BRILINTA- ticagrelor tablet
For Healthcare Providers >

1. Patient Information
2. Advise Patients That They:
3. Call Your Doctor Right Away, If You Have Any Of These Signs Or Symptoms Of Bleeding While Taking Brilinta:
4. Brilinta Is A Prescription Medicine Used To Treat People Who:
5. Do Not Take Brilinta If You:
6. Before You Take Brilinta, Tell Your Doctor If You:
7. Especially Tell Your Doctor If You Take:
8. How Should I Take Brilinta?
9. Brilinta Can Cause Serious Side Effects, Including:
10. Active Ingredient:
11. 60 Mg Tablets:inactive Ingredients:

Patient 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[

BRILINTA is used to lower your chance of having a heart attack or dying from a heart attack or strokebut BRILINTA (and similar drugs) can cause bleeding that can be serious and sometimes lead to death.In cases of serious bleeding, such as internal bleeding, the bleeding may result in the need for blood transfusions or surgery. While you take BRILINTA:

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

Call Your Doctor Right Away, If You Have Any Of These Signs Or Symptoms Of Bleeding While Taking Brilinta: ⮝

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

Do not stop taking BRILINTA without talking to the doctor who prescribes it for you.People who are treated with a stent, and stop taking BRILINTA too soon, have a higher risk of getting a blood clot in the stent, having a heart attack, or dying. If you stop BRILINTA because of bleeding, or for other reasons, your risk of a heart attack or stroke may increase.

Your doctor may instruct you to stop taking BRILINTA 5 days before surgery. This will help to decrease your risk of bleeding with your surgery or procedure. Your doctor should tell you when to start taking BRILINTA again, as soon as possible after surgery.

Taking BRILINTA with aspirin

BRILINTA is taken with aspirin. Talk to your doctor about the dose of aspirin that you should take with BRILINTA. You should not take a dose of aspirin higher than 100 mg daily because it can affect how well BRILINTA works. Do not take doses of aspirin higher than what your doctor tells you to take. Tell your doctor if you take other medicines that contain aspirin, and do not take new over-the-counter medicines with aspirin in them.

Brilinta Is A Prescription Medicine Used To Treat People Who: ⮝

have had a heart attack or severe chest pain that happened because their heart was not getting enough oxygen.

BRILINTA is used with aspirin to lower your chance of having another serious problem with your heart or blood vessels, such as heart attack, stroke, or blood clots in your stent. These can be fatal.

Platelets are blood cells that help with normal blood clotting. BRILINTA helps prevent platelets from sticking together and forming a clot that can block an artery.

It is not known if BRILINTA is safe and effective in children.

Do Not Take Brilinta If You: ⮝

have a history of bleeding in the brain

are bleeding now

are allergic to ticagrelor or any of the ingredients in BRILINTA.

Before You Take Brilinta, Tell Your Doctor If You: ⮝

have had bleeding problems in the past

have had any recent serious injury or surgery

plan to have surgery or a dental procedure

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 doctor 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 and your doctor should decide if you will take BRILINTA or breastfeed. You should not do both without talking with your doctor.

Tell all of your doctors and dentists that you are taking BRILINTA. They should talk to the doctor who prescribed BRILINTA for you before you have any surgery or invasive procedure.

Tell your doctor about all the medicines you take,including prescription and over-the-counter medicines, vitamins, and herbal supplements.BRILINTA may affect the way othermedicines work, and other medicines may affect how BRILINTA works.

Especially Tell Your Doctor If You Take: ⮝

an HIV-AIDS medicine

medicine for heart conditions or high blood pressure

medicine for high blood cholesterol levels

an anti-fungal medicine by mouth

an anti-seizure medicine

a blood thinner medicine

rifampin (Rifater, Rifamate, Rimactane, Rifadin)

Ask your doctor or pharmacist if you are not sure if your medicine is listed above.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How Should I Take Brilinta? ⮝

Take BRILINTA exactly as prescribed by your doctor.

