor was administered immediately before dialysis (49% and 61%, respectively), indicating that ticagrelor is not removed by dialysis. Exposure to the active metabolite increased to a lesser extent (AUC 13–14% and C_max 17–36%). Platelet aggregation inhibition (PAI) by ticagrelor was independent of dialysis in patients with end-stage renal disease and was similar to that in patients with normal renal function (see section "Posology and method of administration").

Hepatic impairment

C_max and AUC of ticagrelor were 12% and 23% higher, respectively, in patients with mild hepatic impairment compared to healthy volunteers, but the PAI effect of ticagrelor was similar in both groups. Dose adjustment is not required for patients with mild hepatic impairment. The use of ticagrelor in patients with severe hepatic impairment has not been studied; pharmacokinetic data in patients with moderate hepatic impairment are lacking. In patients with moderate or marked elevation of one or more baseline liver function laboratory parameters, plasma concentrations of ticagrelor were on average similar or slightly higher compared to patients without baseline abnormalities. Dose adjustment is not required for patients with moderate hepatic impairment (see sections "Posology and method of administration" and "Special warnings and precautions for use").

Ethnicity

In patients of Asian origin, mean bioavailability was 39% higher than in patients of Caucasian race. In patients of African descent, ticagrelor bioavailability was 18% lower than in Caucasian patients; in a clinical pharmacology study, exposure (C_max and AUC) to ticagrelor in Japanese subjects was approximately 40% higher (20% higher after body weight adjustment) than in Caucasian subjects. Drug exposure in patients of Hispanic or Latino origin was similar to that in Caucasian patients.

Clinical characteristics.

Indications.

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

• acute coronary syndrome (ACS) or
• history of myocardial infarction (MI) and high risk of atherothrombotic events (see sections "Method of administration and dosage" and "Pharmacodynamics").

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients (see section "Adverse reactions").
• Active pathological bleeding.
• History of intracranial hemorrhage (see section "Adverse reactions").
• Severe hepatic impairment (see sections "Method of administration and dosage", "Special precautions for use", and "Pharmacokinetics").
• Concomitant use of ticagrelor with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir) is contraindicated, as their concomitant use may lead to a significant increase in ticagrelor exposure (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

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

Effect of medicinal products and other agents on ticagrelor

Inhibitors of CYP3A4

• Strong CYP3A4 inhibitors – Concomitant administration of ketoconazole and ticagrelor resulted in a 2.4-fold and 7.3-fold increase in Cmax and AUC of ticagrelor, respectively. Cmax and AUC of the active metabolite decreased by 89% and 56%, respectively. Other strong CYP3A4 inhibitors (clarithromycin, nefazodone, ritonavir, and atazanavir) are expected to have a similar effect; therefore, concomitant use of strong CYP3A4 inhibitors with ticagrelor is contraindicated (see section "Contraindications").
• Moderate CYP3A4 inhibitors – Concomitant administration of diltiazem with ticagrelor resulted in a 69% increase in Cmax and a 2.7-fold increase in AUC of ticagrelor, as well as a 38% decrease in Cmax of the active metabolite, while its AUC remained unchanged. No effect of ticagrelor on plasma levels of diltiazem was observed. Other moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, erythromycin, and fluconazole) are expected to have a similar effect; therefore, they may be used concomitantly with ticagrelor.
• Daily consumption of large quantities of grapefruit juice (3 × 200 mL) resulted in a doubling of ticagrelor exposure. Such an increase in exposure is not expected to be clinically significant for most patients.

Inducers of CYP3A4

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

Cyclosporine (P-gp and CYP3A inhibitor)

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

Data on concomitant use of ticagrelor with other active substances that are also strong P-gp inhibitors and moderate CYP3A4 inhibitors (e.g., verapamil, quinidine), which may increase ticagrelor exposure, are lacking. If such combination cannot be avoided, concomitant use of these medicinal products should be performed with caution.

Others

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

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

Effect of ticagrelor on other medicinal products

Medicinal products metabolized by CYP3A4

• Simvastatin – Concomitant administration of ticagrelor with simvastatin increased Cmax of simvastatin by 81% and AUC by 56%, and increased Cmax of simvastatin acid by 64% and AUC by 52% (in individual cases, increases of 2–3 times were observed). Concomitant use of ticagrelor with simvastatin at doses exceeding 40 mg/day may cause simvastatin-related adverse effects, which should be weighed against the potential benefit. No effect of simvastatin on plasma levels of ticagrelor was observed. Ticagrelor may have a similar effect on lovastatin. Concomitant use of ticagrelor with simvastatin or lovastatin at doses exceeding 40 mg is not recommended.
• Atorvastatin – Concomitant administration of atorvastatin and ticagrelor increased Cmax of atorvastatin acid by 23% and AUC by 36%. A similar increase in AUC and Cmax was observed for all metabolites of atorvastatin acid. This increase is not considered clinically significant.
• A similar effect on other statins metabolized by CYP3A4 cannot be excluded. In the PLATO study, participants receiving ticagrelor were taking various statins, and no safety issues with statins occurred in 93% of these patients.

