Instructions for Brilinta film-coated tablets 90 mg blister No. 56
Composition
active ingredient: ticagrelor;
1 film-coated tablet contains 90 mg of ticagrelor;
excipients: mannitol (E 421), calcium hydrogen phosphate, sodium starch glycolate (type A), hydroxypropyl cellulose, magnesium stearate, hypromellose 2910, titanium dioxide (E 171), talc, polyethylene glycol 400, iron oxide yellow (E 172).
Dosage form
Film-coated tablets.
Main physicochemical properties: round, biconvex, yellow, film-coated tablets engraved on one side and plain on the other.
Pharmacotherapeutic group
Antithrombotic agent. Platelet aggregation inhibitors, except heparin. ATX code B01A C24.
Pharmacological properties
Pharmacodynamics.
Mechanism of action
Brilinta contains ticagrelor, which belongs to the chemical class of cyclopentyltriazolopyrimidines (CTPs) and is an oral, selective and reversibly binding P2Y12 receptor antagonist of direct action, preventing ADP-mediated P2Y12-dependent platelet activation and aggregation. Ticagrelor does not prevent ADP binding, but by binding to the P2Y12 receptor, it prevents ADP-induced signaling. 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 (CV) events such as death, myocardial infarction (MI), or stroke.
Ticagrelor also increases local levels of endogenous adenosine by inhibiting the equilibrating nucleoside transporter subtype 1 (ENT-1).
Ticagrelor has been reported to potentiate the following adenosine-induced effects in healthy volunteers and patients with acute coronary syndrome (ACS): vasodilation (as measured by increased coronary blood flow in healthy volunteers and patients with ACS; headache), inhibition of platelet function (in human whole blood in vitro), and dyspnea. However, the relationship between the observed increases in adenosine levels and clinical outcomes (e.g., morbidity and mortality) has not been clearly established.
Pharmacodynamic effects
Start of action
In patients with stable coronary artery disease (CAD) receiving acetylsalicylic acid (ASA), the pharmacological effect of ticagrelor is rapid, as evidenced by the mean inhibition of platelet aggregation (PAA) by ticagrelor at 0.5 h after a 180 mg loading dose of approximately 41%, with a maximum PAA effect of 89% at 2–4 h post-dose, which was maintained for 2–8 h. In 90% of patients, the final PAA at 2 h post-dose was >70%.
End of action
If a coronary artery bypass graft (CABG) procedure is planned, the risk of bleeding in patients using ticagrelor is increased compared to those receiving clopidogrel if therapy is discontinued less than 96 hours before the procedure.
Switching from one medication to another
Switching from clopidogrel 75 mg to ticagrelor 90 mg twice daily resulted in an absolute increase in BP of 26.4%, while switching from ticagrelor to clopidogrel resulted in an absolute decrease in BP of 24.5%. Patients can be switched from clopidogrel to ticagrelor without any change in antiplatelet effect (see section 4.2).
Clinical efficacy and safety
Clinical evidence of the efficacy and safety of ticagrelor was obtained in two phase 3 studies:
The PLATO [PLATelet Inhibition and Patient Outcomes] study compared ticagrelor and clopidogrel when used in combination with ASA and other standard therapy.
The PEGASUS TIMI-54 study [PrEvention with TicaGrelor of SecondAry Thrombotic Events in High-RiSk AcUte Coronary Syndrome Patients] compared ticagrelor in combination with ASA and ASA alone.
PLATO study (acute coronary syndrome)
The PLATO study included 18,624 patients with symptoms of unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), or ST-segment elevation myocardial infarction (ST-segment elevation MI) within the previous 24 hours who were treated medically or with percutaneous coronary intervention (PCI) or CABG.
Clinical efficacy
In combination with ASA, ticagrelor 90 mg twice daily was more effective than clopidogrel 75 mg daily in preventing the primary composite endpoint (PCE) of CV death, myocardial infarction (MI), or stroke, based on the difference in CV death and MI. Patients received a loading dose of 300 mg clopidogrel (possibly 600 mg in the case of PCI) or 180 mg ticagrelor.
