Ticabel 90 mg 56 tablets

TICABEL 90 mg film-coated tablets Composition: Each film-coated tablet contains 60 mg ticagrelor as the active substance; iron red oxide (E172), titanium dioxide (E171), iron black oxide (E172) as colorants. Each film-coated tablet contains 90 mg ticagrelor as the active substance; iron yellow oxide (E172) and titanium dioxide (E172) as colorants. Pharmacological properties: Pharmacodynamic properties: Pharmacotherapeutic group: Platelet aggregation inhibitors, excluding heparin. ATC code: B01AC24 Mechanism of action Ticabel contains ticagrelor, a member of the cyclopentyltriazolopyrimidines (CPTP) chemical class, which is an oral, direct-acting, selective, and reversible antagonist of P2Y12 that can prevent ADP-dependent P2Y12-mediated activation and platelet aggregation. Ticagrelor does not inhibit ADP binding, but after binding to the P2Y12 receptor, it prevents ADP-induced signal transduction. Since platelets are involved in the initiation and/or development of thrombotic complications of atherosclerosis, platelet function inhibition has been shown to reduce the risk of cardiovascular events such as death, myocardial infarction, or stroke. Ticagrelor also increases local concentrations of endogenous adenosine by inhibiting the equilibrative nucleoside transporter-1 (ENT-1). In healthy subjects and patients with acute coronary syndrome, ticagrelor has been shown to enhance the following effects of adenosine: vasodilation (assessed as increased coronary blood flow in healthy volunteers and patients with acute coronary syndrome; headache), suppression of platelet function (in vitro in human whole blood), and dyspnea. However, the relationship between increased adenosine concentration and clinical outcomes (e.g., morbidity and mortality rates) has not been established. See also: Brilinta - Brilinta 90mg 56 tablets Pharmacokinetic properties: Ticagrelor exhibits linear pharmacokinetics, with exposure to ticagrelor and its active metabolite (AR-C124910XX) being approximately dose-proportional up to 1260 mg. Absorption Ticagrelor is rapidly absorbed with a median Tmax of approximately 1.5 hours. Distribution The volume of distribution of ticagrelor at steady state is 87.5 L. Ticagrelor and its active metabolite are widely bound to human plasma proteins (>99.0%). Biotransformation CYP3A4 is the major isoform responsible for the metabolism of ticagrelor and the formation of its active metabolite, and their interaction with other CYP3A substrates ranges from activation to inhibition. The main metabolite of ticagrelor is AR-C124910XX, which is also active, as confirmed by in vitro assessment of binding to the P2Y12 platelet ADP receptor. Systemic exposure to the active metabolite accounts for approximately 30-40% of the exposure to ticagrelor. Elimination The primary route of elimination of ticagrelor is hepatic metabolism. Following administration of radiolabeled ticagrelor, the mean radioactivity recovered is approximately 84% (57.8% in feces, 26.5% in urine). Excretion of ticagrelor and its active metabolite in urine accounts for less than 1% of the dose. The primary route of elimination of the active metabolite is likely biliary excretion. The mean t1/2 of ticagrelor is approximately 7 hours, and that of the active metabolite is 8.5 hours. Indications: In combination with acetylsalicylic acid (ASA), Ticabel is indicated for the prevention of atherothrombotic events in adult patients with: - acute coronary syndrome (ACS) or - a history of myocardial infarction or a high risk of developing an atherothrombotic event (see sections "Dosage and administration" and "Pharmacodynamic properties"). Contraindications: - Hypersensitivity to the active substance or any of the excipients listed in the composition (see section "Adverse effects/undesirable events"). - Active pathological bleeding. - History of intracranial hemorrhage (see section "Adverse effects/undesirable events"). - Severe hepatic impairment (see sections "Dosage and administration", "Warnings/Precautions" and "Pharmacokinetic properties"). - Concomitant use of ticagrelor with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir), as the combination may lead to a significant increase in ticagrelor exposure (see section "Drug interactions"). Warnings / Precautions: Risk of bleeding In patients with a known increased risk of bleeding, the benefit-risk ratio of ticagrelor use and prevention of atherothrombotic events should be assessed (see sections "Adverse