PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL – 90 mg

NDC 0186-0777-60

60 tablets

BRILINTA®

ticagrelor tablets

90 mg

Rx only

Dispense the accompanying Medication Guide to each patient.

AstraZeneca

RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

Dosage and Administration (2.2, 2.4) 03/2024

DESCRIPTION SECTION

11 DESCRIPTION

BRILINTA contains ticagrelor, a cyclopentyltriazolopyrimidine, inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP-receptor. Chemically it is (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. The empirical formula of ticagrelor is C23H28F2N6O4S and its molecular weight is 522.57. The chemical structure of ticagrelor is:

Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 μg/mL at room temperature.

BRILINTA 90 mg tablets for oral administration contain 90 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, talc, polyethylene glycol 400, and ferric oxide yellow.

BRILINTA 60 mg tablets for oral administration contain 60 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol 400, ferric oxide black, and ferric oxide red.

CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent.

12.2 Pharmacodynamics

The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6-week study examining both acute and chronic platelet inhibition effects in response to 20 μM ADP as the platelet aggregation agonist.

The onset of IPA was evaluated on Day 1 of the study following loading doses of 180 mg ticagrelor or 600 mg clopidogrel. As shown in Figure 5, IPA was higher in the ticagrelor group at all time points. The maximum IPA effect of ticagrelor was reached at around 2 hours, and was maintained for at least 8 hours.

The offset of IPA was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg daily, again in response to 20 μM ADP.

As shown in Figure 6, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in Figure 6 shows that after 24 hours, IPA in the ticagrelor group (58%) was similar to IPA in clopidogrel group (52%), indicating that patients who miss a dose of ticagrelor would still maintain IPA similar to the trough IPA of patients treated with clopidogrel. After 5 days, IPA in the ticagrelor group was similar to IPA in the placebo group. It is not known how either bleeding risk or thrombotic risk track with IPA, for either ticagrelor or clopidogrel.

Figure 5 - Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel

Figure 6 - Mean inhibition of platelet aggregation (IPA) following 6 weeks on placebo, ticagrelor 90 mg twice daily, or clopidogrel 75 mg daily

Transitioning from clopidogrel to BRILINTA resulted in an absolute IPA increase of 26.4% and from BRILINTA to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to BRILINTA without interruption of antiplatelet effect [see Dosage and Administration (2)].

12.3 Pharmacokinetics

Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers.

Absorption

BRILINTA can be taken with or without food. Absorption of ticagrelor occurs with a median tmax of 1.5 h (range 1.0–4.0). The formation of the major circulating metabolite AR-C124910XX (active) from ticagrelor occurs with a median tmax of 2.5 h (range 1.5-5.0).

The mean absolute bioavailability of ticagrelor is about 36% (range 30%-42%). Ingestion of a high-fat meal had no effect on ticagrelor Cmax, but resulted in a 21% increase in AUC. The Cmax of its major metabolite was decreased by 22% with no change in AUC.

BRILINTA as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to whole tablets (AUC and Cmax within 80-125% for ticagrelor and AR-C124910XX) with a median tmax of 1.0 hour (range 1.0 – 4.0) for ticagrelor and 2.0 hours (range 1.0 –8.0) for AR-C124910XX.

Distribution

The steady state volume of distribution of ticagrelor is 88 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (>99%).

Metabolism

CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Ticagrelor and its major active metabolite are weak P-glycoprotein substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30-40% of the exposure of ticagrelor.

Excretion

The primary route of ticagrelor elimination is hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (58% in feces, 26% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the major metabolite of ticagrelor is most likely to be biliary secretion. The mean t1/2 is approximately 7 hours for ticagrelor and 9 hours for the active metabolite.

Specific Populations

The effects of age, gender, ethnicity, renal impairment and mild hepatic impairment on the pharmacokinetics of ticagrelor are presented in Figure 7. Effects are modest and do not require dose adjustment.