The greater efficacy of ticagrelor compared with clopidogrel was independent of body weight, gender, presence of diabetes mellitus (DM), transient ischemic attack (TIA), non-hemorrhagic stroke, revascularization, concomitant drug therapy including heparins, GpIIb/IIIa inhibitors and proton pump inhibitors (PPIs) (see section 4.5). Efficacy was independent of the treatment modality chosen at randomisation (invasive or medical) in both patients with ACS, STEMI and STEMI.
The hazard ratio (HR) for PCT favored ticagrelor in the rest of the world except North America, which represented approximately 10% of the total study population (p for interaction = 0.045). Exploratory analysis suggested a possible interaction with ASA dose, as increasing ASA dose was associated with decreased ticagrelor efficacy. ASA doses for continuous daily use with Brilinta should be 75–150 mg (see sections 4.2 and 4.4).
Treatment with Brilinta reduced the incidence of PCI compared with clopidogrel in all patients with ACS (NS/STEMI or STEMI). Therefore, Brilinta 90 mg twice daily in combination with low-dose ASA can be used in patients with ACS (NS, STEMI or STEMI), including patients treated medically, with PCI or CABG.
PLATO genetic study
Genotyping of 10,285 patients for CYP2C19 and ABCB1 in the PLATO trial established an association between genotype groups and PLATO outcomes. The benefits of ticagrelor over clopidogrel in reducing the incidence of serious CV events were not significantly dependent on the patients' CYP2C19 or ABCB1 genotype. The overall incidence of major bleeding as defined by the PLATO trial did not differ between the ticagrelor and clopidogrel groups regardless of CYP2C19 or ABCB1 genotype. The incidence of non-CABG major bleeding as defined by the PLATO trial was increased with ticagrelor compared with clopidogrel in patients with loss of one or more functional CYP2C19 alleles but was similar to that with clopidogrel in patients without loss of function alleles.
A comprehensive component of efficiency and safety
The composite of efficacy and safety (cardiovascular death, MI, stroke, or total major bleeding as defined by the PLATO study) indicates that the efficacy advantage of ticagrelor compared with clopidogrel is not offset by major bleeding events (MAB – 1.4%, VZR – 8%, VR – 0.92; p=0.0257) within 12 months after ACS.
Clinical safety
Holter study in PLATO
According to Holter monitoring data from the PLATO study, there were more patients with episodes of ventricular asystole ≥3 s in the acute phase of ACS in the ticagrelor group than in the clopidogrel group; such episodes were observed more often in patients with chronic heart failure (CHF) compared with the general population; however, there was no statistically significant difference between the ticagrelor and clopidogrel groups at 1 month. No adverse clinical outcomes (including syncope or pacemaker implantation) due to this discrepancy were observed in this patient population.
PEGASUS study (history of myocardial infarction)
The PEGASUS TIMI-54 study is a randomized, double-blind, placebo-controlled, parallel-group, international multicenter case-control study involving 21,162 patients, conducted to evaluate the prevention of atherothrombotic events with the use of ticagrelor in 2 doses (90 mg twice daily or 60 mg twice daily) in combination with low-dose ASA (75–150 mg) compared with ASA therapy alone in patients with a history of MI and the presence of additional risk factors for atherothrombosis.
Inclusion criteria for the study were as follows: age ≥50 years, history of MI (1–3 years before randomization), and at least one of the following risk factors for atherothrombosis: age ≥65 years, diabetes requiring medical treatment, history of second MI, evidence of multivessel coronary artery disease, or non-end-stage chronic renal failure (CKD).
Exclusion criteria were planned use of a P2Y12 receptor antagonist, dipyridamole, cilostazol, or anticoagulant therapy during the study period; history of coagulation disorders, ischemic stroke, or intracranial hemorrhage (ICH), central nervous system tumor, or intracranial vascular anomaly; gastrointestinal bleeding within the previous 6 months, or major surgery within the previous 30 days.
