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BRIEF SUMMARY of PRESCRIBING INFORMATION
For full Prescribing Information, see package insert.
WARNING: (A) BLEEDING RISK, (B) ASPIRIN DOSE AND BRILINTA EFFECTIVENESS
A. BLEEDING RISK
• BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding [see
Warnings and Precautions (5.1) and Adverse Reactions (6.1) in full Prescribing Information].
• Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial
hemorrhage [see Contraindications (4.1, 4.2) in full Prescribing Information].
• Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft
surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery [see
Warnings and Precautions (5.1) in full Prescribing Information].
• Suspect bleeding in any patient who is hypotensive and has recently undergone coronary
angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in
the setting of BRILINTA [see Warnings and Precautions (5.1) in full Prescribing Information].
• If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases
the risk of subsequent cardiovascular events [see Warnings and Precautions (5.5) in full
Prescribing Information].
B. ASPIRIN DOSE AND BRILINTA EFFECTIVENESS
• Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should
be avoided. After any initial dose, use with aspirin 75-100 mg per day [see Warnings and
Precautions (5.2) and Clinical Studies (14) in full Prescribing Information].
INDICATIONS AND USAGE
Acute Coronary Syndromes
BRILINTA is a P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in
patients with acute coronary syndrome (ACS) (unstable angina, non-ST elevation myocardial infarction, or
ST elevation myocardial infarction). BRILINTA has been shown to reduce the rate of a combined endpoint
of cardiovascular death, myocardial infarction or stroke compared to clopidogrel. The difference between
treatments was driven by CV death and MI with no difference in stroke. In patients treated with PCI, it also
reduces the rate of stent thrombosis [see Clinical Studies (14) in full Prescribing Information].
BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above
100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin above 100 mg daily
[see Warnings and Precautions (5.2) and Clinical Studies (14) in full Prescribing Information].
DOSAGE AND ADMINISTRATION
Initiate BRILINTA treatment with a 180 mg (two 90 mg tablets) loading dose and continue treatment with
90 mg twice daily.
After the initial loading dose of aspirin (usually 325 mg), use BRILINTA with a daily maintenance dose of
aspirin of 75-100 mg.
ACS patients who have received a loading dose of clopidogrel may be started on BRILINTA.
BRILINTA can be administered with or without food.
A patient who misses a dose of BRILINTA should take one 90 mg tablet (their next dose) at its scheduled time.
Administration Options
For patients who are unable to swallow the tablet(s) whole, BRILINTA tablets can be crushed, mixed with
water and drunk immediately. The glass should be refilled with water, stirred and the contents drunk.
The mixture can also be administered via a nasogastric tube (CH8 or greater). It is important to flush the
nasogastric tube through with water after administration of the mixture [see Clinical Pharmacology (12.3)
in full Prescribing Information].
CONTRAINDICATIONS
History of Intracranial Hemorrhage
BRILINTA is contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high
risk of recurrent ICH in this population [see Clinical Studies (14) in full Prescribing Information].
Active Bleeding
BRILINTA is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial
hemorrhage [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) in full Prescribing Information].
Severe Hepatic Impairment
BRILINTA is contraindicated in patients with severe hepatic impairment because of a probable increase
in exposure, and it has not been studied in these patients. Severe hepatic impairment increases the risk
o f bleeding because of reduced synthesis of coagulation proteins [see Clinical Pharmacology (12.3) in full
Prescribing Information].
Hypersensitivity
BRILINTA is contraindicated in patients with hypersensitivity (e.g. angioedema) to ticagrelor or any
component of the product [see Adverse Reactions (6.2) in full Prescribing Information].
WARNINGS AND PRECAUTIONS
General Risk of Bleeding
Drugs that inhibit platelet function including BRILINTA increase the risk of bleeding. BRILINTA increased
the overall risk of bleeding (Major + Minor) to a somewhat greater extent than did clopidogrel. The increase
was seen for non-CABG-related bleeding, but not for CABG-related bleeding. Fatal and life-threatening
bleeding rates were not increased [see Adverse Reactions (6.1) in full Prescribing Information].
In general, risk factors for bleeding include older age, a history of bleeding disorders, performance of
percutaneous invasive procedures, and concomitant use of medications that increase the risk of bleeding
(e.g., anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic nonsteroidal antiinflammatory drugs [NSAIDS]).
When possible, discontinue BRILINTA five days prior to surgery. Suspect bleeding in any patient who is
hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures,
even if the patient does not have any signs of bleeding.
If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of
subsequent cardiovascular events [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) in
full Prescribing Information].