Patients with End-Stage Renal Disease on Hemodialysis

In patients with end stage renal disease on hemodialysis AUC and Cmax of BRILINTA 90 mg administered on a day without dialysis were 38% and 51% higher respectively, compared to subjects with normal renal function. A similar increase in exposure was observed when BRILINTA was administered immediately prior to dialysis showing that BRILINTA is not dialyzable. Exposure of the active metabolite increased to a lesser extent. The IPA effect of BRILINTA was independent of dialysis in patients with end stage renal disease and similar to healthy adults with normal renal function.

Figure 7 - Impact of intrinsic factors on the pharmacokinetics of ticagrelor

Effects of Other Drugs on BRILINTA

CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. The effects of other drugs on the pharmacokinetics of ticagrelor are presented in Figure 8 as change relative to ticagrelor given alone (test/reference). Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, and clarithromycin) substantially increase ticagrelor exposure. Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem). CYP3A inducers (e.g., rifampin) substantially reduce ticagrelor blood levels. P-gp inhibitors (e.g., cyclosporine) increase ticagrelor exposure.

Co-administration of 5 mg intravenous morphine with 180 mg loading dose of ticagrelor decreased observed mean ticagrelor exposure by up to 25% in healthy adults and up to 36% in ACS patients undergoing PCI. Tmax was delayed by 1-2 hours. Exposure of the active metabolite decreased to a similar extent. Morphine co-administration did not delay or decrease platelet inhibition in healthy adults. Mean platelet aggregation was higher up to 3 hours post loading dose in ACS patients co-administered with morphine.

Co-administration of intravenous fentanyl with 180 mg loading dose of ticagrelor in ACS patients undergoing PCI resulted in similar effects on ticagrelor exposure and platelet inhibition.

Figure 8 - Effect of co-administered drugs on the pharmacokinetics of ticagrelor

*See Dosage and Administration (2)

Effects of BRILINTA on Other Drugs

In vitro metabolism studies demonstrate that ticagrelor and its major active metabolite are weak inhibitors of CYP3A4, potential activators of CYP3A5 and inhibitors of the P-gp transporter. Ticagrelor and AR-C124910XX were shown to have no inhibitory effect on human CYP1A2, CYP2C19, and CYP2E1 activity. For specific in vivo effects on the pharmacokinetics of simvastatin, atorvastatin, ethinyl estradiol, levonorgesterol, tolbutamide, digoxin and cyclosporine, see Figure 9.

Figure 9 - Impact of BRILINTA on the pharmacokinetics of co-administered drugs

12.5 Pharmacogenomics

In a genetic substudy cohort of PLATO, the rate of thrombotic CV events in the BRILINTA arm did not depend on CYP2C19 loss of function status.

INDICATIONS & USAGE SECTION

Highlight: BRILINTA is a P2Y12 platelet inhibitor indicated

•

to reduce the risk of cardiovascular (CV) death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. For at least the first 12 months following ACS, it is superior to clopidogrel.  

BRILINTA also reduces the risk of stent thrombosis in patients who have been stented for treatment of ACS. (1.1)

•

to reduce the risk of a first MI or stroke in patients with coronary artery disease (CAD) at high risk for such events. While use is not limited to this setting, the efficacy of BRILINTA was established in a population with type 2 diabetes mellitus (T2DM). (1.2)

•

to reduce the risk of stroke in patients with acute ischemic stroke (NIH Stroke Scale score ≤5) or high-risk transient ischemic attack (TIA). (1.3)

1 INDICATIONS AND USAGE

1.1 Acute Coronary Syndrome or a History of Myocardial Infarction

BRILINTA is indicated to reduce the risk of cardiovascular (CV) death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. For at least the first 12 months following ACS, it is superior to clopidogrel.

BRILINTA also reduces the risk of stent thrombosis in patients who have been stented for treatment of ACS [see Clinical Studies (14.1)].

1.2 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction

BRILINTA is indicated to reduce the risk of a first MI or stroke in patients with coronary artery disease (CAD) at high risk for such events [see Clinical Studies (14.2)]. While use is not limited to this setting, the efficacy of BRILINTA was established in a population with type 2 diabetes mellitus (T2DM).

