Brilinta, 56 pcs., 90 mg, film-coated tablets

Description of the drug BRILINTA® ° (BRILINTA®)

Ticagrelor should be used with caution in patients with a predisposition to bleeding (eg, recent trauma, recent surgery, bleeding disorders, active or recent gastrointestinal bleeding); in patients with concomitant therapy with drugs that increase the risk of bleeding (i.e. NSAIDs, oral anticoagulants and/or fibrinolytics) within 24 hours before taking ticagrelor; in patients with an increased risk of developing bradycardia (for example, patients with CVS without a pacemaker, with AV blockade of the second or third degree; syncope associated with bradycardia) due to insufficient experience of clinical use; together with drugs that cause bradycardia; in patients with bronchial asthma and COPD (if the patient reports a new episode of shortness of breath, prolonged shortness of breath or worsening shortness of breath, an examination should be carried out, and in case of intolerance, treatment with ticagrelor should be discontinued).

With the use of ticagrelor, an increase in serum creatinine is possible, and therefore renal function should be assessed in accordance with routine clinical practice, paying particular attention to patients aged 75 years and older, patients with moderate to severe renal insufficiency, patients receiving therapy with angiotensin receptor antagonists.

Caution is required when using ticagrelor in patients with a history of hyperuricemia or gouty arthritis. As a preventive measure, the use of ticagrelor should be avoided in patients with hyperuricemic nephropathy.

The combined use of ticagrelor and acetylsalicylic acid in a high maintenance dose (more than 300 mg) is not recommended.

When using digoxin and ticagrelor together, careful clinical and laboratory monitoring (heart rate, and, if clinically indicated, also ECG and digoxin concentration in the blood) is recommended. There are no data on the combined use of ticagrelor with strong P-glycoprotein inhibitors (for example, verapamil, quinidine and cyclosporine), so simultaneous therapy with these drugs should be carried out with caution.

In patients with acute coronary syndrome treated with ticagrelor and acetylsalicylic acid, there was an increased risk of non-CABG bypass major and medically alert bleeding, but no increased risk of fatal/life-threatening bleeding.

When using ticagrelor, the benefit of preventing atherothrombotic events should be assessed against the risk in patients with an increased risk of bleeding.

Ticagrelor may inhibit transfused platelets in the blood.

Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa may enhance hemostasis. Once the cause of the bleeding has been determined and it has been controlled, ticagrelor therapy can be resumed.

If the patient is undergoing elective surgery and the antithrombotic effect is not desired, then ticagrelor should be discontinued 7 days before surgery.

When planning coronary artery bypass surgery, the risk of bleeding increases if ticagrelor is discontinued less than 96 hours before the procedure.

Impact on the ability to drive vehicles and operate machinery

Ticagrelor does not affect or only slightly affects the ability to drive vehicles and use machines. Dizziness and confusion have been reported during treatment for acute coronary syndrome. In case of development of these phenomena, patients should be careful when driving a car and other mechanisms.

Compound

Directions for use and doses

Inside.

Brilinta® can be taken with or without food.

The use of Brilinta® should be started with a single loading dose of 180 mg (2 tablets of 90 mg each) and then continued at 90 mg 2 times a day.

Patients taking Brilinta® should take acetylsalicylic acid from 75 to 150 mg daily with continuous use (see “Pharmacodynamics”), unless there are specific contraindications.

Interruptions in therapy should be avoided. A patient who has missed a dose of Brilinta® should take only 1 tablet. 90 mg (next dose) at scheduled time.

If necessary, patients taking clopidogrel can be switched to taking Brilinta® (see “Pharmacodynamics”).

It is recommended to carry out therapy with Brilinta® for 12 months, except in cases of clinical need for early discontinuation of the drug (see “Pharmacodynamics”). Data on the use of ticagrelor for more than 12 months are limited. In patients with acute coronary syndrome, early discontinuation of any antiplatelet therapy, including Brilinta®, may increase the risk of cardiovascular death or myocardial infarction as a result of the underlying disease (see "Special Instructions"). Premature discontinuation of the drug should be avoided.

Elderly patients.

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

Patients with renal failure.

There is no need to adjust the dose of the drug in patients with renal failure (see “Pharmacokinetics”). There is no information on the use of Brilinta® in patients on hemodialysis, therefore its use in these patients is not indicated.

