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.

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

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.

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.

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.

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

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

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

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.

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

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

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

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

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

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

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

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.

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.