1.3 Acute Ischemic Stroke or Transient Ischemic Attack (TIA)

BRILINTA is indicated to reduce the risk of stroke in patients with acute ischemic stroke (NIH Stroke Scale score ≤5) or high-risk transient ischemic attack (TIA) [see Clinical Studies (14.3)].

DOSAGE FORMS & STRENGTHS SECTION

Highlight: •

60 mg and 90 mg tablets (3)

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.

CONTRAINDICATIONS SECTION

Highlight: •

History of intracranial hemorrhage. (4.1)

•

Active pathological bleeding. (4.2)

•

Hypersensitivity to ticagrelor or any component of the product. (4.3)

4 CONTRAINDICATIONS

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.

Boxed Warning section

WARNING: BLEEDING RISK

See full prescribing information for complete boxed warning.

•

**BRILINTA, like other antiplatelet agents, can cause significant,**
**sometimes fatal bleeding. (****5.1****,****6.1****)**

•

**Do not use BRILINTA in patients with active pathological**
**bleeding or a history of intracranial hemorrhage. (****4.1****,****4.2****)**

•

**Do not start BRILINTA in patients undergoing urgent coronary**
**artery bypass graft surgery (CABG). (****5.1****,****6.1****)**

•

**If possible, manage bleeding without discontinuing BRILINTA.**
**Stopping BRILINTA increases the risk of subsequent**
**cardiovascular events. (****5.2****)**

WARNINGS AND PRECAUTIONS SECTION

Highlight: •

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 WARNINGS AND PRECAUTIONS

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, 2nd or 3rd 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.

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

14.1 Acute Coronary Syndromes and Secondary Prevention after Myocardial

Infarction

PLATO

PLATO (NCT00391872) was a randomized double-blind study comparing BRILINTA (N=9333) to clopidogrel (N=9291), both given in combination with aspirin and other standard therapy, in patients with acute coronary syndromes (ACS), who presented within 24 hours of onset of the most recent episode of chest pain or symptoms. The study’s primary endpoint was the composite of first occurrence of cardiovascular death, non-fatal MI (excluding silent MI), or non-fatal stroke.

Patients who had already been treated with clopidogrel could be enrolled and randomized to either study treatment. Patients with previous intracranial hemorrhage, gastrointestinal bleeding within the past 6 months, or with known bleeding diathesis or coagulation disorder were excluded. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. Patients could be included whether there was intent to manage the ACS medically or invasively, but patient randomization was not stratified by this intent.

All patients randomized to BRILINTA received a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. Patients in the clopidogrel arm were treated with an initial loading dose of clopidogrel 300 mg, if clopidogrel therapy had not already been given. Patients undergoing PCI could receive an additional 300 mg of clopidogrel at investigator discretion. A daily maintenance dose of aspirin 75-100 mg was recommended, but higher maintenance doses of aspirin were allowed according to local judgment. Patients were treated for at least 6 months and for up to 12 months.

PLATO patients were predominantly male (72%) and Caucasian (92%). About 43% of patients were >65 years and 15% were >75 years. Median exposure to study drug was 276 days. About half of the patients received pre-study clopidogrel and about 99% of the patients received aspirin at some time during PLATO. About 35% of patients were receiving a statin at baseline and 93% received a statin sometime during PLATO.

Table 7 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint. Separate secondary endpoint analyses are shown for the overall occurrence of CV death, MI, and stroke and overall mortality.

The Kaplan-Meier curve (Figure 10) shows time to first occurrence of the primary composite endpoint of CV death, non-fatal MI or non-fatal stroke in the overall study.

Figure 10 - Time to first occurrence of CV death, MI, or stroke (PLATO)

The curves separate by 30 days [relative risk reduction (RRR) 12%] and continue to diverge throughout the 12‑month treatment period (RRR 16%).

Among 11,289 patients with PCI receiving any stent during PLATO, there was a lower risk of stent thrombosis (1.3% for adjudicated “definite”) than with clopidogrel (1.9%) (HR 0.67, 95% CI 0.50-0.91; p=0.009). The results were similar for drug-eluting and bare metal stents.