Clinical efficacy
The use of ticagrelor 60 mg twice daily and 90 mg twice daily in combination with ASA was 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, with a 16% CVD and 1.27% ADR for ticagrelor 60 mg and 15% and 1.19%, respectively, for ticagrelor 90 mg.
Compared with ASA monotherapy, ticagrelor 60 mg twice daily in combination with ASA significantly reduced the incidence of CVD (CV death, MI, and stroke). The reduction in CVD was due to a reduction in the incidence of each component (CV death by 17%, CV MI by 16%, and CV stroke by 25%).
The overall survival rate for the composite endpoint was similar from day 1 to 360 (17% survival rate) and from day 361 onwards (16% survival rate). There are limited data on the efficacy and safety of ticagrelor when treatment is continued beyond 3 years.
There was no evidence of benefit (no reduction in the incidence of CVD (CV death, MI and stroke) and no increase in the incidence of major bleeding) of ticagrelor 60 mg twice daily in clinically stable patients more than 2 years after MI or more than 1 year after discontinuation of previous ADP receptor inhibitor treatment (see also section “Method of administration and dosage”).
Clinical safety
The rate of premature discontinuation of ticagrelor 60 mg due to bleeding and dyspnea was higher in patients >75 years of age (42%) than in younger patients (range: 23–31%), with a difference compared to placebo of more than 10% (42% vs. 29%) in patients >75 years of age.
Children
In a randomized, double-blind, parallel-group, phase III study (HESTIA 3), 193 pediatric patients (2 to 18 years of age) with sickle cell disease were randomized to placebo or ticagrelor at doses ranging from 15 mg to 45 mg twice daily based on body weight. In the ticagrelor group, median platelet inhibition was 35% pre-dose and 56% 2 hours post-dose at steady state.
No advantage of ticagrelor was found over placebo in terms of the impact on the incidence of vaso-occlusive crises.
The European Medicines Agency has waived the obligation to submit the results of studies with Brilinta in all subsets of the paediatric population with acute coronary syndrome (ACS) and history of myocardial infarction (MI) (see section 4.2 for information on paediatric use).
Pharmacokinetics.
The pharmacokinetics of ticagrelor are linear, and exposure to ticagrelor and its active metabolite (AR-C124910XX) is approximately dose proportional up to 1260 mg.
Absorption
Ticagrelor is rapidly absorbed with a median tmax of approximately 1.5 hours. The formation of the major circulating metabolite of ticagrelor, AR-C124910XX (also active), occurs rapidly with a median tmax of approximately 2.5 hours. After a single oral dose of 90 mg ticagrelor in fasted healthy volunteers, Cmax is 529 ng/mL and AUC is 3451 ng*h/mL. The metabolite to parent ratio is 0.28 for Cmax and 0.42 for AUC.
The pharmacokinetics of ticagrelor and AR-C124910XX in patients with a history of MI were generally similar to those observed in the ACS population. In the population pharmacokinetic analysis of the PEGASUS study, the median Cmax of ticagrelor was 391 ng/mL and AUC was 3801 ng*h/mL at steady state for the 60 mg dose. For ticagrelor 90 mg, the Cmax was 627 ng/mL and AUC was 6255 ng*h/mL at steady state.
The mean absolute bioavailability of ticagrelor was estimated to be 36%. Consuming a high-fat meal increased ticagrelor AUC by 21% and decreased Cmax of the active metabolite by 22%, but had no effect on Cmax of ticagrelor or AUC of the active metabolite. These changes are of minimal clinical significance; therefore, ticagrelor can be administered without regard to food intake. Ticagrelor and its active metabolite are substrates of P-gp.
Ticagrelor crushed tablets mixed with water, when administered orally or via nasogastric tube into the stomach, have comparable bioavailability to whole tablets with respect to AUC and Cmax of ticagrelor and its active metabolite. Initial exposure (0.5 and 1 hour post-dose) of crushed and water-mixed ticagrelor tablets was higher than initial exposure of whole tablets, with generally similar concentration profiles over time (2 to 48 hours).