Patients with liver failure.

There is no need to adjust the dose of the drug in patients with mild hepatic impairment. Brilinta® has not been studied in patients with moderate or severe hepatic impairment, therefore its use in these patients is contraindicated (see “Pharmacokinetics”, “Contraindications”).

Children.

The safety and effectiveness of Brilinta® in children under 18 years of age for its approved indication in adults has not been established.

Side effects

According to the PLATO

, the most common adverse events reported in patients taking ticagrelor were shortness of breath, bruises and nosebleeds.

Adverse reactions are classified by frequency and organ system class. The frequency of adverse reactions is determined using the following symbols: very often (≥1/10); often (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000).

Table

Adverse drug reactions by incidence and organ system class ( SOC

)

a

Hyperuricemia, increased concentration of uric acid in the blood;
see Laboratory Abnormalities
below.

b

Cerebral hemorrhage, intracranial hemorrhage, hemorrhagic stroke.

c

Dyspnea, dyspnea on exertion, dyspnea at rest, dyspnea at night.

d

Gastrointestinal bleeding, rectal bleeding, intestinal bleeding, melena, positive occult blood test.

e

Bleeding from a gastrointestinal ulcer, bleeding from a gastric ulcer, bleeding from a duodenal ulcer, bleeding from a peptic ulcer.

f

Subcutaneous hematoma, cutaneous and subcutaneous hemorrhages, petechiae.

g

Contusion, hematoma, ecchymosis, increased tendency to bruise, traumatic hematoma.

h

Hematuria, bleeding from the urinary tract.

i

Bleeding from the site of vascular puncture, hematoma at the site of vascular puncture, bleeding from the injection site, bleeding from the puncture site, bleeding from the catheterization site.

Description of some adverse reactions

Bleeding

In the PLATO

The following definitions of bleeding were used:

— Major lethal/life-threatening bleeding:

fatal or intracranial hemorrhage, or bleeding into the pericardial cavity with cardiac tamponade, or hypovolemic shock, or severe hypotension caused by bleeding and requiring the use of vasoconstrictors or surgery, or clinically obvious bleeding accompanied by a decrease in hemoglobin level by more than 50 g/l or requiring transfusion of 4 or more units of whole blood or red blood cells;

— major other bleeding:

causing significant disability of the patient (for example, intraocular hemorrhage with irreversible loss of vision) or clinically obvious bleeding, accompanied by a decrease in hemoglobin levels by 30-50 g/l or requiring transfusion of 2-3 units of whole blood or red blood cells;

— minor bleeding:

requires medical intervention to stop or treat bleeding (eg, nosebleeds requiring a hospital visit for nasal packing).

Brilinta® and clopidogrel did not differ in the incidence of major bleeding overall according to PLATO

(11.6%/year and 11.2%/year, respectively), fatal/life-threatening bleeding according to
PLATO
(5.8%/year in both groups).
However, the incidence of combined major and minor bleeding according to PLATO
was higher in the ticagrelor group (16.1%) compared with clopidogrel (14.6%, p = 0.0084).

Age, sex, weight, race, geographic region, comorbidities, concomitant medications, and medical history, including prior stroke and transient ischemic attack, did not affect the incidence of overall and nonprocedure-related major bleeding according to PLATO

. No groups were identified with an increased risk of bleeding.

Bleeding associated with CABG.

PLATO
study, 42% of 1584 patients (12% of the cohort) undergoing CABG experienced major fatal/life-threatening bleeding, with no significant differences in both treatment groups. Fatal bleeding associated with CABG surgery occurred in 6 patients in each treatment group.

Non-CABG-related bleeding and non-procedure-related bleeding.

Brilinta® and clopidogrel did not differ in the incidence of major fatal/life-threatening bleeding not related to CABG according to
PLATO
, but Brilinta® was more likely to develop major bleeding overall according to the
PLATO
(4.5%/year compared with 3.8%/year; p=0.0264). When removing cases of CABG-related bleeding, there were more bleeding events in the ticagrelor group (3.1%/year) than in the clopidogrel group (2.3%/year; p=0.0058). Discontinuation due to non-procedure-related bleeding was more common with ticagrelor (2.9%) compared with clopidogrel (1.2%, p<0.001).

Intracranial hemorrhage.