A wide range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcome. Some of these are shown in Figure 11. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. Most of the analyses show effects consistent with the overall results, but there are two exceptions: a finding of heterogeneity by region and a strong influence of the maintenance dose of aspirin. These are considered further below.

Most of the characteristics shown are baseline characteristics, but some reflect post-randomization determinations (e.g., aspirin maintenance dose, use of PCI).

Figure 11 – Subgroup analyses of (PLATO)

Note: The figure above presents effects in various subgroups most of which are baseline characteristics and most of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Regional Differences

Results in the rest of the world compared to effects in North America (US and Canada) show a smaller effect in North America, numerically inferior to the control and driven by the US subset. The statistical test for the US/non-US comparison is statistically significant (p=0.009), and the same trend is present for both CV death and non-fatal MI. The individual results and nominal p-values, like all subset analyses, need cautious interpretation, and they could represent chance findings. The consistency of the differences in both the CV mortality and non-fatal MI components, however, supports the possibility that the finding is reliable.

A wide variety of baseline and procedural differences between the US and non- US (including intended invasive vs. planned medical management, use of GPIIb/IIIa inhibitors, use of drug eluting vs. bare-metal stents) were examined to see if they could account for regional differences, but with one exception, aspirin maintenance dose, these differences did not appear to lead to differences in outcome.

Aspirin Dose

The PLATO protocol left the choice of aspirin maintenance dose up to the investigator and use patterns were different in US sites from sites outside of the US. About 8% of non-US investigators administered aspirin doses above 100 mg, and about 2% administered doses above 300 mg. In the US, 57% of patients received doses above 100 mg and 54% received doses above 300 mg. Overall results favored BRILINTA when used with low maintenance doses (≤100 mg) of aspirin, and results analyzed by aspirin dose were similar in the US and elsewhere. Figure 10 shows overall results by median aspirin dose. Figure 12 shows results by region and dose.

Figure 12 – CV death, MI, stroke by maintenance aspirin dose in the US and outside the US (PLATO)

Like any unplanned subset analysis, especially one where the characteristic is not a true baseline characteristic (but may be determined by usual investigator practice), the above analyses must be treated with caution. It is notable, however, that aspirin dose predicts outcome in both regions with a similar pattern, and that the pattern is similar for the two major components of the primary endpoint, CV death and non-fatal MI.

Despite the need to treat such results cautiously, there appears to be good reason to restrict aspirin maintenance dosage accompanying ticagrelor to 100 mg. Higher doses do not have an established benefit in the ACS setting, and there is a strong suggestion that use of such doses reduces the effectiveness of BRILINTA.

PEGASUS

The PEGASUS TIMI-54 study (NCT01225562) was a 21,162-patient, randomized, double-blind, placebo-controlled, parallel-group study. Two doses of ticagrelor, either 90 mg twice daily or 60 mg twice daily, co-administered with 75-150 mg of aspirin, were compared to aspirin therapy alone in patients with history of MI. The primary endpoint was the composite of first occurrence of CV death, non-fatal MI and non-fatal stroke. CV death and all-cause mortality were assessed as secondary endpoints.

Patients were eligible to participate if they were ≥50 years old, with a history of MI 1 to 3 years prior to randomization, and had at least one of the following risk factors for thrombotic cardiovascular events: age ≥65 years, diabetes mellitus requiring medication, at least one other prior MI, evidence of multivessel coronary artery disease, or creatinine clearance <60 mL/min. Patients could be randomized regardless of their prior ADP receptor blocker therapy or a lapse in therapy. Patients requiring or who were expected to require renal dialysis during the study were excluded. Patients with any previous intracranial hemorrhage, gastrointestinal bleeding within the past 6 months, or with known bleeding diathesis or coagulation disorder were excluded. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. A small number of patients with a history of stroke were included. Based on information external to PEGASUS, 102 patients with a history of stroke (90 of whom received study drug) were terminated early and no further such patients were enrolled.