Distribution
The steady-state volume of distribution of ticagrelor is 87.5 L. Ticagrelor and its active metabolite are extensively bound to human plasma proteins (> 99.0%).
Biotransformation
CYP3A4 is the main enzyme responsible for the metabolism of ticagrelor and the formation of the active metabolite, and their interactions with other CYP3A substrates range from activation to inhibition.
The major metabolite of ticagrelor is AR-C124910XX, which is also active, as demonstrated by in vitro binding to platelet ADP-receptor P2Y12. The systemic exposure of the active metabolite is approximately 30–40% of the systemic exposure of ticagrelor.
Breeding
The primary route of elimination of ticagrelor is hepatic metabolism. When radiolabeled ticagrelor is administered, the mean level of radioactivity recovered is approximately 84% (57.8% in feces and 26.5% in urine). The urinary recovery of ticagrelor and the active metabolite was less than 1% of the dose. The primary route of elimination of the active metabolite is most likely biliary secretion. The mean t1/2 of ticagrelor was approximately 7 hours and that of the active metabolite was 8.5 hours.
Special patient groups
Based on population pharmacokinetic analysis, elderly patients (aged ≥75 years) with ACS had higher exposures to ticagrelor (approximately 25% for both Cmax and AUC) and the active metabolite than younger patients. These differences are not considered clinically relevant (see section 4.2).
Children
Data on the use of ticagrelor in children with sickle cell disease are limited (see sections 4.2 and 5.1).
In HESTIA 3, patients aged 2 to 18 years with body weight ≥ 12 to ≤ 24 kg, > 24 to ≤ 48 kg, and > 48 kg received ticagrelor 15 mg children's lozenges at doses of 15, 30, and 45 mg twice daily, respectively. In a population pharmacokinetic analysis, the mean AUC of ticagrelor ranged from 1095 ng*h/mL to 1458 ng*h/mL and the mean Cmax ranged from 143 ng/mL to 206 ng/mL at steady state.
Sex
Higher exposures of ticagrelor and the active metabolite were observed in women than in men. These differences are not considered clinically relevant.
Kidney dysfunction
Ticagrelor exposure was approximately 20% lower and active metabolite exposure was approximately 17% higher in patients with severe renal impairment (creatinine clearance <30 mL/min) than in patients with normal renal function.
In patients with end-stage renal disease undergoing hemodialysis, the AUC and Cmax of ticagrelor 90 mg when administered on a non-hemodialysis day 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 dialyzed. The exposure of the active metabolite was increased to a lesser extent (AUC 13-14% and Cmax 17-36%). The inhibition of platelet aggregation (PAA) by ticagrelor was independent of dialysis in patients with end-stage renal disease and was similar in patients with normal renal function (see section 4.2).
Liver dysfunction
Cmax and AUC of ticagrelor were 12% and 23% higher, respectively, in patients with mild hepatic impairment compared to healthy volunteers, however, the effect of ticagrelor on the AUC was similar in both groups. No dose adjustment is required in patients with mild hepatic impairment. Ticagrelor has not been studied in patients with moderate or severe hepatic impairment, and there is no pharmacokinetic information in patients with moderate hepatic impairment. In patients with moderate or severe elevations in one or more liver function tests at baseline, plasma concentrations of ticagrelor were on average similar to or slightly higher than in patients without baseline abnormalities. No dose adjustment is required in patients with moderate hepatic impairment (see sections 4.2 and 4.4).
Ethnicity
In Asian patients, the mean bioavailability was 39% higher than in Caucasian patients. In Black patients, the bioavailability of ticagrelor was 18% lower than in Caucasian patients; in a clinical pharmacology study, ticagrelor exposure (Cmax and AUC) in Japanese subjects was approximately 40% (20% after weight adjustment) higher than in Caucasian patients. Drug exposure in Hispanic or Latino patients was similar to that in Caucasian patients.