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

Take BRILINTA with a low dose (not more than 100 mg daily) of aspirin. You may take BRILINTA with or without food.

Take your doses of BRILINTA around the same time every day.

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

If you take too much BRILINTA or overdose, call your doctor or poison control center right away, or go to the nearest emergency room.

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 Can Cause Serious Side Effects, Including: ⮝

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

Keep BRILINTA and all medicines out of the reach of children.

General information about BRILINTA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BRILINTA for a condition for which it was not prescribed. Do not give BRILINTA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about BRILINTA that is written for health professionals.

Active Ingredient: ⮝

ticagrelor.

90 mg tablets:
Inactive ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, talc, polyethylene glycol 400, and ferric oxide yellow.

60 Mg Tablets:inactive 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.

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850

For more information call 1-800-236-9933 or go towww.Brilinta.com.

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 04/2019

1. Highlights Of Prescribing Information
2. See Full Prescribing Information For Complete Boxed Warning.
3. Indications And Usage
4. Dosage And Administration
5. Dosage Forms And Strengths
6. Contraindications
7. Warnings And Precautions
8. Adverse Reactions
9. Drug Interactions
10. Use In Specific Populations
11. Warning: (a) Bleeding Risk, (b) Aspirin Dose And Brilinta Effectiveness
12. 1 Indications And Usage
13. 2 Dosage And Administration
14. 3 Dosage Forms And Strengths
15. 4 Contraindications
16. 5 Warnings And Precautions
17. 6 Adverse Reactions
18. 7 Drug Interactions
19. 8 Use In Specific Populations
20. 10 Overdosage
21. 11 Description
22. 12 Clinical Pharmacology
23. 13 Nonclinical Toxicology
24. 14 Clinical Studies
25. 16 How Supplied/storage And Handling
26. Package/label Display Panel
27. Warning: (a) Bleeding Risk, (b) Aspirin Dose And Brilinta Effectiveness
28. Package/label Principal Display Panel 60 Mg
29. Package/label Principal Display Panel 90 Mg

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use BRILINTA safely and effectively. See full prescribing information for BRILINTA.

BRILINTA (ticagrelor) tablets, for oral use
Initial U.S. Approval: 2011

See Full Prescribing Information For Complete Boxed Warning. ⮝

BLEEDING RISK

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 (5.4).

ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. (2.1, 5.2, 14.1).

Indications And Usage ⮝

BRILINTA is a P2Y12 platelet inhibitor indicated to reduce the rate of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction (MI). For at least the first 12 months following ACS, it is superior to clopidogrel.

BRILINTA also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS. (1)

Dosage And Administration ⮝

Initiate treatment with 180 mg oral loading dose following an ACS event. Continue treatment with 90 mg twice daily during the first year after an ACS event. After one year, administer 60 mg twice daily. (2.1)

Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg. (2.1, 5.2)

Dosage Forms And Strengths ⮝

60 mg and 90 mg tablets (3)

Contraindications ⮝

History of intracranial hemorrhage. (4.1)

Active pathological bleeding. (4.2)

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

Warnings And Precautions ⮝

Dyspnea was reported more frequently with BRILINTA than with control agents in clinical trials. Dyspnea resulting from BRILINTA is self-limiting. (5.3)

Severe Hepatic Impairment: Likely increase in exposure to ticagrelor. (5.6)

Adverse Reactions ⮝

Most common adverse reactions are bleeding 12% and dyspnea 14%. (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.

Drug Interactions ⮝

Avoid use with strong CYP3A inhibitors or CYP3A inducers. (7.1, 7.2)

Opioids: Decreased exposure to ticagrelor. Consider use of parenteral anti-platelet agent. (7.4)

Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse effects. (7.5)

Monitor digoxin levels with initiation of or any change in BRILINTA. (7.6)

Use In Specific Populations ⮝

Lactation: Breastfeeding not recommended (8.2)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 4/2019

Warning: (a) Bleeding Risk, (b) Aspirin Dose And Brilinta Effectiveness ⮝

A. BLEEDING RISK

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 (5.4).

B. ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided (2.1, 5.2, 14.1).

1 Indications And Usage ⮝

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

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

2 Dosage And Administration ⮝

2.1 Dosing

In the management of ACS, initiate BRILINTA treatment with a 180 mg loading dose. Administer 90 mg twice daily during the first year after an ACS event. After one year administer 60 mg twice daily.

Do not administer BRILINTA with another oral P2Y12 platelet inhibitor.

Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg [see Warnings and Precautions (5.2) and Clinical Studies (14.1)]. A patient who misses a dose of BRILINTA should take one tablet (their next dose) at its scheduled time.

2.2 Administration

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)].

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.

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)].

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 ⮝

5.1 General Risk of Bleeding

Drugs that inhibit platelet function including BRILINTA increase the risk of bleeding [see Adverse Reactions (6.1)].

If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

5.2 Concomitant Aspirin Maintenance Dose

In PLATO the use of BRILINTA with maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Therefore, after the initial loading dose of aspirin, use BRILINTA with a maintenance dose of aspirin of 75-100 mg [see Dosage and Administration (2.1) and Clinical Studies (14.1)].

5.3 Dyspnea

In clinical trials, about 14% 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% of BRILINTA and 0.1% of clopidogrel patients in PLATO and 4.3% of BRILINTA 60 mg and 0.7% on aspirin alone patients in PEGASUS.

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 Discontinuation of BRILINTA

Discontinuation of BRILINTA will increase the risk of myocardial infarction, stroke, and death. 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.

5.5 Bradyarrhythmias

Ticagrelor 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 PLATO and PEGASUS and may be at increased risk of developing bradyarrhythmias with ticagrelor.

5.6 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)].

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)]

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 27000 patients, including more than 13000 patients treated for at least 1 year.

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* N=9235	Clopidogrel N=9186
* 90 mg BID
	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 haemostatic 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)

* 90 mg BID
	BRILINTA* 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* N=9235	Clopidogrel N=9186
* 90 mg BID
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)

* 60 mg BID
	BRILINTA* + Aspirin N=6958		Aspirin Alone N=6996
	n (%) patients with event	Events /100 pt yrs	n (%) patients with event	Events /100 pt yrs
TIMI Major	115 (1.7)	0.78	54 (0.8)	0.34
Fatal	11 (0.2)	0.08	12 (0.2)	0.08
Intracranial hemorrhage	28 (0.4)	0.19	23 (0.3)	0.14
TIMI Major or Minor	168 (2.4)	1.15	72 (1.0)	0.45
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* + Aspirin N=6958	Aspirin Alone N=6996
* 60 mg BID
Dyspnea	14.2	5.5
Dizziness	4.5	4.1
Diarrhea	3.3	2.5

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 and PEGASUS excluded patients at increased risk of bradycardic events (e.g., patients who have sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker). In PLATO, syncope, pre-syncope and loss of consciousness were reported by 1.7% and 1.5% of BRILINTA 90 mg and clopidogrel patients, respectively. In PEGASUS, syncope was reported by 1.2% and 0.9% of patients on BRILINTA 60 mg and aspirin alone, respectively.

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.

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

Skin and subcutaneous tissue disorders: Rash

7 Drug Interactions ⮝

7.1 Strong CYP3A Inhibitors

Strong CYP3A inhibitors substantially increase ticagrelor exposure and so increase the risk of dyspnea, bleeding, and other adverse events. Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin) [seeClinical Pharmacology (12.3)].

7.2 Strong CYP3A Inducers

Strong CYP3A inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor. Avoid use with strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine and phenobarbital) [see Clinical Pharmacology (12.3)].

7.3 Aspirin

Use of BRILINTA with aspirin maintenance doses above 100 mg reduced the effectiveness of BRILINTA [see Warnings and Precautions (5.2) and Clinical Studies (14.1)].