Patients were treated for at least 12 months and up to 48 months with a median follow up time of 33 months.

Patients were predominantly male (76%) Caucasian (87%) with a mean age of 65 years, and 99.8% of patients received prior aspirin therapy.

The Kaplan-Meier curve (Figure 13) shows time to first occurrence of the primary composite endpoint of CV death, non-fatal MI or non-fatal stroke.

Figure 13 – Time to First Occurrence of CV death, MI or Stroke (PEGASUS)

Ti = Ticagrelor BID, CI = Confidence interval; HR = Hazard ratio; KM = Kaplan- Meier; N = Number of patients.

Both the 60 mg and 90 mg regimens of BRILINTA in combination with aspirin were superior to aspirin alone in reducing the incidence of CV death, MI or stroke. The absolute risk reductions for BRILINTA plus aspirin vs. aspirin alone were 1.27% and 1.19% for the 60 and 90 mg regimens, respectively. Although the efficacy profiles of the two regimens were similar, the lower dose had lower risks of bleeding and dyspnea.

Table 8 shows the results for the 60 mg plus aspirin regimen vs. aspirin alone.

In PEGASUS, the relative risk reduction (RRR) for the composite endpoint from 1 to 360 days (17% RRR) and from 361 days and onwards (16% RRR) were similar.

The treatment effect of BRILINTA 60 mg over aspirin appeared similar across most pre-defined subgroups, see Figure 14.

Figure 14 – Subgroup analyses of ticagrelor 60 mg (PEGASUS)

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and most of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

14.2 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction

THEMIS

The THEMIS study (NCT01991795) was a double-blind, parallel group, study in which 19,220 patients with CAD and Type 2 Diabetes Mellitus (T2DM) but no history of MI or stroke were randomized to twice daily BRILINTA or placebo, on a background of 75-150 mg of aspirin. The primary endpoint was the composite of first occurrence of CV death, MI, and stroke. CV death, MI, ischemic stroke, and all-cause death were assessed as secondary endpoints.

Patients were eligible to participate if they were ≥ 50 years old with CAD, defined as a history of PCI or CABG, or angiographic evidence of ≥ 50% lumen stenosis of at least 1 coronary artery and T2DM treated for at least 6 months with glucose-lowering medication. Patients with previous intracerebral hemorrhage, gastrointestinal bleeding within the past 6 months, known bleeding diathesis, and coagulation disorder were excluded. Patients taking anticoagulants or ADP receptor antagonists were excluded from participating, and patients who developed an indication for those medications during the trial were discontinued from study drug.

Patients were treated for a median of 33 months and up to 58 months.

Patients were predominantly male (69%) with a mean age of 66 years. At baseline, 80% had a history of coronary artery revascularization; 58% had undergone PCI, 29% had undergone a CABG and 7% had undergone both. The proportion of patients studied in the US was 12%. Patients in THEMIS had established CAD and other risk factors that put them at higher cardiovascular risk.

BRILINTA was superior to placebo in reducing the incidence of CV death, MI, or stroke. The effect on the composite endpoint was driven by the individual components MI and stroke; see Table 9.

The Kaplan-Meier curve (Figure 15) shows time to first occurrence of the primary composite endpoint of CV death, MI, or stroke.

Figure 15 - Time to First Occurrence of CV death, MI or Stroke (THEMIS)

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

The treatment effect of BRILINTA appeared similar across patient subgroups, see Figure 16.

Figure 16 – Subgroup analyses of ticagrelor (THEMIS)

Note: The figure above presents effects in various subgroups all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

14.3 Acute Ischemic Stroke or Transient Ischemic Attack (TIA)

THALES

The THALES study (NCT03354429) was a 11016-patient, randomized, double-blind, parallel-group study of BRILINTA 90 mg twice daily versus placebo in patients with acute ischemic stroke or transient ischemic attack (TIA). The primary endpoint was the first occurrence of the composite of stroke and death up to 30 days. Ischemic stroke was assessed as one of the secondary endpoints.