There were more non-procedure-related intracranial hemorrhages in the ticagrelor group (n=27 bleedings in 26 patients, 0.3%) than in the clopidogrel group (n=14 bleedings, 0.2%), of which 11 bleedings were associated with ticagrelor. and 1 on clopidogrel were fatal. However, there was no significant difference in the total number of fatal bleeding events.

Dyspnea

Adverse events in the form of dyspnea (shortness of breath, dyspnea at rest, dyspnea on exercise, paroxysmal nocturnal dyspnea and nocturnal dyspnea) in combination developed in 13.8% of patients receiving Brilinta® and in 7.8% of patients taking clopidogrel. The researchers found that 2.2% of patients in the ticagrelor group had treatment-related shortness of breath. Most cases of shortness of breath were mild or moderate in intensity and occurred as single episodes immediately after initiation of therapy.

Approximately 30% of all cases of shortness of breath resolved within 7 days. Dyspnea developed more often in older patients, in patients with congestive heart failure, COPD or bronchial asthma at the beginning of the study. Brilinta® was discontinued in 0.9% of patients due to shortness of breath. Dyspnea was not associated with the development of new or worsening of existing heart or lung disease (see "Special Instructions").

Brilinta® does not affect respiratory function parameters.

Deviations in laboratory values

Serum creatinine concentrations increased by more than 30% in 25.5% of patients and by more than 50% in 8.3% of patients receiving Brilinta®. An increase in creatinine of more than 50% was more common in patients over 75 years of age, patients with severe renal impairment at study entry, and patients receiving angiotensin receptor antagonist therapy. The overall incidence of renal adverse events was 4.9% in patients on ticagrelor, but investigators attributed them to the drug in 0.6% of cases.

Serum uric acid concentrations increased above the ULN in 22% of patients receiving Brilinta®. Adverse events associated with hyperuricemia were observed in 0.5% of cases with ticagrelor, of which the researchers associated 0.05% of cases with ticagrelor. Gouty arthritis occurred in 0.2% of patients treated with ticagrelor, none of which were considered drug-related by the investigator.

Drug interactions

Impact of other medicinal products on Brilinta®

Drugs metabolized by the CYP3A4 isoenzyme

CYP3A4 inhibitors

Potent CYP3A4 inhibitors: Coadministration of ketoconazole with ticagrelor increases the Cmax and AUC of ticagrelor by 2.4 and 7.3 times, respectively. Cmax and AUC of the active metabolite are reduced by 89 and 56%, respectively. Other strong CYP3A4 inhibitors (clarithromycin, nefazodone, ritonavir and atazanavir) will have the same effects, so their combined use with Brilinta® is contraindicated (see “Contraindications”, “Special Instructions”).

Moderate inhibitors of CYP3A4: co-administration of diltiazem with ticagrelor increases the Cmax of ticagrelor by 69% and the AUC by 2.7 times and reduces the Cmax of the active metabolite by 38%, and the AUC does not change. Ticagrelor does not affect plasma concentrations of diltiazem. Other moderate CYP3A4 inhibitors (eg amprenavir, aprepitant, erythromycin, fluconazole) can be co-administered with Brilinta.

CYP3A4 inducers

Co-administration of rifampicin with ticagrelor reduced the Cmax and AUC of ticagrelor by 73 and 86%, respectively. The Cmax of the active metabolite does not change, and the AUC decreases by 46%. Other CYP3A4 inducers (eg dexamethasone, phenytoin, carbamazepine and phenobarbital) are likely to reduce the exposure of Brilinta. Potent inducers of CYP3A4 may reduce the exposure and effectiveness of Brilint®.

Other

According to the results of pharmacological interaction studies, the concomitant use of ticagrelor with heparin, enoxaparin and acetylsalicylic acid or desmopressin does not affect the pharmacokinetics of ticagrelor, its active metabolite and ADP-dependent platelet aggregation. If there are clinical indications for prescribing drugs that affect hemostasis, they should be used with caution in combination with Brilinta® (see “Contraindications”, With caution

).

There are no data on the combined use of Brilinta® with potent P-gp inhibitors (for example, verapamil, quinidine and cyclosporine), which may increase the exposure of ticagrelor. If their combined use cannot be avoided, it should be used with caution (see “Contraindications”, With caution

, "Special instructions").

