BRILINTA (ticagrelor 60 mg) Dailymed

• • ACS or History of MI
  • •Initiate treatment with 180 mg oral loading dose of BRILINTA. Then administer 90 mg twice daily during the first year. After one year, administer 60 mg twice daily. (2.2)
• • Patients with CAD and No Prior Stroke or MI
  • •Administer 60 mg BRILINTA twice daily. (2.3)
• • Acute Ischemic Stroke
  • •Initiate treatment with a 180 mg loading dose of BRILINTA then continue with 90 mg twice daily for up to 30 days. (2.4)

Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg. (2) However, in patients who have undergone PCI, consider single antiplatelet therapy with BRILINTA based on the evolving risk for thrombotic versus bleeding events. (2.2)

2.1 General Instructions

Advise patients who miss a dose of BRILINTA to take their next dose at its scheduled time.

For patients who are unable to swallow tablets whole, BRILINTA tablets can be crushed, mixed with water, and drunk.

The mixture can also be administered via a nasogastric tube (CH8 or greater) [see Clinical Pharmacology (12.3)].

Do not administer BRILINTA with another oral P2Y₁₂ platelet inhibitor.

Avoid aspirin at doses higher than recommended [see Clinical Studies (14.1)].

2.2 Acute Coronary Syndrome or a History of Myocardial Infarction

Initiate treatment with a 180 mg loading dose of BRILINTA. Administer the first 90 mg maintenance dose of

BRILINTA, 6 to 12 hours after the loading dose. Administer 90 mg of BRILINTA twice daily during the first year after

an ACS event. After one year, administer 60 mg of BRILINTA twice daily.

Initiate BRILINTA with a daily maintenance dose of aspirin of 75 mg to 100 mg. However, in patients who have

undergone percutaneous coronary intervention (PCI), consider single antiplatelet therapy with BRILINTA based on the

evolving risk for thrombotic versus bleeding events [see Warnings and Precautions (5.1) and Clinical Studies (14)].

2.3 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction

Administer 60 mg of BRILINTA twice daily.

Generally, use BRILINTA with a daily maintenance dose of aspirin of 75 mg to 100 mg [see Clinical Studies (14)].

2.4 Acute Ischemic Stroke or Transient Ischemic Attack (TIA)

Initiate treatment with a 180 mg loading dose of BRILINTA and then continue with 90 mg twice daily for up to 30 days.

Administer the first maintenance dose 6 to 12 hours after the loading dose.

Use BRILINTA with a loading dose of aspirin (300 mg to 325 mg) and a daily maintenance dose of aspirin of 75 mg to

100 mg [see Clinical Studies (14)].

3 Dosage Forms And Strengths

BRILINTA (ticagrelor) 90 mg is supplied as a round, biconvex, yellow, film-coated tablet marked with a “90” above “T” on one side.

BRILINTA (ticagrelor) 60 mg is supplied as a round, biconvex, pink, film-coated tablet marked with “60” above “T” on one side.

• •60 mg and 90 mg tablets (3)

4 Contraindications

• •History of intracranial hemorrhage. (4.1)
• •Active pathological bleeding. (4.2)
• •Hypersensitivity to ticagrelor or any component of the product. (4.3)

4.1 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 (14.1), (14.2)].

4.2 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)].

4.3 Hypersensitivity

BRILINTA is contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product.

5 Warnings And Precautions

• •Dyspnea was reported more frequently with BRILINTA than with control agents in clinical trials. Dyspnea from BRILINTA is self-limiting. (5.3)
• •Severe Hepatic Impairment: Likely increase in exposure to ticagrelor. (5.6)
• •Laboratory Test Interference: False negative platelet functional test results have been reported for Heparin Induced Thrombocytopenia (HIT). BRILINTA is not expected to impact PF4 antibody testing for HIT. (5.8)

5.1 Risk of Bleeding

Drugs that inhibit platelet function including BRILINTA increase the risk of bleeding [see Warnings and Precautions

(5.2) and Adverse Reactions (6.1)].

Patients treated for acute ischemic stroke or TIA

Patients at NIHSS >5 and patients receiving thrombolysis were excluded from THALES and use of BRILINTA in such patients is not recommended.