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

Substrates of P-gp (including digoxin and cyclosporine)

Concomitant administration of ticagrelor increased Cmax of digoxin by 75% and AUC by 28%. Mean minimum digoxin levels increased by approximately 30% with concomitant use of ticagrelor, and in some cases, maximum levels increased up to 2-fold. In the presence of digoxin, Cmax and AUC of ticagrelor and its active metabolite remained unchanged. Therefore, when concomitantly using P-gp-dependent medicinal products with a narrow therapeutic index, such as digoxin, with ticagrelor, appropriate clinical and/or laboratory monitoring is recommended.

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

Medicinal products metabolized by CYP2C9

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

Rosuvastatin (BCRP substrate)

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 has led to worsening renal function, increased creatine kinase (CK) levels, and rhabdomyolysis.

It has been shown that ticagrelor increases rosuvastatin concentration, which may lead to an increased risk of myopathy, including rhabdomyolysis. The benefits of preventing serious adverse cardiovascular events by using rosuvastatin should be weighed against the risks associated with increased plasma concentration of rosuvastatin.

Oral contraceptives

Concomitant administration of ticagrelor with levonorgestrel and ethinylestradiol increased ethinylestradiol exposure by approximately 20%, but did not alter the pharmacokinetics of levonorgestrel. Clinically significant effects on the efficacy of oral contraceptives are 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 (see section "Special precautions for use"). However, in the PLATO study, no clinically significant adverse reactions (ARs) were observed after concomitant use of one or more medicinal products capable of causing bradycardia (e.g., 96% of patients received beta-blockers, 33% received calcium channel blockers diltiazem and verapamil, and 4% received digoxin).

Other concomitant therapy

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

Concomitant administration of ticagrelor with heparin, enoxaparin, or desmopressin did not affect activated partial thromboplastin time (aPTT), activated clotting time (ACT), or quantitative factor Xa assay results. However, due to possible pharmacodynamic interactions, ticagrelor should be used with caution when administered concomitantly with medicinal products capable of affecting hemostasis.

Due to reports of pathological skin bleeding associated with the use of selective serotonin reuptake inhibitors (SSRIs) (e.g., paroxetine, sertraline, and citalopram), caution is recommended when using SSRIs 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 in relation to the benefit of the medicinal product in preventing atherothrombotic events (see sections "Side effects" and "Pharmacodynamics"). Ticagrelor should be used with caution in the following patient groups when clinically indicated:

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

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, desmopressin is unlikely to be effective in treating clinical bleeding (see section "Interaction with other medicinal products and other forms of interaction").

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

Surgical intervention

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

In the PLATO study, in patients undergoing CABG, bleeding events were more frequent in the ticagrelor group compared to the clopidogrel group when therapy was discontinued one day before surgery; however, major bleeding occurred with similar frequency in both groups when therapy was stopped two or more days prior to surgery (see section "Side effects"). If a patient requires elective surgery and antiplatelet effect is undesirable, ticagrelor should be discontinued five days before surgery (see section "Pharmacodynamics").

Patients who have experienced ischemic stroke

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

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

Hepatic impairment

Ticagrelor is contraindicated in patients with severe hepatic impairment (see sections "Posology and method of administration" and "Contraindications"). Experience with ticagrelor in patients with moderate hepatic impairment is limited; therefore, the medicinal product should be used with caution in such patients (see sections "Posology and method of administration" and "Pharmacokinetics").

Patients at risk of bradycardia

Holter ECG monitoring revealed an increased frequency of predominantly asymptomatic ventricular asystole episodes during ticagrelor treatment compared to clopidogrel. Patients at increased risk of bradycardia (e.g., patients without pacemakers who have sick sinus syndrome, second- or third-degree atrioventricular block, or syncope due to bradycardia) were not included in the main studies evaluating the safety and efficacy of ticagrelor. Therefore, due to limited clinical experience, ticagrelor should be used with caution in such patients (see section "Pharmacodynamics").

Concomitant use of ticagrelor with medicinal products capable of causing bradycardia requires caution. However, in the PLATO study, no signs of clinically significant adverse events were observed after concomitant use of one or more medicinal products capable of causing bradycardia (e.g., 96% of patients received beta-blockers, 33% received calcium channel blockers diltiazem and verapamil, and 4% received digoxin) (see section "Interaction with other medicinal products and other forms of interaction").