Patients were eligible to participate if they were ≥40 years old, with non- cardioembolic acute ischemic stroke (NIHSS score ≤5) or high-risk TIA (defined as ABCD2 score ≥6 or ipsilateral atherosclerotic stenosis ≥50% in the internal carotid or an intracranial artery). Patients who received thrombolysis or thrombectomy within 24 hours prior to randomization were not eligible.

Patients were randomized within 24 hours of onset of an acute ischemic stroke or TIA to receive 30 days of either BRILINTA (90 mg twice daily, with an initial loading dose of 180 mg) or placebo, on a background of aspirin initially 300-325 mg then 75-100 mg daily. The median treatment duration was 31 days.

BRILINTA was superior to placebo in reducing the rate of the primary endpoint (composite of stroke and death), corresponding to a relative risk reduction (RRR) of 17% and an absolute risk reduction (ARR) of 1.1% (Table 10). The effect was driven primarily by a significant reduction in the stroke component of the primary endpoint (19% RRR, 1.1% ARR).

The Kaplan-Meier curve (Figure 17) shows the time to first occurrence of the primary composite endpoint of stroke and death.

Figure 17 – Time to First Occurrence of Stroke or Death (THALES)

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

BRILINTA’s treatment effect on stroke and on death accrued over the first 10 days and was sustained at 30 days. Although not studied, this suggests that shorter treatment could result in similar benefit and reduced bleeding risk.

The treatment effect of BRILINTA was generally consistent across pre-defined subgroups (Figure 18).

Figure 18 - Subgroup analyses of ticagrelor 90 mg (THALES)

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

At Day 30, there was an absolute reduction of 1.2% (95% CI: -2.1%, -0.3%) in the incidence of non-hemorrhagic stroke and death (excluding fatal bleed) favoring ticagrelor (294 events: 5.3%) over placebo (359 events: 6.5%) in the intention-to-treat population. In the same population, there was an absolute increase of 0.4% (95% CI: 0.2%, 0.6%) in the incidence of GUSTO severe bleeding unfavorable to ticagrelor arm (28 events: 0.5%) compared to the placebo arm (7 events: 0.1%).

OVERDOSAGE SECTION

10 OVERDOSAGE

There is currently no known treatment to reverse the effects of BRILINTA, and ticagrelor is not dialyzable. Treatment of overdose should follow local standard medical practice. Bleeding is the expected pharmacologic effect of overdosing. If bleeding occurs, appropriate supportive measures should be taken.

Platelet transfusion did not reverse the antiplatelet effect of BRILINTA in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding.

Other effects of overdose may include gastrointestinal effects (nausea, vomiting, diarrhea) or ventricular pauses. Monitor the ECG.

NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Ticagrelor was not carcinogenic in the mouse at doses up to 250 mg/kg/day or in the male rat at doses up to 120 mg/kg/day (19 and 15 times the MRHD of 90 mg twice daily on the basis of AUC, respectively). Uterine carcinomas, uterine adenocarcinomas and hepatocellular adenomas were seen in female rats at doses of 180 mg/kg/day (29‑fold the maximally recommended dose of 90 mg twice daily on the basis of AUC), whereas 60 mg/kg/day (8‑fold the MRHD based on AUC) was not carcinogenic in female rats.

Mutagenesis

Ticagrelor did not demonstrate genotoxicity when tested in the Ames bacterial mutagenicity test, mouse lymphoma assay and the rat micronucleus test. The active O-demethylated metabolite did not demonstrate genotoxicity in the Ames assay and mouse lymphoma assay.

Impairment of Fertility

Ticagrelor had no effect on male fertility at doses up to 180 mg/kg/day or on female fertility at doses up to 200 mg/kg/day (>15-fold the MRHD on the basis of AUC). Doses of ≥10 mg/kg/day given to female rats caused an increased incidence of irregular duration estrus cycles (1.5-fold the MRHD based on AUC).

INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Advise patients daily doses of aspirin should not exceed 100 mg and to avoid taking any other medications that contain aspirin.