5.2 Discontinuation of BRILINTA in Patients Treated for Coronary Artery Disease

Discontinuation of BRILINTA will increase the risk of myocardial infarction, stroke, and death in patients being treated

for coronary artery disease. If BRILINTA must be temporarily discontinued (e.g., to treat bleeding or for significant

surgery), restart it as soon as possible. When possible, interrupt therapy with BRILINTA for five days prior to surgery that

has a major risk of bleeding. Resume BRILINTA as soon as hemostasis is achieved.

5.3 Dyspnea

In clinical trials, about 14% (PLATO and PEGASUS) to 21% (THEMIS) of patients treated with BRILINTA developed dyspnea. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment but led to study drug discontinuation in 0.9% (PLATO), 1.0% (THALES), 4.3% (PEGASUS), and 6.9% (THEMIS) of patients.

In a substudy of PLATO, 199 subjects underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment.

If a patient develops new, prolonged, or worsened dyspnea that is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption if possible. In the case of intolerable dyspnea requiring discontinuation of BRILINTA, consider prescribing another antiplatelet agent.

5.4 Bradyarrhythmias

BRILINTA can cause ventricular pauses [see Adverse Reactions (6.1)]. Bradyarrhythmias including AV block have been

reported in the postmarketing setting. Patients with a history of sick sinus syndrome, 2^nd or 3^rd degree AV block or

bradycardia-related syncope not protected by a pacemaker were excluded from clinical studies and may be at increased

risk of developing bradyarrhythmias with ticagrelor.

5.5 Severe Hepatic Impairment

Avoid use of BRILINTA in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase

serum concentration of ticagrelor. There are no studies of BRILINTA patients with severe hepatic impairment [see

Clinical Pharmacology (12.3)].

5.6 Central Sleep Apnea

Central sleep apnea (CSA) including Cheyne-Stokes respiration (CSR) has been reported in the post-marketing setting in

patients taking ticagrelor, including recurrence or worsening of CSA/CSR following rechallenge. If central sleep apnea is

suspected, consider further clinical assessment.

5.7 Laboratory Test Interferences

False negative functional tests for Heparin Induced Thrombocytopenia (HIT)

BRILINTA has been reported to cause false negative results in platelet functional tests (including the heparin-induced

platelet aggregation (HIPA) assay) for patients with Heparin Induced Thrombocytopenia (HIT). This is related to

inhibition of the P2Y₁₂-receptor on the healthy donor platelets in the test by ticagrelor in the affected patient’s

serum/plasma. Information on concomitant treatment with BRILINTA is required for interpretation of HIT functional

tests. Based on the mechanism of BRILINTA interference, BRILINTA is not expected to impact PF4 antibody testing for

HIT.

6 Adverse Reactions

The following adverse reactions are also discussed elsewhere in the labeling:

• •Bleeding [see Warnings and Precautions (5.1)]
• •Dyspnea [see Warnings and Precautions (5.3)]

Most common adverse reactions (>5%) are bleeding and dyspnea. (5.1, 5.3, 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 58,000 patients.

Bleeding in PLATO (Reduction in risk of thrombotic events in ACS)

Figure 1 is a plot of time to the first non-CABG major bleeding event.

Figure 1 - Kaplan-Meier estimate of time to first non-CABG PLATO-defined major bleeding event (PLATO)

Frequency of bleeding in PLATO is summarized in Tables 1 and 2. About half of the non-CABG major bleeding events were in the first 30 days.

Table 1 - Non-CABG related bleeds (PLATO)

	BRILINTA 90 mg BID N=9235	Clopidogrel N=9186
	n (%) patients with event	n (%) patients with event
PLATO Major + Minor	713 (7.7)	567 (6.2)
Major	362 (3.9)	306 (3.3)
Fatal/Life-threatening	171 (1.9)	151 (1.6)
Fatal	15 (0.2)	16 (0.2)
Intracranial hemorrhage (Fatal/Life-threatening)	26 (0.3)	15 (0.2)
PLATO Minor bleed: requires medical intervention to stop or treat bleeding. PLATO Major bleed: any one of the following: fatal; intracranial; intrapericardial with cardiac tamponade; hypovolemic shock or severe hypotension requiring intervention; significantly disabling (e.g., intraocular with permanent vision loss); associated with a decrease in Hb of at least 3 g/dL (or a fall in hematocrit (Hct) of at least 9%); transfusion of 2 or more units. PLATO Major bleed, fatal/life-threatening: any major bleed as described above and associated with a decrease in Hb of more than 5 g/dL (or a fall in hematocrit (Hct) of at least 15%); transfusion of 4 or more units. Fatal: A bleeding event that directly led to death within 7 days.