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

During the post-marketing period, cases of bradyarrhythmia and atrioventricular block have been reported in patients receiving ticagrelor, predominantly in patients with ACS, where myocardial ischemia and concomitant use of medicinal products that reduce heart rate or affect cardiac conduction are potential contributing factors. Before adjusting treatment, the patient's clinical condition and concomitant medicinal products 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 requiring discontinuation of treatment. In patients with asthma (BA)/chronic obstructive pulmonary disease (COPD), the absolute risk of developing dyspnea with ticagrelor may be increased. Ticagrelor should be used with caution in patients with a history of BA and/or COPD. The mechanism of this phenomenon is not fully understood. If a patient reports new, prolonged, or worsening dyspnea, a full clinical evaluation should be performed, and if intolerance to the medicinal product is suspected, treatment with ticagrelor should be discontinued. For detailed information, see section "Side effects".

Central sleep apnea

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

Elevated creatinine levels

Renal function (serum creatinine levels) should be monitored one month after initiation of ticagrelor therapy, with particular attention to patients aged ≥75 years, patients with moderate to severe renal impairment, and those concomitantly using ARBs.

Elevated uric acid levels

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

Thrombotic thrombocytopenic purpura (TTP)

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

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

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

False-negative results in platelet function tests (including the HIPA test, but not limited to it) for 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 on concomitant ticagrelor therapy is required for correct interpretation of platelet function test results for HIT diagnosis.

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

Other

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

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

Early discontinuation of treatment

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

Use during pregnancy or breastfeeding.

Women of childbearing potential

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

Pregnancy

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

Breastfeeding

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

Reproductive function

Ticagrelor did not affect fertility in male and female animals.

Ability to influence reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Dosage

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

Acute Coronary Syndrome

Treatment with the medicinal product Decegrel should be initiated with a single loading dose of 180 mg (two 90 mg tablets), followed by 90 mg twice daily. The recommended duration of treatment with Decegrel 90 mg in patients with ACS is 12 months in the absence of clinical reasons for premature discontinuation (see section "Pharmacodynamics").

History of Myocardial Infarction

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

If switching from another medicinal product to Decegrel, the first dose of Decegrel should be taken 24 hours after the last dose of the previous antithrombotic medicinal product.

Missed Dose

Patients should avoid missing doses of the medicinal product. If a patient misses a dose of Decegrel, 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 (see section "Pharmacodynamics").

Renal Impairment

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

Hepatic Impairment

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

Method of Administration

For oral use.

The medicinal product Decegrel can be administered regardless of food intake.

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

Children

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

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

Overdose

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

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

Currently, there is no known antidote for ticagrelor; ticagrelor is not removed by dialysis (see section "Pharmacokinetics"). Management of overdose should follow local standards of medical practice. The expected consequence of excessive ticagrelor dosing is prolonged bleeding risk due to platelet inhibition. Platelet transfusion is unlikely to be an effective treatment method for patients with bleeding (see section "Special Warnings and Precautions for Use"). In case of bleeding, other appropriate supportive measures should be implemented.

Adverse reactions.

The safety profile of ticagrelor was evaluated in two large-scale phase 3 clinical trials conducted to assess treatment outcomes (the PLATO and PEGASUS studies), involving over 39,000 patients (see section "Pharmacodynamics").

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

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

Adverse reactions are listed by MedDRA system organ class. Within each system organ class, adverse reactions are categorized by frequency. Frequency groups are defined as follows: 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).

Table 1.

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

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

c Identified during the post-marketing period.

d Frequency determined based on laboratory data (increase in uric acid levels > upper limit of normal from baseline, where baseline was below or within the normal range; increase in creatinine levels > 50% from baseline). This does not reflect the reporting frequency of the adverse event.

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

d For example, epistaxis, haemoptysis.

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

z For example, ecchymosis, skin haemorrhage, petechiae.

z For example, haemarthrosis, muscle haemorrhage.

z For example, haematuria, haemorrhagic cystitis.

i For example, vaginal bleeding, haematospermia, postmenopausal bleeding.

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

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

Description of selected adverse reactions

Bleeding

Incidence of bleeding in the PLATO study

The overall results regarding the frequency of bleeding events in the PLATO study are presented in Table 2.

Table 2.

Analysis of total number of bleeding events, Kaplan-Meier estimate over 12 months (PLATO)

Determination of bleeding types:

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

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

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

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

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

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

There was no difference between ticagrelor and clopidogrel in the incidence of major fatal/life-threatening bleeds according to PLATO criteria, overall number of major bleeds, or frequency of major or minor bleeds according to TIMI criteria. However, the incidence of combined PLATO major and minor bleeds was higher in the ticagrelor group compared to the clopidogrel group. A small number of patients in the PLATO study experienced fatal bleeds: 20 (0.2%) in the ticagrelor group and 23 (0.3%) in the clopidogrel group (see section "Special precautions").