Advise patients that they:

•

Will bleed and bruise more easily

•

Will take longer than usual to stop bleeding

•

Should report any unanticipated, prolonged or excessive bleeding, or blood in their stool or urine.

Advise patients to contact their doctor if they experience unexpected shortness of breath, especially if severe.

Advise patients to inform physicians and dentists that they are taking BRILINTA before any surgery or dental procedure.

Advise women that breastfeeding is not recommended during treatment with BRILINTA [see Use in Specific Populations (8.2)].

BRILINTA® is a trademark of the AstraZeneca group of companies.

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850

© AstraZeneca 2024

SPL MEDGUIDE SECTION

you may bruise and bleed more easily

you are more likely to have nose bleeds

it will take longer than usual for any bleeding to stop

bleeding that is severe or that you cannot control

pink, red or brown urine

vomiting blood or your vomit looks like “coffee grounds”

red or black stools (looks like tar)

coughing up blood or blood clots

decrease your risk of death, heart attack, and stroke in people with a blockage of blood flow to the heart (acute coronary syndrome or ACS) or a history of a heart attack. BRILINTA can also decrease your risk of blood clots in your stent in people who have received stents for the treatment of ACS.

decrease your risk of a first heart attack or stroke in people who have a condition where the blood flow to the heart is decreased (coronary artery disease or CAD) who are at high risk for having a heart attack or stroke.

decrease your risk of stroke in people who are having a stroke (acute ischemic stroke) or mini-stroke (transient ischemic attack or TIA).

have a history of bleeding in the brain

are bleeding now

are allergic to ticagrelor or any of the ingredients in BRILINTA. See the end of this Medication Guide for a complete list of ingredients in BRILINTA.

have had bleeding problems in the past

have had any recent serious injury or surgery

plan to have surgery or a dental procedure. See “**What is the most important information I should know about BRILINTA?”**

have a history of stomach ulcers or colon polyps

have lung problems, such as COPD or asthma

have liver problems

have a history of stroke

are pregnant or plan to become pregnant. It is not known if BRILINTA will harm your unborn baby. You and your healthcare provider should decide if you will take BRILINTA.

are breastfeeding or plan to breastfeed. It is not known if BRILINTA passes into your breast milk. You should not breastfeed during treatment with BRILINTA. Talk to your healthcare provider about the best way to feed your baby during treatment with BRILINTA.

Take BRILINTA exactly as prescribed by your healthcare provider.

Your healthcare provider will tell you how many BRILINTA tablets to take and when to take them.

Take BRILINTA with aspirin, unless your healthcare provider specifically tells you otherwise. See**“What is the most important information I should know about BRILINTA?”**

You may take BRILINTA with or without food.

Take BRILINTA two times each day, around the same times each day.

If you miss your scheduled dose of BRILINTA, take your next dose at its scheduled time. Do not take 2 doses at the same time unless your healthcare provider tells you to.

If you take too much BRILINTA, call your healthcare provider or local poison control center or go to the nearest emergency room right away.
**If you are unable to swallow the tablet(s) whole**, you may crush the BRILINTA tablet(s) and mix it with water. Drink all the water right away. Refill the glass with water, stir, and drink all the water.
BRILINTA may also be given through certain nasogastric (NG) tubes. Ask your healthcare provider for instructions on how to take BRILINTA through a NG tube.

**See “What is the most important information I should know about BRILINTA?”**

**Shortness of breath**. Tell your healthcare provider if you have new, worsening or unexpected shortness of breath when you are at rest, at night, or when you are doing any activity. 

**Irregular breathing.** Tell your healthcare provider if you develop irregular breathing patterns when asleep or awake such as speeding up, slowing down or short pauses in breathing. Your healthcare provider will decide if you need further evaluation.

Store BRILINTA at room temperature between 68°F to 77°F (20°C to 25°C).

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 03/2024

HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

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

Bottles of 60 – NDC 0186-0777-60

100 count Hospital Unit Dose – NDC 0186-0777-39

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

Bottles of 60 – NDC 0186-0776-60

Storage and Handling

Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP controlled room temperature].