effects/undesirable events" and "Pharmacodynamic properties"). Ticagrelor should be used with caution in the following patient groups if clinically indicated: - Patients with a predisposition to bleeding (e.g., recent trauma, recent surgery, bleeding disorders, acute or recent gastrointestinal bleeding). Ticagrelor is contraindicated in patients with active pathological bleeding, a history of intracranial hemorrhage, and in patients with severe hepatic impairment (see section "Contraindications"). - Concomitant use of medications that may increase the risk of bleeding (e.g., non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, and/or fibrinolytic agents) within 24 hours of ticagrelor administration. In healthy volunteers, the antiplatelet effect of ticagrelor was not reversed by platelet transfusion, and this procedure is unlikely to be beneficial in patients with bleeding. Since the concomitant use of ticagrelor and desmopressin does not reduce the standard bleeding time, desmopressin is not expected to be effective in managing cases of clinical bleeding (see section "Drug interactions"). Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or treatment with recombinant factor VIIa preparations may increase hemostasis. Continuation of ticagrelor treatment may be considered after the cause of bleeding has been identified and treated. Surgery Patients should inform their doctor and dentist about taking ticagrelor before planning any surgery and before taking any medical product. In the PLATO study, in patients undergoing coronary artery bypass grafting (CABG), ticagrelor caused more bleeding than clopidogrel when therapy was discontinued within 1 day before surgery, although the incidence of major bleeding was similar to that observed in the clopidogrel group when therapy was discontinued 2 or more days before surgery (see section "Adverse effects/undesirable events"). If a patient is undergoing elective surgery and antiplatelet effect is desired to be avoided, ticagrelor should be discontinued 5 days before surgery (see section "Pharmacodynamic properties"). Patients with a history of ischemic stroke In patients with acute coronary syndrome who have a history of ischemic stroke, treatment with ticagrelor may be continued for a 12-month course (PLATO study). Patients with a history of myocardial infarction who have also had an ischemic stroke were not included in the PEGASUS study. Therefore, due to the lack of data, treatment for more than one year in these patients is not recommended. Hepatic impairment Ticagrelor use is contraindicated in patients with severe hepatic impairment (see sections "Dosage and administration" and "Contraindications"). Due to limited experience with ticagrelor use in patients with moderate hepatic impairment, caution is recommended when using it in this patient group (see sections "Dosage and administration" and "Pharmacokinetic properties"). Patients at risk of developing bradycardia In patients treated with ticagrelor, Holter ECG monitoring has shown an increase in the frequency of predominantly asymptomatic ventricular pauses compared to the clopidogrel treatment group. Patients at increased risk of developing bradycardia (e.g., patients with pacemakers, sinoatrial node dysfunction, second or third-degree AV block, or bradycardic syncope) were excluded from the main studies evaluating the safety and efficacy of ticagrelor. Therefore, due to limited clinical experience, ticagrelor is used with caution in these patients (see section "Pharmacodynamic properties"). Caution is also advised when ticagrelor is used concomitantly with medications that cause bradycardia. However, in the PLATO study, no clinically significant adverse reactions were observed with the concomitant use of one or more bradycardia-inducing drugs (e.g., 96% beta-blockers, 33% calcium channel blockers diltiazem and verapamil, and 4% digoxin) (see section "Drug interactions"). In the PLATO study, during the acute phase of acute coronary syndrome, more patients in the ticagrelor group had ventricular pauses > 3 seconds on Holter monitoring compared to the clopidogrel group. The rate of increased ventricular pauses detected by Holter monitoring was higher in patients with chronic heart failure in the ticagrelor treatment group than in the overall study population during the acute phase of acute coronary syndrome, but this rate was not observed within one month of ticagrelor administration or compared to clopidogrel. No adverse clinical outcomes (including