Effect of Brilinta® on other drugs

Drugs metabolized by the CYP3A4 isoenzyme

Simvastatin: Concomitant use of ticagrelor and simvastatin increases the Cmax and AUC of simvastatin by 81 and 56%, respectively, and increases the Cmax and AUC of simvastatin acid by 64 and 52%, respectively, with some cases increasing these values ​​by 2-3 times. Concomitant use of simvastatin at a dose above 40 mg/day with ticagrelor may lead to the development of side effects of simvastatin, and the potential risk-benefit ratio must be assessed. The combined use of Brilinta® with simvastatin and lovastatin at a dose exceeding 40 mg is not recommended.

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

Similar effects to statins metabolized by CYP3A4 cannot be excluded. In the PLATO

Patients receiving ticagrelor took various statins, with no safety concerns reported in 93% of patients taking this group of drugs.

Ticagrelor is a moderate CYP3A4 inhibitor. Concomitant use of Brilint® with CYP3A4 substrates with a narrow therapeutic index (for example, cisapride or ergot alkaloids) is not recommended, because Ticagrelor may increase the exposure of these drugs.

Drugs metabolized by the CYP2C9 isoenzyme

Concomitant use of ticagrelor and tolbutamide did not change plasma concentrations of either drug, indicating that ticagrelor is not a CYP2C9 inhibitor and is unlikely to affect the CYP2C9-mediated metabolism of drugs like warfarin and tolbutamide.

Oral contraceptives

Coadministration of ticagrelor, levonorgestrel and ethinyl estradiol increases the exposure of ethinyl estradiol by approximately 20% but does not affect the pharmacokinetics of levonorgestrel. No clinically significant effect on the effectiveness of contraception is expected with the simultaneous use of levonorgestrel, ethinyl estradiol and Brilinta®.

P-gp substrates (including digoxin and cyclosporine)

Concomitant use of digoxin with ticagrelor increases the Cmax and AUC of digoxin by 75 and 28%, respectively. When taken together with ticagrelor, on average, the lowest level of digoxin increased by 30%, in some individual cases by two times. Cmax and AUC of ticagrelor did not change with digoxin. Therefore, it is recommended to carry out appropriate clinical and/or laboratory monitoring during simultaneous use of Brilinta® and P-gp-dependent drugs with a narrow therapeutic index, such as digoxin and cyclosporine.

Other concomitant therapy

When using Brilinta® together with drugs that can cause bradycardia, caution should be exercised. However, in the PLATO

no clinically significant adverse events were observed when used concomitantly with one or more drugs that can cause bradycardia (for example, 96% - beta-blockers, 33% - calcium channel blockers, including diltiazem and verapamil, and 4% - digoxin).

In the PLATO

Brilinta® was predominantly prescribed in combination with acetylsalicylic acid, proton pump inhibitors, statins, β-blockers, ACE inhibitors and angiotensin receptor antagonists as part of long-term administration, as well as with heparin, low molecular weight heparins, glycoprotein IIb/IIIa receptor inhibitors for intravenous administration. within short-term therapy. The results of these studies did not reveal clinically significant adverse interactions.

Co-administration of Brilinta® with heparin, enoxaparin or desmopressin had no effect on aPTT, activated clotting time and factor Xa test, however, due to potential pharmacodynamic interactions, caution is required when combined with drugs that affect hemostasis.

Due to reports of subcutaneous hemorrhage with selective serotonin reuptake inhibitors (eg paroxetine, sertraline and citalopram), caution is recommended when co-administering them with Brilinta.

Pharmacodynamics

Mechanism of action

Brilinta® contains ticagrelor, a member of the cyclopentyltriazolopyrimidine chemical class, which is a selective and reversible antagonist of the P2Y12 ADP receptor and can prevent ADP-mediated platelet activation and aggregation. Ticagrelor is active when taken orally and interacts reversibly with the platelet P2Y12 ADP receptor. Ticagrelor does not interact with the binding site of ADP itself, but its interaction with the platelet P2Y12 receptor for ADP prevents signal transduction.

Start of action

In patients with stable coronary artery disease, while using acetylsalicylic acid, ticagrelor begins to act quickly, which is confirmed by the results of determining the average value of platelet aggregation inhibition (IAT): 0.5 hours after taking a loading dose of 180 mg of ticagrelor, the average IAT value is approximately 41%, the maximum the IAT value - 89% - is achieved 2-4 hours after taking the drug and is maintained for 2-8 hours. In 90% of patients, the final IAT value - more than 70% - is achieved 2 hours after taking the drug.