Concomitant Aspirin Maintenance Dose
In PLATO, use of BRILINTA with maintenance doses of aspirin above 100 mg decreased the effectiveness
of BRILINTA. Therefore, after the initial loading dose of aspirin (usually 325 mg), use BRILINTA with a
maintenance dose of aspirin of 75-100 mg [see Dosage and Administration (2) and Clinical Studies (14)
in full Prescribing Information].
Moderate Hepatic Impairment
BRILINTA has not been studied in patients with moderate hepatic impairment. Consider the risks and
benefits of treatment, noting the probable increase in exposure to ticagrelor.
Dyspnea
In PLATO, dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients taking
clopidogrel. Dyspnea was usually mild to moderate in intensity and often resolved during continued
treatment, but occasionally required discontinuation (0.9% of patients taking BRILINTA versus 0.1% of
patients taking clopidogrel). If a patient develops new, prolonged, or worsened dyspnea during treatment
with BRILINTA, exclude underlying diseases that may require treatment. If dyspnea is determined to be
related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption. In the case of
intolerable dyspnea requiring discontinuation of BRILINTA, consider prescribing another antiplatelet agent.
In a substudy, 199 patients from PLATO underwent pulmonary function testing irrespective of whether
they reported dyspnea. There was no significant difference between treatment groups for FEV1. There
was no indication of an adverse effect on pulmonary function assessed after one month or after at least
6 months of chronic treatment.
Discontinuation of BRILINTA
Avoid interruption of BRILINTA treatment. If BRILINTA must be temporarily discontinued (e.g., to treat
bleeding or for elective surgery), restart it as soon as possible. Discontinuation of BRILINTA will increase
the risk of myocardial infarction, stent thrombosis, and death.
Strong Inhibitors of Cytochrome CYP3A
Ticagrelor is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors, such as atazanavir,
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin
and voriconazole [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) in full Prescribing Information].
Cytochrome CYP3A Potent Inducers
Avoid use with potent CYP3A inducers, such as rifampin, phenytoin, carbamazepine, and phenobarbital
[see Drug Interactions (7.2) and Clinical Pharmacology (12.3) in full Prescribing Information].
ADVERSE REACTIONS
The following adverse reactions are also discussed elsewhere in the labeling:
Dyspnea [see Warnings and Precautions (5.4) in full Prescribing Information]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
BRILINTA has been evaluated for safety in more than 10000 patients, including more than 3000 patients
treated for more than 1 year.
Bleeding
PLATO used the following bleeding severity categorization:
• Major bleed – fatal/life-threatening. Any one of the following: fatal; intracranial; intrapericardial bleed
with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring
pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin
(Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells
(PRBCs)) for bleeding.
• Major bleed – other. Any one of the following: significantly disabling (e.g., intraocular with permanent
vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL;
transfusion of 2-3 units (whole blood or PRBCs) for bleeding.
• Minor bleed. Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to
medical facility for packing).
• Minimal bleed. All others (e.g., bruising, bleeding gums, oozing from injection sites, etc.) not requiring
intervention or treatment.
Figure 1 shows major bleeding events over time. Many events are early, at a time of coronary angiography,
PCI, CABG, and other procedures, but the risk persists during later use of antiplatelet therapy.
Figure 1 - Kaplan-Meier estimate of time to first PLATO-defined ‘Total Major’ bleeding event
15
Kaplan–Meier Percentage (%)
BRILINTA® (ticagrelor) tablets, for oral use
Ticagrelor (T) 961/9235
Clopidogrel (C) 929/9186
11.58%
11.20%
10
5
T vs C: HR (95% CI) = 1.04 (0.95, 1.13), p–value: 0.434
0
0
N at risk
T
9235
C
9186
60
120
180
240
300
360
Days from First Study Drug Dose
7246
7305
6826
6930
6545
6670
5129
5209
3783
3841
3433
3479
Annualized rates of bleeding are summarized in Table 1 below. About half of the bleeding events were in
the first 30 days.
Table 1 - Non-CABG related bleeds (KM%)
BRILINTA
Clopidogrel
N=9235
N=9186
Total (Major + Minor)
8.7
7.0
Major
4.5
3.8
Fatal/Life-threatening
2.1
1.9
Fatal
0.2
0.2
Intracranial (Fatal/Life-threatening)
0.3
0.2
As shown in Table 1, BRILINTA was associated with a somewhat greater risk of non-CABG bleeding
than was clopidogrel. No baseline demographic factor altered the relative risk of bleeding with BRILINTA
compared to clopidogrel.
In PLATO, 1584 patients underwent CABG surgery. The percentages of those patients who bled are shown
in Table 2. Rates were very high but similar for BRILINTA and clopidogrel.