syncope or pacemaker implantation) associated with this imbalance were reported in these patients (see section "Pharmacodynamic properties"). Post-marketing studies have reported cases of bradyarrhythmia and AV block with ticagrelor (see section "Adverse effects/undesirable events"), mainly in patients with acute coronary syndrome, where potential causes include cardiac ischemia and concomitant use of drugs that reduce heart rate or affect cardiac conduction. The patient's clinical condition and concomitant medications should be considered as potential causes before initiating treatment. Dyspnea Cases of dyspnea have been reported during treatment with ticagrelor. Dyspnea is usually mild to moderate in severity and often resolves without the need to discontinue treatment. In patients with asthma/chronic obstructive pulmonary disease (COPD), there may be an absolute increase in the risk of dyspnea with ticagrelor treatment. Ticagrelor should be used with caution in patients with a history of asthma and/or COPD. The mechanism is not established. If a patient experiences a new episode of dyspnea, its persistence or worsening, detailed investigations should be carried out, and if intolerance is established, ticagrelor treatment should be discontinued. See section "Adverse effects/undesirable events" for additional information. Increase in creatinine concentration During ticagrelor treatment, creatinine levels may increase. The mechanism is not established. Renal function should be checked according to established medical practice. In patients with acute coronary syndrome, renal function should also be checked one month after initiating ticagrelor treatment, especially in patients > 75 years of age, patients with moderate/severe renal impairment, and those receiving concomitant treatment with angiotensin receptor blockers. Increase in uric acid concentration Hyperuricemia may develop during ticagrelor treatment (see section "Adverse effects/undesirable events"). Caution is advised in patients with a history of hyperuricemia or gouty arthritis. As a precaution, ticagrelor use is not recommended in patients with uric acid nephropathy. Thrombotic thrombocytopenic purpura (TTP) Very rare cases of thrombotic thrombocytopenic purpura (TTP) have been reported with ticagrelor use. It is characterized by thrombocytopenia and microangiopathic hemolytic anemia, with neurological consequences, renal dysfunction, or fever. TTP is a potentially fatal condition requiring urgent treatment, including plasmapheresis. Effect on assays determining platelet function for heparin-induced thrombocytopenia (HIT) When performing assays for heparin-induced platelet activation for heparin-induced thrombocytopenia (HIT), anti-platelet factor 4/anti-heparin antibodies in the patient's serum activate platelets from healthy donors in the presence of heparin. False-negative results for heparin-induced thrombocytopenia have been observed in patients treated with ticagrelor in platelet function assays (including, but not limited to, assays for heparin-induced platelet activation). This is related to P2Y12 receptor inhibition on healthy donor platelets in the assay with patient serum/plasma containing ticagrelor. Information regarding concomitant treatment with ticagrelor is necessary for the interpretation of the results of platelet function assays for heparin-induced thrombocytopenia. In patients with heparin-induced thrombocytopenia, the benefit-risk of continuing ticagrelor treatment should be assessed, considering the prothrombotic state of heparin-induced thrombocytopenia and the increased risk of bleeding with concomitant use of anticoagulants and ticagrelor. In another study, PLATO, based on the observed relationship between the comparative efficacy of acetylsalicylic acid maintenance dose and ticagrelor (compared to clopidogrel), concomitant use of high maintenance doses of ticagrelor and acetylsalicylic acid (>300 mg) is not recommended (see section "Pharmacodynamic properties"). Premature discontinuation of treatment Premature discontinuation of treatment with any antiplatelet agent, including Ticabel, may increase the risk of death from cardiovascular causes, myocardial infarction, or stroke due to the patient's underlying disease. Therefore, premature discontinuation of treatment should be avoided. Sodium Each dose of Ticabel contains less than 1 mmol (23 mg) of sodium, i.e., it is practically "sodium-free". Fertility, pregnancy and lactation: Women of childbearing