Indication
The use of Brilinta concomitantly with acetylsalicylic acid (ASA) is indicated for the prevention of atherothrombotic events in adult patients with
- acute coronary syndrome (ACS) or
- history of myocardial infarction (MI) and high risk of developing atherothrombotic events (see sections “Method of administration and dosage” and “Pharmacodynamics”).
Contraindication
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 instructions for use” and “Pharmacokinetics”).
The concomitant use of ticagrelor with potent CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir) is contraindicated as their co-administration may lead to a significant increase in ticagrelor exposure (see section 4.5).
Interaction with other medicinal products and other types of interactions
Ticagrelor is primarily a substrate of CYP3A4 and a moderate inhibitor of CYP3A4. Ticagrelor is also a substrate of P-gp and a weak inhibitor of P-gp and may increase the exposure of P-gp substrates.
Effects of drugs and other agents on ticagrelor
Potent CYP3A4 inhibitors: Co-administration of ketoconazole and ticagrelor resulted in a 2.4- and 7.3-fold increase in ticagrelor Cmax and AUC, respectively. The Cmax and AUC of the active metabolite were decreased by 89% and 56%, respectively. Other potent CYP3A4 inhibitors (clarithromycin, nefazodone, ritonavir, and atazanavir) are expected to have a similar effect, and therefore concomitant use of potent CYP3A4 inhibitors with ticagrelor is contraindicated (see section 4.3).
Moderate CYP3A4 inhibitors: Co-administration of diltiazem with ticagrelor resulted in a 69% increase in ticagrelor Cmax and a 2.7-fold increase in AUC, and a 38% decrease in Cmax of the active metabolite, with no change in AUC. No effect of ticagrelor on diltiazem plasma levels was observed. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, erythromycin and fluconazole) are expected to have a similar effect and can therefore be co-administered with ticagrelor.
A 2-fold increase in ticagrelor exposure was observed after daily consumption of large quantities of grapefruit juice (3 × 200 ml). This increase in exposure is not expected to be clinically relevant for most patients.
CYP3A4 inducers
Co-administration of rifampicin with ticagrelor resulted in a 73% and 86% decrease in ticagrelor Cmax and AUC, respectively. The 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 decrease ticagrelor exposure. Co-administration of ticagrelor with strong CYP3A inducers may result in decreased ticagrelor exposure and efficacy, and therefore their co-administration with ticagrelor is not recommended.
Cyclosporine (P-gp and CYP3A inhibitor)
Co-administration of cyclosporine (600 mg) and ticagrelor resulted in a 2.3- and 2.8-fold increase in ticagrelor Cmax and AUC, respectively. In the presence of cyclosporine, the AUC of the active metabolite increased by 32% and Cmax decreased by 15%.
There are no data on the concomitant use of ticagrelor with other active substances that are also strong P-gp inhibitors and moderate CYP3A4 inhibitors (e.g. verapamil, quinidine) and may lead to increased ticagrelor exposure. If the combination cannot be avoided, the concomitant use of these medicinal products should be undertaken with caution.
Others
Clinical pharmacology interaction studies have shown that co-administration of ticagrelor with heparin, enoxaparin, and ASA or desmopressin does not affect the pharmacokinetics of ticagrelor or its active metabolite or ADP-induced platelet aggregation compared to ticagrelor alone. Medicinal products that affect hemostasis should be used with caution in combination with ticagrelor when clinically indicated.
In patients with ACS receiving morphine, there was a delay and reduction in the exposure of oral P2Y12 inhibitors, including ticagrelor and its active metabolites (35% reduction in ticagrelor exposure). This interaction may be related to decreased gastrointestinal (GI) motility and may apply to other opioids. The clinical significance of this interaction is unknown, but data suggest a possible reduction in the efficacy of ticagrelor in patients receiving ticagrelor and morphine concomitantly. In patients with ACS in whom morphine administration cannot be delayed and rapid P2Y12 inhibition is considered essential, the use of a parenteral P2Y12 inhibitor may be considered.