End of action

When planning coronary artery bypass grafting (CABG), the risk of bleeding increases if ticagrelor is discontinued less than 96 hours before the procedure.

Data on switching from one drug to another

Switching from clopidogrel to ticagrelor resulted in a 26.4% increase in the absolute value of the IAT, and a change in therapy from ticagrelor to clopidogrel resulted in a decrease in the absolute value of the IAT by 24.5%. It is possible to change therapy from clopidogrel to ticagrelor without interrupting the antithrombotic effect.

Clinical effectiveness

In the PLATO

(
PLATelet Inhibition and Patient Outcomes
) enrolled 18,624 patients who developed symptoms of unstable angina, non-ST-segment elevation myocardial infarction, or ST-segment elevation myocardial infarction in the past 24 hours and were treated conservatively or with percutaneous coronary artery disease. intervention (PCI), or CABG (see “Indications”). This study compared ticagrelor 90 mg twice daily with daily acetylsalicylic acid therapy to clopidogrel 75 mg once daily for effectiveness in preventing the composite endpoint of cardiovascular death, myocardial infarction, or stroke through its effect on cardiovascular disease. vascular deaths and myocardial infarction. The loading dose was 300 mg clopidogrel (a dose of 600 mg was also allowed during PCI) or 180 mg ticagrelor.

The effect of ticagrelor appeared early (on the 30th day, an absolute risk reduction (ARR) of 0.6% and a relative risk reduction (RRR) of 12%), with the maintenance of a constant effect of therapy for 12 months, which led to an RRR of 1. 9% and COP by 16% during the year.

Brilinta® reduces the relative risk of the composite endpoint (composite of cardiovascular death, heart attack and stroke) in patients with unstable angina, non-ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction by 16% (hazard ratio (HR) 0.84 ; 95% confidence interval (CI) 0.77–0.92; p=0.0003), cardiovascular death by 21% (RR 0.79; 95% CI 0.69–0.91; p=0 .0013), myocardial infarction by 16% (RR 0.84; 95% CI 0.75–0.95; p=0.0045).

The effectiveness of Brilinta® is shown in various subgroups of patients, regardless of body weight, gender, history of diabetes mellitus, transient ischemic attack or non-hemorrhagic stroke, revascularization, concomitant therapy (including heparin, glycoprotein IIb/IIIa receptor inhibitors (see “Interactions”) ), final diagnosis (non-ST-segment elevation myocardial infarction, ST-segment elevation myocardial infarction, and unstable angina) and treatment planned at randomization (invasive or conservative).

Additional analysis suggested a possible relationship with the dose of acetylsalicylic acid, which was expressed in the fact that reduced effectiveness was observed when taking Brilinta® in combination with increased doses of acetylsalicylic acid. The recommended dose of acetylsalicylic acid for continuous use in combination with Brilinta® is 75–150 mg (see “Method of administration and dosage”, “Special instructions”).

Brilinta® demonstrated a statistically significant RR for the composite criterion of death from cardiovascular causes, myocardial infarction and stroke in patients with acute coronary syndrome who were scheduled for invasive intervention (RR 16%, RR 1.7%, p=0.0025) . In an exploratory analysis, Brilinta® also demonstrated an ARR for the primary endpoint in patients with acute coronary syndrome treated with conservative therapy (ARR 15%, ARR 2.3%, nominal p=0.0444). In patients undergoing stenting, ticagrelor showed a reduction in the incidence of stent thrombosis (RR 32%, ARR 0.6%, nominal p=0.0123).

Brilinta® caused a statistically significant RR of 16% (RR 2.1%) for the composite criterion of death from all causes, myocardial infarction and stroke.

The COP of death from all causes while taking Brilinta® was 22% with a nominal significance level of p = 0.0003 and ARR was 1.4%.

Cumulative criterion for combined effectiveness and safety

Pooled outcome measure of combined efficacy and safety (cardiovascular death, myocardial infarction, stroke, or major bleeding as defined by the PLATO

) confirms that within 12 months after an acute coronary syndrome, the beneficial effect of ticagrelor is not counteracted by major bleeding events (RR 8%, ARR 1.4%, OP 0.92; p=0.0257).