potential Women of childbearing potential should use adequate contraceptive measures to avoid pregnancy during ticagrelor treatment. Pregnancy Data on the use of ticagrelor in pregnant women are absent or limited. Animal studies have shown reproductive toxicity. Ticagrelor is not recommended during pregnancy. Breastfeeding Animal data show excretion of ticagrelor and its active metabolites in milk. A risk to newborns/infants cannot be excluded. A decision on whether to discontinue breastfeeding or to discontinue/withhold ticagrelor treatment should be made taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother. Fertility Ticagrelor has no effect on the fertility of male and female animals. Effects on ability to drive and use machinery: Ticagrelor has no or negligible influence on the ability to drive and operate machinery. Dizziness and confusion have been reported during ticagrelor treatment. Therefore, patients should exercise caution when driving or operating machinery if these symptoms occur. Adverse effects/undesirable events: Summary of safety profile The safety profile of ticagrelor was evaluated in two large phase III studies (PLATO and PEGASUS) involving over 39,000 patients (see section "Pharmacodynamic properties"). In the PLATO study, the rate of treatment discontinuation due to adverse events was higher in the ticagrelor group than in the clopidogrel group (7.4% vs. 5.4%). In the PEGASUS study, the rate of treatment discontinuation due to adverse events was higher in the ticagrelor group than in the acetylsalicylic acid monotherapy group (16.1% in the ticagrelor 60 mg plus acetylsalicylic acid group vs. 8.5% in the acetylsalicylic acid monotherapy group). The most frequently reported adverse reactions in patients treated with ticagrelor were bleeding and dyspnea (see section "Warnings/Precautions" 4). List of adverse reactions The following adverse reactions were identified from studies or reported during post-marketing use of ticagrelor. Adverse reactions are listed by MedDRA system organ class. Within each category, adverse reactions are ranked by frequency. Frequency is defined by the following categories: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10000 to <1/1000), very rare (<1/10000), unknown (frequency cannot be estimated from the available data). Table 1. Adverse reactions by frequency and system organ class System organ class | Very common | Common | Uncommon | Rare | Very rare | Unknown -------------------|-------------|--------|----------|------|-----------|--------- Neoplasms benign, malignant and unspecified (including cysts and polyps) | | | | | | Bleeding from tumor a Blood and lymphatic system disorders | | Bleeding b | | | | Thrombotic thrombocytopenic purpura Immune system disorders | | | Hypersensitivity, including angioedema c | | | Metabolism and nutrition disorders | | Hyperuricemia d | Gout/gouty arthritis | | | Psychiatric disorders | | | | | | Confusion Nervous system disorders | | Dizziness, syncope, headache | Intracranial hemorrhage n | | | Eye disorders | | | Hemorrhage in the eye e | | | Ear and labyrinth disorders | Dizziness | Bleeding from ear | | | | Cardiac disorders | | | | Bradyarrhythmia, AV block c | | Vascular disorders | | Hypotension | | | | Respiratory, thoracic and mediastinal disorders | Dyspnea | Bleeding from respiratory tract f | | | | Gastrointestinal disorders | | Gastrointestinal bleeding z, diarrhea, nausea, dyspepsia, constipation | Retroperitoneal hemorrhage | | | Skin and subcutaneous tissue disorders | | Subcutaneous or skin bleeding h, rash, pruritus | | | | Musculoskeletal and connective tissue disorders | | Muscle bleeding i | | | | Renal and urinary disorders | | Urinary tract bleeding k | | | | Reproductive system and breast disorders | | Reproductive system bleeding l | | | | Investigations | | Increase in blood creatinine concentration d | | | | Injury, poisoning and procedural complications | | Post-procedural bleeding, traumatic bleeding m | | | | a e.g., bleeding from bladder cancer, stomach cancer, colon cancer b e.g., increased risk of developing ecchymoses, spontaneous hematomas, hemorrhagic diathesis c Reported during post-marketing use d Frequency is based on laboratory analyses (uric acid concentration increases from low or normal baseline to above the upper limit of normal. Creatinine clearance increases by more than 50% compared to baseline), as well as reporting of unprocessed adverse events. e e.g., conjunctival, retinal, intraocular hemorrhage