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 Figure 2 and Table 2.

Figure 2 - ‘Major fatal/life-threatening’ CABG-related bleeding by days from last dose of study drug to CABG procedure (PLATO)

X-axis is days from last dose of study drug prior to CABG.

The PLATO protocol recommended a procedure for withholding study drug prior to CABG or other major surgery without unblinding. If surgery was elective or non-urgent, study drug was interrupted temporarily, as follows: If local practice was to allow antiplatelet effects to dissipate before surgery, capsules (blinded clopidogrel) were withheld 5 days before surgery and tablets (blinded ticagrelor) were withheld for a minimum of 24 hours and a maximum of 72 hours before surgery. If local practice was to perform surgery without waiting for dissipation of antiplatelet effects capsules and tablets were withheld 24 hours prior to surgery and use of aprotinin or other hemostatic agents was allowed. If local practice was to use IPA monitoring to determine when surgery could be performed both the capsules and tablets were withheld at the same time and the usual monitoring procedures followed.

T Ticagrelor; C Clopidogrel.

Table 2 - CABG-related bleeding (PLATO)

	BRILINTA 90 mg BID N=770	Clopidogrel N=814
	n (%) patients with event	n (%) patients with event
PLATO Total Major	626 (81.3)	666 (81.8)
Fatal/Life-threatening	337 (43.8)	350 (43.0)
Fatal	6 (0.8)	7 (0.9)
PLATO Major bleed: any one of the following: fatal; intracranial; intrapericardial with cardiac tamponade; hypovolemic shock or severe hypotension requiring intervention; significantly disabling (e.g., intraocular with permanent vision loss); associated with a decrease in Hb of at least 3 g/dL (or a fall in hematocrit (Hct) of at least 9%); transfusion of 2 or more units. PLATO Major bleed, fatal/life-threatening: any major bleed as described above and associated with a decrease in Hb of more than 5 g/dL (or a fall in hematocrit (Hct) of at least 15%); transfusion of 4 or more units.

When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of BRILINTA treated patients and 79% on clopidogrel.

Other Adverse Reactions in PLATO

Adverse reactions that occurred at a rate of 4% or more in PLATO are shown in Table 3.

Table 3 - Percentage of patients reporting non-hemorrhagic adverse reactions at least 4% or more in either group and more frequently on BRILINTA (PLATO)

	BRILINTA 90 mg BID N=9235	Clopidogrel N=9186
Dyspnea	13.8	7.8
Dizziness	4.5	3.9
Nausea	4.3	3.8

Bleeding in PEGASUS (Secondary Prevention in Patients with a History of Myocardial Infarction)

Overall outcome of bleeding events in the PEGASUS study are shown in Table 4.

Table 4 - Bleeding events (PEGASUS)

	BRILINTA 60 mg BID N=6958	Placebo N=6996
	Events / 1000 patient years	Events / 1000 patient years
TIMI Major	8	3
Fatal	1	1
Intracranial hemorrhage	2	1
TIMI Major or Minor	11	5
TIMI Major: Fatal bleeding, OR any intracranial bleeding, OR clinically overt signs of hemorrhage associated with a drop in hemoglobin (Hgb) of ≥5 g/dL, or a fall in hematocrit (Hct) of ≥15%. Fatal: A bleeding event that directly led to death within 7 days. TIMI Minor: Clinically apparent with 3-5 g/dL decrease in hemoglobin.

The bleeding profile of BRILINTA 60 mg compared to aspirin alone was consistent across multiple pre-defined subgroups (e.g., by age, gender, weight, race, geographic region, concurrent conditions, concomitant therapy, stent, and medical history) for TIMI Major and TIMI Major or Minor bleeding events.

Other Adverse Reactions in PEGASUS

Adverse reactions that occurred in PEGASUS at rates of 3% or more are shown in Table 5.