7.4 Opioids

As with other oral P2Y12 inhibitors, co-administration of opioid agonists delay and reduce the absorption of ticagrelor and its active metabolite presumably because of slowed gastric emptying [see Clinical Pharmacology (12.3)]. Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

7.5 Simvastatin, Lovastatin

BRILINTA increases serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg [see Clinical Pharmacology (12.3)].

7.6 Digoxin

BRILINTA inhibits the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in BRILINTA therapy [see Clinical Pharmacology (12.3)].

8 Use In Specific Populations ⮝

8.1 Pregnancy

Risk Summary

Available data from case reports with BRILINTA use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Ticagrelor given to pregnant rats and pregnant rabbits during organogenesis caused structural abnormalities in the offspring at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. When ticagrelor was given to rats during late gestation and lactation, pup death and effects on pup growth were seen at approximately 10 times the MRHD (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. 20 mg/kg/day is approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m2 basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m2 basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae. At the mid-dose of 100 mg/kg/day (5.5 times the MRHD on a mg/m2 basis), delayed development of liver and skeleton was seen. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, fetuses exposed to the highest maternal dose of 63 mg/kg/day (6.8 times the MRHD on a mg/m2 basis) had delayed gall bladder development and incomplete ossification of the hyoid, pubis and sternebrae occurred.

In a prenatal/postnatal study, pregnant rats received ticagrelor at doses of 10 to 180 mg/kg/day during late gestation and lactation. Pup death and effects on pup growth were observed at 180 mg/kg/day (approximately 10 times the MRHD on a mg/m2 basis). Relatively minor effects such as delays in pinna unfolding and eye opening occurred at doses of 10 and 60 mg/kg (approximately one-half and 3.2 times the MRHD on a mg/m2 basis).

8.2 Lactation

Risk Summary

There are no data on the presence of ticagrelor or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Ticagrelor and its metabolites were present in rat milk at higher concentrations than in maternal plasma. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Breastfeeding is not recommended during treatment with BRILINTA.

8.4 Pediatric Use

The safety and effectiveness of BRILINTA in pediatric patients have not been established.

8.5 Geriatric Use

In PLATO and PEGASUS, about half of patients in each study were 65 years of age and about 15% were 75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients.

8.6 Hepatic Impairment

Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Avoid use of BRILINTA in patients with severe hepatic impairment. There is limited experience with BRILINTA in patients with moderate hepatic impairment; consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor. No dosage adjustment is needed in patients with mild hepatic impairment [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dosage adjustment is needed in patients with renal impairment [see Clinical Pharmacology (12.3)].

Patients with End-Stage Renal Disease on dialysis

Clinical efficacy and safety studies with BRILINTA did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, no clinically significant difference in concentrations of ticagrelor and its metabolite and platelet inhibition are expected compared to those observed in patients with normal renal function [see Clinical Pharmacology (12.3)]. It is not known whether these concentrations will lead to similar reductions in risk of CV death, myocardial infarction or stroke or similar bleeding risk in patients with ESRD on dialysis as were seen in PLATO and PEGASUS.

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.

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 g/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.

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 M 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 3, 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 M ADP.

As shown in Figure 4, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in Figure 4 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 3 - Mean inhibition of platelet aggregation ( SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel

Figure 4 - 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 5. 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 5 - 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 6 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 6 - 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 7.

Figure 7 - Impact of BRILINTA on the pharmacokinetics of co-administered drugs

12.5 Pharmacogenetics

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.

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).

14 Clinical Studies ⮝

14.1 Acute Coronary Syndromes and Secondary Prevention after Myocardial Infarction

PLATO

PLATO 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 277 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 6 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.