f e.g., epistaxis, hemoptysis z e.g., gingival bleeding, rectal bleeding, bleeding from gastric ulcer h e.g., ecchymosis, subcutaneous hemorrhage, petechiae i e.g., hemarthrosis, muscle bleeding k e.g., hematuria, hemorrhagic cystitis l e.g., vaginal bleeding, hematospermia, postmenopausal bleeding m e.g., confusion, traumatic hematoma, traumatic bleeding n e.g., spontaneous, procedure-related or traumatic intracranial hemorrhage. Consult your doctor if you notice any adverse reactions. Drug interactions: Ticagrelor is primarily a substrate and moderate inhibitor of CYP3A4. It is also a substrate and weak inhibitor of P-glycoprotein and may increase the exposure to P-glycoprotein substrates. Effect of medicinal products and other substances on ticagrelor CYP3A4 inhibitors - Strong CYP3A4 inhibitors - Concomitant use of ketoconazole with ticagrelor increased ticagrelor Cmax and AUC by 2.4-fold and 7.3-fold, respectively. Cmax and AUC of the active metabolite decreased by 89% and 56%, respectively. Similar effects are expected with other strong CYP3A4 inhibitors (clarithromycin, nefazodone, ritonavir, and atazanavir), therefore, the use of strong CYP3A4 inhibitors with ticagrelor is contraindicated (see section "Contraindications"). - Moderate CYP3A4 inhibitors - Concomitant use of diltiazem with ticagrelor increased ticagrelor Cmax by 69% and AUC by 2.7-fold, decreased active metabolite Cmax by 38%, while AUC remained unchanged. Ticagrelor has no effect on plasma diltiazem levels. Similar effects are expected with other moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, erythromycin, and fluconazole), and their use with ticagrelor may also be possible. - A twofold increase in ticagrelor exposure was observed with the intake of a large amount of grapefruit juice (3x200 ml) during the day. Such an increase in exposure is not clinically significant in most cases. CYP3A inducers Concomitant use of rifampicin with ticagrelor decreased ticagrelor Cmax and AUC by 73% and 86%, respectively. Cmax of the active metabolite remained unchanged, while AUC decreased by 46%, respectively. Other CYP3A inducers (e.g., phenytoin, carbamazepine, and phenobarbital) are expected to also reduce ticagrelor exposure. Concomitant use of ticagrelor with strong CYP3A inhibitors may reduce ticagrelor exposure and efficacy, therefore their use with ticagrelor is not recommended. Cyclosporine (P-glycoprotein and CYP3A inhibitor) Concomitant administration of cyclosporine (600 mg) with ticagrelor increased ticagrelor Cmax and AUC by 2.3-fold and 2.8-fold, respectively. AUC of the active metabolite increased by 32%, and Cmax decreased by 15% in the presence of cyclosporine. There are no data on the use of ticagrelor with other active substances that are also strong P-glycoprotein inhibitors or moderate CYP3A4 inhibitors (e.g., verapamil, quinidine) that may also increase ticagrelor exposure. If combination cannot be avoided, caution should be exercised during concomitant use. Clinical studies of other pharmacological interactions have shown that concomitant administration of ticagrelor with heparin, enoxaparin, and ASA or desmopressin has no effect on the pharmacokinetic parameters of ticagrelor or its active metabolite, or on ADP-induced platelet aggregation, compared to ticagrelor alone. If clinically indicated, the use of medicinal products affecting hemostasis in combination with ticagrelor should be done with caution. In patients with acute coronary syndrome receiving morphine, delayed and reduced exposure to oral P2Y12 inhibitors, including ticagrelor and its active metabolite, was observed (a 35% reduction in ticagrelor exposure). This interaction may be caused by reduced gastrointestinal motility and the use of other opioids. The clinical significance is unknown, but data suggest a potential decrease in ticagrelor efficacy with concomitant use of ticagrelor and morphine. In patients with acute coronary syndrome where morphine use cannot be discontinued and rapid P2Y12 inhibition is critical, the use of a parenteral P2Y12 inhibitor may be considered. Effect of ticagrelor on other medicinal products CYP3A4 metabolizers Simvastatin - Concomitant administration of ticagrelor with simvastatin increased simvastatin Cmax by 81% and AUC by 56%, and also simvastatin acid Cmax by 64% and AUC by 52%, with some individual increases of 2-3 fold. Concomitant use of ticagrelor with simvastatin at doses greater than 40 mg per day may lead to adverse reactions of simvastatin, which