Use during pregnancy and breastfeeding

There are no or limited data on the use of Brilinta® in pregnant women.

In animal studies, ticagrelor caused a slight decrease in maternal weight gain, a decrease in the viability of the newborn and its body weight, and growth retardation. Brilinta® is not recommended during pregnancy.

Available pharmacodynamic and toxicological data in animals have shown that ticagrelor and its active metabolites are excreted in milk. A risk to the newborn/infant cannot be excluded. It is not recommended to use Brilinta® while breastfeeding.

Pharmacokinetics

Ticagrelor exhibits linear pharmacokinetics, and the exposure of ticagrelor and the active metabolite ( AR-C124910XX

) is approximately proportional to the dose up to 1260 mg.

Absorption

Ticagrelor is rapidly absorbed with an average Tmax of approximately 1.5 hours. Formation of the main metabolite circulating in the blood AR-C124910XX

(also active) from ticagrelor occurs quickly with an average Tmax of approximately 2.5 hours. After taking ticagrelor on an empty stomach at a dose of 90 mg, Cmax is 529 ng/ml and AUC is 3451 ng·h/ml.

The average absolute bioavailability of ticagrelor is 36%. Ingestion of a high-fat meal does not affect the Cmax of ticagrelor or the AUC of the active metabolite, but leads to a 21% increase in the AUC of ticagrelor and a 22% decrease in the Cmax of the active metabolite. These small changes are of minimal clinical significance; therefore, ticagrelor can be administered without regard to food intake.

Distribution

Vss of ticagrelor is 87.5 l. Ticagrelor and the active metabolite are actively bound to plasma proteins (>99%).

Metabolism

CYP3A4 is the main isoenzyme responsible for the metabolism of ticagrelor and the formation of the active metabolite, and their interactions with other CYP3A substrates range from activation to inhibition. Ticagrelor and its active metabolite are weak inhibitors of P-glycoprotein (P-gp).

The main metabolite of ticagrelor is AR-C124910XX

, which is also active, as confirmed by the results of assessing binding to the platelet P2Y12 ADP receptor
in vitro
. Systemic exposure of the active metabolite is approximately 30–40% of the exposure of ticagrelor.

Excretion

The main route of elimination of ticagrelor is through hepatic metabolism. When isotope-labeled ticagrelor is administered, on average, approximately 57.8% of the radioactivity is excreted in feces and 26.5% in urine. Excretion of ticagrelor and the active metabolite in urine is less than 1% of the dose. The active metabolite is mainly excreted in bile. The average half-life of ticagrelor and the active metabolite was 7 and 8.5 hours, respectively.

Special populations of patients

Elderly patients.

Elderly patients (aged 75 years and older) had higher exposure to ticagrelor (Cmax and AUC approximately 25% higher) and the active metabolite compared to younger patients. These differences are not considered clinically significant (see "Dosage and Administration").

Children.

There are no data on the use of ticagrelor in children.

Floor.

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

Ethnic groups.

The average bioavailability of the drug in Asian patients is 39% higher than in Caucasians. The bioavailability of Brilinta® is 18% lower in black patients compared to Caucasian patients.

Kidney failure.

Exposure to ticagrelor and the active metabolite is approximately 20% lower in patients with severe renal impairment (Cl creatinine <30 ml/min) compared to patients with normal renal function (see "Dosage and Administration").

Liver failure.

Ticagrelor Cmax and AUC were 12% and 23% higher in patients with mild hepatic impairment compared to healthy volunteers. Ticagrelor has not been studied in patients with moderate or severe hepatic impairment and its use in these patients is contraindicated (see Dosage and Administration, Contraindications).

Overdose

Ticagrelor is well tolerated in a single dose of up to 900 mg.

Symptoms:

in the only dose-escalation study, GI adverse effects were dose-limiting. Other clinically significant adverse events that could occur with overdose were shortness of breath and ventricular pauses.

In case of overdose, it is recommended to monitor for these adverse effects and perform ECG monitoring.

Treatment:

in case of overdose, symptomatic therapy should be carried out in accordance with local standards. Brilinta® is not excreted during hemodialysis (see “Special Instructions”), the antidote is unknown.

Due to platelet inhibition, an increase in the duration of bleeding is the expected pharmacological effect of overdose with Brilinta®, therefore, if bleeding develops, appropriate supportive measures should be taken.