Table 6 - Patients with outcome events (KM%)(PLATO)

* Dosed at 90 mg bid. Note: rates of first events for the components CV Death, MI and Stroke are the actual rates for first events for each component and do not add up to the overall rate of events in the composite endpoint. Including patients who could have had other non-fatal events or died.
	BRILINTA* N=9333	Clopidogrel N=9291	Hazard Ratio (95% CI)	p-value
Composite of CV death, MI, or stroke	9.8	11.7	0.84 (0.77, 0.92)	0.0003
CV death	2.9	4.0	0.74
Non-fatal MI	5.8	6.9	0.84
Non-fatal stroke	1.4	1.1	1.24
Secondary endpoints
CV death	4.0	5.1	0.79 (0.69, 0.91)	0.0013
MI	5.8	6.9	0.84 (0.75, 0.95)	0.0045
Stroke	1.5	1.3	1.17 (0.91, 1.52)	0.22
All-cause mortality	4.5	5.9	0.78 (0.69, 0.89)	0.0003

The Kaplan-Meier curve (Figure 8) 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 8 - 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 11289 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 9. 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 9 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 10 shows results by region and dose.

Figure 10 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 was a 21162-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. See Table 7 for key baseline features.

Table 7 - Baseline features (PEGASUS)

Demographic	% Patients
<65 years	45%
Diabetes	32%
Multivessel disease	59%
History of >1 MI	17%
Chronic non-end stage renal disease	19%
Stent	80%
Prior P2Y12 platelet inhibitor therapy	89%
Lipid lowering therapy	94%

The Kaplan-Meier curve (Figure 11) shows time to first occurrence of the primary composite endpoint of CV death, non-fatal MI or non-fatal stroke.

Figure 11 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.

Table 8 - Incidences of the primary composite endpoint, primary composite endpoint components, and secondary endpoints (PEGASUS)

* 60 mg BID Primary endpoint For the components, the first-occurring component of the composite is included. Secondary endpoints The number of first events for the components CV Death, MI and Stroke are the actual number of first events for each component and do not add up to the number of events in the composite endpoint.
	BRILINTA* + Aspirin N=7045		Aspirin Alone N=7067		HR (95% CI)	p-value
	n (patients with event)	KM%	n (patients with event)	KM%
Time to first CV death, MI, or stroke	487	7.8	578	9.0	0.84 (0.74, 0.95)	0.0043
CV Death	116		128
Myocardial infarction	283		336
Stroke	88		114
Subjects with events at any time CV Death ,	174	2.9	210	3.4	0.83 (0.68, 1.01)
Myocardial infarction	285	4.5	338	5.2	0.84 (0.72, 0.98)
Stroke	91	1.5	122	1.9	0.75 (0.57, 0.98)
All-cause mortality	289	4.7	326	5.2	0.89 (0.76, 1.04)
CI = Confidence interval; CV = Cardiovascular; HR = Hazard ratio; KM = Kaplan-Meier percentage calculated at 36 months; MI = Myocardial infarction; N = Number of patients.

In PEGASUS, the 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 12.

Figure 12 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.

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].

Package/label Display Panel  ⮝

Brilinta Tablets 90 mg

Ticagrelor

10 Tablets

BRILINTA ticagrelor tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55154-9618(NDC:0186-0777) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength TICAGRELOR (UNII: GLH0314RVC) (TICAGRELOR - UNII:GLH0314RVC) TICAGRELOR 90 mg

Inactive Ingredients Ingredient Name Strength MANNITOL (UNII: 3OWL53L36A) DIBASIC CALCIUM PHOSPHATE DIHYDRATE (UNII: O7TSZ97GEP) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) Hydroxypropyl Cellulose (1600000 WAMW) (UNII: RFW2ET671P) MAGNESIUM STEARATE (UNII: 70097M6I30) WATER (UNII: 059QF0KO0R) HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TALC (UNII: 7SEV7J4R1U) POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ) FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Product Characteristics Color YELLOW Score no score Shape ROUND (biconvex) Size 9mm Flavor Imprint Code 90;T Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:55154-9618-0 10 in 1 BAG 08/05/2011 1 1 in 1 BLISTER PACK; Type 0: Not a Combination Product 2 NDC:55154-9618-8 1440 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 08/05/2011