should be considered against the potential benefits. Ticagrelor has no effect on plasma ticagrelor levels. Ticagrelor may have a similar effect on lovastatin. Concomitant use of simvastatin or lovastatin at doses exceeding 40 mg with ticagrelor is not recommended. Atorvastatin - Concomitant administration of atorvastatin and ticagrelor increased atorvastatin acid Cmax by 23% and AUC by 36%. A similar increase in AUC and Cmax values was observed for all metabolites of atorvastatin acid. Such an increase in values is not clinically significant. A similar effect of other statins metabolized by CYP3A4 cannot be excluded. In the PLATO study, patients in the ticagrelor group received various statins, with 93% of the cohort receiving statins in PLATO, without considering any association with statin safety. Ticagrelor is a weak inhibitor of CYP3A4. Concomitant use of ticagrelor with substrates of CYP3A4 with a narrow therapeutic index (e.g., cisapride and ergot alkaloids) is not recommended, as ticagrelor may increase the exposure to these medicinal products. P-glycoprotein substrates (including digoxin, cyclosporine) Concomitant administration of ticagrelor increased digoxin Cmax by 75% and AUC by 28%. The mean trough plasma concentration of digoxin increased by approximately 30% when taken in combination with ticagrelor, with some individual maximum twofold increases. Cmax and AUC values of ticagrelor and its active metabolite did not change in the presence of digoxin. Therefore, concomitant use of P-glycoprotein-dependent medicinal products with a narrow therapeutic index, such as digoxin, with ticagrelor is recommended with appropriate clinical and/or laboratory monitoring. Ticagrelor does not affect plasma cyclosporine levels. The effect of ticagrelor on other P-glycoprotein substrates has not been studied. CYP2C9 metabolizers The combination of ticagrelor with tolbutamide does not alter the plasma levels of these drugs, indicating that ticagrelor is not a CYP2C9 inhibitor and is unlikely to alter CYP2C9-mediated metabolism of drugs such as warfarin and tolbutamide. Rosuvastatin Ticagrelor may affect the renal excretion of rosuvastatin and increase the risk of rosuvastatin accumulation. Although the exact mechanism is unknown, concomitant use of ticagrelor and rosuvastatin has in some cases led to impaired renal function, increased CK levels, and rhabdomyolysis. Other contraceptives Concomitant administration of ticagrelor with levonorgestrel and ethinylestradiol increased ethinylestradiol exposure by approximately 20%, but did not alter levonorgestrel pharmacokinetic parameters. No clinically significant effect on the efficacy of oral contraceptives is expected when levonorgestrel and ethinylestradiol are taken with ticagrelor. Bradycardia-inducing medicinal products Mainly due to the observation of predominantly asymptomatic ventricular pauses and bradycardia, caution should be exercised when taking ticagrelor with bradycardia-inducing medicinal products (see section "Warnings/Precautions"). However, in the PLATO study, no evidence of clinically significant adverse reactions was observed with the combination of one or more bradycardia-inducing medicinal products (e.g., 96% beta-blockers, 33% calcium channel blockers diltiazem and verapamil, and 4% digoxin) (see section "Drug interactions"). Other concomitant therapies In clinical studies, ticagrelor was frequently used in combination with acetylsalicylic acid, proton pump inhibitors, statins, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers, as needed for concomitant diseases for prolonged periods, as well as with heparin, low molecular weight heparin, and intravenous GpIIb/IIIa inhibitors for short-term treatment (see section "Pharmacodynamic properties"). No clinically significant adverse interactions with these medicinal products were reported. The combination of ticagrelor with heparin, enoxaparin, or desmopressin had no effect on activated partial thromboplastin time, coagulation activation time, or factor Xa assay. However, due to potential pharmacodynamic interactions, caution should be exercised when concomitantly administering ticagrelor and medicinal products affecting the hemostasis system. Since reports of skin bleeding have been associated with selective serotonin reuptake inhibitors (e.g., paroxetine, sertraline, and citalopram), caution is recommended when taking selective serotonin reuptake inhibitors with ticagrelor, as the risk of bleeding may increase. Dosage and