Effects of ticagrelor on other medicinal products
Drugs metabolized by CYP3A4
Simvastatin: Co-administration of ticagrelor with simvastatin increased simvastatin Cmax by 81% and AUC by 56%, and increased simvastatin acid Cmax by 64% and AUC by 52% (in isolated cases, a 2- to 3-fold increase was observed). Co-administration of ticagrelor with simvastatin at doses above 40 mg/day may result in adverse effects of simvastatin, which should be weighed against the potential benefit. No effect of simvastatin on ticagrelor plasma levels was observed. Ticagrelor may have a similar effect on lovastatin. Co-administration of ticagrelor with simvastatin or lovastatin at doses above 40 mg is not recommended.
Atorvastatin: Co-administration of atorvastatin and ticagrelor increased the Cmax of atorvastatin acid by 23% and AUC by 36%. Similar increases in AUC and Cmax were observed for all metabolites of atorvastatin acid. This increase is not considered clinically significant.
Similar effects on other statins metabolized by CYP3A4 cannot be excluded. Participants in the PLATO trial who received ticagrelor were taking a variety of statins, and 93% of these patients had no statin safety concerns.
Ticagrelor is a weak inhibitor of CYP3A4. Concomitant use of ticagrelor and CYP3A4 substrates with a narrow therapeutic index (e.g. cisapride or ergot alkaloids) is not recommended as ticagrelor may increase the exposure of these medicinal products.
Co-administration of ticagrelor increased digoxin Cmax by 75% and AUC by 28%. Mean trough digoxin levels increased by approximately 30% with co-administration of ticagrelor, and in some cases a maximum increase of 2-fold was observed. In the presence of digoxin, Cmax and AUC of ticagrelor and its active metabolite were unchanged. Therefore, appropriate clinical and/or laboratory monitoring is recommended when P-gp-dependent drugs with a narrow therapeutic index, such as digoxin, are co-administered with ticagrelor.
No effect of ticagrelor on cyclosporine blood concentrations was observed. The effect of ticagrelor on other P-gp substrates has not been studied.
Drugs metabolized by CYP2C9
Co-administration of ticagrelor with tolbutamide did not alter the plasma levels of either drug, indicating that ticagrelor is not a CYP2C9 inhibitor and is therefore unlikely to affect the CYP2C9-mediated metabolism of drugs such as warfarin and tolbutamide.
Rosuvastatin
Ticagrelor may affect the renal excretion of rosuvastatin, increasing the risk of accumulation of the latter. Although the exact mechanism is unknown, in some cases, concomitant use of ticagrelor and rosuvastatin has resulted in deterioration of renal function, increased CPK levels, and rhabdomyolysis.
Oral contraceptives
Co-administration of ticagrelor with levonorgestrel and ethinyl estradiol increased ethinyl estradiol exposure by approximately 20% but did not alter the pharmacokinetics of levonorgestrel. No clinically significant effect on oral contraceptive efficacy is expected when levonorgestrel and ethinyl estradiol are co-administered with ticagrelor.
Drugs that can cause bradycardia
Since cases of mostly asymptomatic ventricular asystole and bradycardia have been observed, caution should be exercised when ticagrelor is used concomitantly with medicinal products that can induce bradycardia (see section 4.4). However, in the PLATO study, no clinically significant adverse reactions (ADRs) were observed following concomitant administration of one or more medicinal products that can induce bradycardia (e.g., 96% of patients were receiving concomitant beta-blockers, 33% were receiving calcium channel blockers diltiazem and verapamil, and 4% were receiving digoxin).
Other concomitant therapy
In the PLATO study, ticagrelor was frequently used with ASA, PPIs, statins, beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) for long periods of time, as required by the patients' underlying conditions; and with heparin, low molecular weight heparin and intravenous GpIIb/IIIa inhibitors for short periods of time (see section 5.1). No evidence of clinically significant adverse drug interactions with these medicinal products was observed.
Co-administration of ticagrelor with heparin, enoxaparin, or desmopressin did not affect activated partial thromboplastin time (aPTT), activated clotting time (ACT), or factor Xa assays. However, caution should be exercised when ticagrelor is administered concomitantly with medicinal products that may affect haemostasis due to potential pharmacodynamic interactions.