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022433 08/05/2011

Labeler - Cardinal Health (603638201)

Revised: 5/2019 Document Id: 948986c2-8999-418c-9d9e-733c65087d5e 34391-3 Set id: 4f9bd52a-99a7-4606-92b4-456a917aabef Version: 6 Effective Time: 20190513 Cardinal Health

Warning: (a) Bleeding Risk, (b) Aspirin Dose And Brilinta Effectiveness ⮝

A. BLEEDING RISK

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 (5.4).

B. ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided (2.1, 5.2, 14.1).

Package/label Principal Display Panel 60 Mg  ⮝

NDC 0186-0776-60

60 tablets

BRILINTA

ticagrelor tablets

60 mg

Rx only

Dispense the accompanying Medication Guide to each patient.

AstraZeneca

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

BRILINTA ticagrelor tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0186-0777 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength TICAGRELOR (UNII: GLH0314RVC) (TICAGRELOR - UNII:GLH0314RVC) TICAGRELOR 90 mg

Inactive Ingredients Ingredient Name Strength MANNITOL (UNII: 3OWL53L36A) CALCIUM PHOSPHATE, DIBASIC, DIHYDRATE (UNII: O7TSZ97GEP) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P) MAGNESIUM STEARATE (UNII: 70097M6I30) WATER (UNII: 059QF0KO0R) HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TALC (UNII: 7SEV7J4R1U) POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ) FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Product Characteristics Color YELLOW Score no score Shape ROUND (biconvex) Size 9mm Flavor Imprint Code 90;T Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0186-0777-08 8 in 1 BOTTLE; Type 0: Not a Combination Product 08/05/2011 2 NDC:0186-0777-60 60 in 1 BOTTLE; Type 0: Not a Combination Product 08/05/2011 3 NDC:0186-0777-18 180 in 1 BOTTLE; Type 0: Not a Combination Product 08/05/2011 08/05/2011 4 NDC:0186-0777-39 10 in 1 BOX, UNIT-DOSE 08/05/2011 4 10 in 1 BLISTER PACK; Type 0: Not a Combination Product 5 NDC:0186-0777-28 14 in 1 BOTTLE; Type 0: Not a Combination Product 08/05/2011 04/28/2017

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022433 08/05/2011

BRILINTA ticagrelor tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0186-0776 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength TICAGRELOR (UNII: GLH0314RVC) (TICAGRELOR - UNII:GLH0314RVC) TICAGRELOR 60 mg

Inactive Ingredients Ingredient Name Strength MANNITOL (UNII: 3OWL53L36A) CALCIUM PHOSPHATE, DIBASIC, DIHYDRATE (UNII: O7TSZ97GEP) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P) MAGNESIUM STEARATE (UNII: 70097M6I30) WATER (UNII: 059QF0KO0R) HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TALC (UNII: 7SEV7J4R1U) POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ) FERROSOFERRIC OXIDE (UNII: XM0M87F357) FERRIC OXIDE RED (UNII: 1K09F3G675)

Product Characteristics Color PINK Score no score Shape ROUND (biconvex) Size 8mm Flavor Imprint Code 60;T Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0186-0776-60 60 in 1 BOTTLE; Type 0: Not a Combination Product 09/04/2015 2 NDC:0186-0776-94 1 in 1 BOX, UNIT-DOSE 09/04/2015 2 14 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022433 09/04/2015

Labeler - AstraZeneca Pharmaceuticals LP (938368834)

Registrant - AstraZeneca PLC (230790719)

Revised: 4/2019 Document Id: 8b84cc44-94df-4e15-9fca-517f8e2e648d 34391-3 Set id: f7b3f443-e83d-4bf2-0e96-023448fed9a8 Version: 37 Effective Time: 20190403 AstraZeneca Pharmaceuticals LP