administration: Dosage Patients taking Ticabel should also take a low maintenance dose of acetylsalicylic acid 75-150 mg daily, unless there is a specific contraindication. Acute coronary syndromes Treatment with Ticabel should be initiated with a single loading dose of 180 mg (two 90 mg tablets) and then continued with 90 mg twice daily. In patients with acute coronary syndrome, the recommended duration of treatment with Ticabel 90 mg twice daily is 12 months, unless there is a clinical indication to discontinue treatment (see section "Pharmacodynamic properties"). History of myocardial infarction A Ticabel dose of 60 mg twice daily is recommended as extended treatment in patients with a history of myocardial infarction of at least one year and a high risk of atherothrombotic events (see section "Pharmacodynamic properties"). Treatment may be initiated without interruption of the initial one-year treatment with 90 mg Ticabel or an adenosine diphosphate (ADP) receptor inhibitor in patients with acute coronary syndrome and a high risk of atherothrombotic events. Treatment may also be initiated up to two years after myocardial infarction or one year after discontinuation of previous treatment with an ADP receptor inhibitor. Data on the efficacy and safety of treatment longer than 3 years are limited. If the drug needs to be switched, the first dose of Ticabel should be taken within 24 hours of the last dose of the other antiplatelet drug. Missed dose Missed doses should be avoided. If a dose of Ticabel is missed, the patient should take only one tablet (their next dose) at the scheduled time. Special populations Elderly No dose adjustment is required in the elderly (see section "Pharmacokinetic properties"). Renal impairment No dose adjustment is required in patients with renal impairment (see section "Pharmacokinetic properties"). Hepatic impairment No studies of ticagrelor in patients with severe hepatic impairment have been conducted, and therefore, its use in these patients is contraindicated (see section "Contraindications"). Limited information is available regarding patients with moderate hepatic impairment. Dose adjustment is not recommended, but ticagrelor is used with caution (see sections "Warnings/Precautions" and "Pharmacokinetic properties"). No dose adjustment is required in patients with mild hepatic impairment (see section "Pharmacokinetic properties"). Pediatric population The safety and efficacy of ticagrelor in children under 18 years of age have not been established. There is no data on the appropriate use of ticagrelor in children with sickle cell disease (see sections "Pharmacodynamic properties" and "Pharmacokinetic properties"). Method of administration For oral use. Ticabel can be taken with or without food. Patients who cannot swallow the tablet whole can finely crush it, mix it with half a glass of water, and drink immediately. Rinse the glass with half a glass of water and drink the contents. The mixture can also be administered via a nasogastric tube (CH8 or larger). The nasogastric tube must be flushed with water after administration of the mixture. Overdose: A single dose of ticagrelor up to 900 mg is well tolerated. In a single dose-escalation study, gastrointestinal toxicity was dose-dependent. Other clinically significant adverse reactions that may occur with overdose include dyspnea and ventricular pauses (see section "Adverse effects/undesirable events"). In case of overdose, the potential adverse reactions mentioned above may occur, and the issue of ECG monitoring should be considered. There is no known antidote to reverse the effect of ticagrelor, and it is not dialyzable (see section "Pharmacokinetic properties"). Treatment of overdose should be carried out according to local standard medical practice. The expected effect of ticagrelor overdose is a prolonged risk of bleeding associated with platelet inhibition. Platelet transfusion is unlikely to provide clinical benefit in patients with bleeding (see section "Warnings/Precautions"). In case of bleeding, other supportive measures should be taken. Dispensing: Pharmaceutical product group II, dispensed by prescription form №3 Ticabel 60 mg film-coated tablets: 56 film-coated tablets in blister packs. Ticabel 90 mg film-coated tablets: 56 and 168 film-coated tablets in blister packs. Storage conditions: The preparation should be stored at a temperature not exceeding 25°C, in its original packaging. The preparation should be stored out of reach of children.