Table 5 - Non-hemorrhagic adverse reactions reported in >3.0% of patients in the ticagrelor 60 mg treatment group (PEGASUS)

	BRILINTA 60 mg BID N=6958	Placebo N=6996
Dyspnea	14.2%	5.5%
Dizziness	4.5%	4.1%
Diarrhea	3.3%	2.5%

Bleeding in THEMIS (Prevention of major CV events in patients with CAD and Type 2 Diabetes Mellitus)

The Kaplan-Meier curve of time to first TIMI Major bleeding event is presented in Figure 3.

Figure 3 – Time to first TIMI Major bleeding event (THEMIS)

T = Ticagrelor; P = Placebo; N = Number of patients

The bleeding events in THEMIS are shown below in Table 6.

Table 6 – Bleeding events (THEMIS)

	BRILINTA N=9562	Placebo N=9531
	Events / 1000 patient years	Events / 1000 patient years
TIMI Major	9	4
TIMI Major or Minor	12	5
TIMI Major or Minor or Requiring medical attention	46	18
Fatal bleeding	1	0
Intracranial hemorrhage	3	2

Bleeding in THALES (Reduction in risk of stroke in patients with acute ischemic stroke or TIA)

The Kaplan-Meier curve of time course of GUSTO severe bleeding events is presented in Figure 4.

Figure 4 – Time course of GUSTO severe bleeding events

KM%: Kaplan-Meier percentage evaluated at Day 30; T = Ticagrelor; P = placebo; N = Number of patients

GUSTO Severe: Any one of the following: fatal bleeding, intracranial bleeding (excluding asymptomatic hemorrhagic transformations of ischemic brain infarctions and excluding microhemorrhages < 10 mm evident only on gradient-echo magnetic resonance imaging), bleeding that caused hemodynamic compromise requiring intervention (eg, systolic blood pressure <90 mmg Hg that required blood or fluid replacement, or vasopressor/inotropic support, or surgical intervention).

Intracranial bleeding and fatal bleeding in THALES: In total, there were 21 intracranial hemorrhages (ICHs) for BRILINTA and 6 ICHs for placebo. Fatal bleedings, almost all ICH, occurred in 11 for BRILINTA and in 2 for placebo.

Bradycardia

In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with BRILINTA (6.0%) than with clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6%, respectively, after 1 month. PLATO, PEGASUS, THEMIS and THALES excluded patients at increased risk of bradycardic events (e.g., patients who have sick sinus syndrome, 2^nd or 3^rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker).

Lab abnormalities

Serum Uric Acid:

In PLATO, serum uric acid levels increased approximately 0.6 mg/dL from baseline on BRILINTA 90 mg and approximately 0.2 mg/dL on clopidogrel. The difference disappeared within 30 days of discontinuing treatment. Reports of gout did not differ between treatment groups in PLATO (0.6% in each group).

In PEGASUS, serum uric acid levels increased approximately 0.2 mg/dL from baseline on BRILINTA 60 mg and no elevation was observed on aspirin alone. Gout occurred more commonly in patients on BRILINTA than in patients on aspirin alone (1.5%, 1.1%). Mean serum uric acid concentrations decreased after treatment was stopped.

Serum Creatinine:

In PLATO, a >50% increase in serum creatinine levels was observed in 7.4% of patients receiving BRILINTA 90 mg compared to 5.9% of patients receiving clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Evidence of reversibility upon discontinuation was observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for renal-related serious adverse events such as acute renal failure, chronic renal failure, toxic nephropathy, or oliguria.

In PEGASUS, serum creatinine concentration increased by >50% in approximately 4% of patients receiving BRILINTA 60 mg, similar to aspirin alone. The frequency of renal related adverse events was similar for ticagrelor and aspirin alone regardless of age and baseline renal function.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of BRILINTA. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: Thrombotic Thrombocytopenic Purpura (TTP) has been rarely reported with the use of BRILINTA. TTP is a serious condition which can occur after a brief exposure (<2 weeks) and requires prompt treatment.

Immune system disorders: Hypersensitivity reactions including angioedema [see Contraindications (4.3)].

Respiratory Disorders: Central sleep apnea, Cheyne-Stokes respiration

Skin and subcutaneous tissue disorders: Rash