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

Bleeding related to CABG: The incidence of major fatal/life-threatening bleeds related to coronary artery bypass grafting (CABG) according to PLATO criteria was similar between treatment groups, with no statistically significant difference. Fatal bleeding related to CABG occurred in 6 patients in each treatment group (see section "Special precautions").

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

Intracranial hemorrhage (ICH): More non-procedure-related ICHs occurred with ticagrelor (n = 27 bleeds in 26 patients, 0.3%) than with clopidogrel (n = 14 bleeds, 0.2%), of which 11 bleeds in the ticagrelor group and 1 bleed in the clopidogrel group were fatal. There was no difference in the overall rate of fatal bleeds.

Bleeding events in the PEGASUS study

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

Table 3.

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

Definition of bleeding types:

Major bleeds according to TIMI criteria: Fatal bleeding OR any type of ICH OR bleeding associated with clinical symptoms and related to a drop in hemoglobin (Hb) ≥50 g/L, or, if Hb levels are unavailable, a decrease in hematocrit (Hct) by 15%.

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

ICH: Intracranial hemorrhage.

Other major bleeds according to TIMI criteria: Non-fatal major bleeds not related to ICH according to TIMI criteria.

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

Medically significant bleeds according to TIMI criteria: Require intervention OR lead to hospitalization OR require investigation.

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

Other major bleeds according to PLATO criteria: Leading to persistent loss of function OR clinically significant with a decrease in Hb level by 30–50 g/L OR transfusion of 2–3 units of packed red blood cells.

Minor bleeds according to PLATO criteria: Requiring medical intervention to stop or manage bleeding.

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

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

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

Intracranial hemorrhage (ICH): Spontaneous ICH occurred with similar frequency with ticagrelor 60 mg and with aspirin-only (n = 13, 0.2% in both treatment groups). Traumatic and procedure-related ICH occurred slightly more frequently with ticagrelor 60 mg (n = 15, 0.2%) than with aspirin-only (n = 10, 0.1%). There were 6 fatal ICH cases with ticagrelor 60 mg and 5 fatal ICH cases with aspirin-only. The frequency of ICH was low in both treatment groups, considering the significant comorbidities and cardiovascular risk factors in the studied population.

Dyspnea

Patients treated with the medicinal product Ticagrelor reported dyspnea, sensation of breathlessness. In the PLATO study, the adverse reaction of dyspnea (dyspnea, dyspnea at rest, exertional dyspnea, paroxysmal nocturnal dyspnea, and nocturnal dyspnea) occurred overall in 13.8% of patients treated with ticagrelor and in 7.8% of patients treated with clopidogrel. In the PLATO study, dyspnea was considered by investigators to be treatment-related in 2.2% of patients receiving ticagrelor and in 0.6% of patients receiving clopidogrel; some of these cases were serious (0.14% in the ticagrelor group; 0.02% in the clopidogrel group) (see section "Special precautions for use"). Most dyspnea symptoms were mild or moderate; in most cases, a single episode occurred shortly after initiation of treatment.

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

Approximately 30% of dyspnea episodes resolved within 7 days. The PLATO study included patients with baseline conditions such as congestive heart failure, COPD, or bronchial asthma; these patients, as well as elderly patients, were more prone to developing dyspnea. 0.9% of patients receiving the medicinal product Decagrel discontinued study treatment prematurely due to dyspnea, compared to 0.1% of patients receiving clopidogrel. The higher frequency of dyspnea with Decagrel is not associated with the development of new or worsening pre-existing heart or lung disease (see section "Special precautions for use"). Decagrel does not affect pulmonary function test results.

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

Laboratory findings

Increased uric acid levels: In the PLATO study, serum uric acid concentration increased above the upper normal limit in 22% of patients receiving ticagrelor compared to 13% of patients receiving clopidogrel. Corresponding rates in the PEGASUS study were 9.1%, 8.8%, and 5.5% with ticagrelor 90 mg, 60 mg, and placebo, respectively. Mean serum uric acid levels increased by approximately 15% with ticagrelor compared to approximately 7.5% with clopidogrel; after discontinuation of treatment, levels decreased by approximately 7% with ticagrelor but did not decrease with clopidogrel. In the PEGASUS study, a reversible increase in mean serum uric acid levels of 6.3% and 5.6% was 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 and 0.1% with clopidogrel. Corresponding rates for gout/gouty arthritis in the PEGASUS study were 1.6%, 1.5%, and 1.1% in the ticagrelor 90 mg, 60 mg, and placebo groups, respectively.

Reporting of adverse reactions

Reporting of adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, 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.

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

Packaging.

14 tablets per blister pack. 4 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Pharmaceutical Plant "POLFARMA" S.A.

Manufacturer's location and address of place of business.

Pelplinska 19, 83-200 Starogard Gdanski, Poland.