Due to reports of abnormal skin bleeding with selective serotonin reuptake inhibitors (SSRIs) (e.g. paroxetine, sertraline and citalopram), caution is recommended when SSRIs are used with ticagrelor as this may increase the risk of bleeding.
Application features
Risk of bleeding
The use of ticagrelor in patients with a known increased risk of bleeding should be weighed against the benefit of the drug in preventing atherothrombotic events (see sections 4.8 and 5.1). Ticagrelor should be used with caution in the following patient groups, if clinically indicated:
Patients with a predisposition to bleeding (e.g., due to recent trauma or surgery, coagulation disorders, active or recent gastrointestinal bleeding) or at increased risk of trauma. Ticagrelor is contraindicated in patients with active pathological bleeding, a history of ICH, and patients with moderate to severe hepatic impairment (see section 4.3).
Patients taking concomitant medications that may increase the risk of bleeding (e.g. nonsteroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of ticagrelor administration.
The use of antifibrinolytic agents (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa may improve hemostasis. Ticagrelor may be resumed once the cause of bleeding has been identified and controlled.
Surgical intervention
Patients should be advised to inform their physicians and dentists that they are taking ticagrelor before planning any surgery and before taking any new medication.
In the PLATO study, in patients undergoing CABG, the ticagrelor group had a higher incidence of bleeding than the clopidogrel group when therapy was stopped 1 day before surgery, but major bleeding was observed at a similar rate to the clopidogrel group when therapy was stopped 2 or more days before surgery (see section 4.8). If the patient requires elective surgery and the antiplatelet effect is undesirable, ticagrelor should be discontinued 5 days before surgery (see section 5.2).
Patients who have had an ischemic stroke
Patients with ACS who have had an ischemic stroke can be treated with ticagrelor for up to 12 months (PLATO study).
The PEGASUS study did not include patients with a history of MI who had suffered an ischemic stroke. Therefore, due to the lack of data, treatment for more than one year in such patients is not recommended.
Liver dysfunction
Ticagrelor is contraindicated in patients with severe hepatic impairment (see sections 4.2 and 4.3). Experience with ticagrelor in patients with moderate hepatic impairment is limited and caution is recommended in such patients (see sections 4.2 and 4.4).
Patients at risk of bradycardia
Holter ECG monitoring has shown an increased incidence of episodes of predominantly asymptomatic ventricular asystole with ticagrelor compared with clopidogrel. Patients at increased risk of bradycardia (e.g., non-pacemaker patients with sick sinus syndrome, 2nd or 3rd degree atrioventricular block, or bradycardia-induced syncope) were not included in the pivotal 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 5.1).
Caution is advised when using ticagrelor with medicinal products that can induce bradycardia. However, in the PLATO study, there was no evidence of clinically significant ADRs following concomitant use of one or more medicinal products that can induce bradycardia (e.g., 96% of patients were taking beta-blockers, 33% were taking the calcium channel blockers diltiazem and verapamil, and 4% were taking digoxin) (see section 4.5).
In the Holter substudy of the PLATO trial, episodes of ventricular asystole lasting ≥3 seconds during the acute phase of ACS were more frequently observed with ticagrelor than with clopidogrel. The increase in the incidence of ventricular asystole with ticagrelor was more pronounced in patients with CHF than in the general study population during the acute phase of ACS, but this difference was not observed after one month of treatment with ticagrelor or compared to clopidogrel. No adverse clinical outcomes associated with this difference (including syncope or pacemaker implantation) were observed in this patient population (see section 5.2).
In the post-marketing period, cases of bradyarrhythmia and atrioventricular block have been reported in patients taking ticagrelor (see sections "Adverse reactions"), mainly in patients with ACS, in whom cardiac ischemia and concomitant medications that reduce heart rate or affect cardiac conduction are potential complicating factors. Before adjusting treatment, it is necessary to evaluate the clinical condition of the patient and concomitant medications as potential causes.
Dyspnea
In patients receiving ticagrelor,
