Make an Impact by OEM65

FOR YOUR stemi & non-stemi ACS PATIENTS

DECISIONS TODAY CAN IMPACT A LIFE

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ELEVATED TROPONIN IN ACute coronary syndrome (acs) IS ASSOCIATED WITH HIGHER RISK OF DEATH OR REINFARCTION1-4

Troponin-positive ACS indicates myocardial damage1 Troponin elevation is independently associated with worse clinical outcomes in ACS patients2-4

Please read additional Important Safety Information on adjacent pages and on page 16 and accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide. 2

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MORE MORETHAN THAN11OUT OUTOF OF44WOMEN WOMEN** DIED DIEDWITHIN WITHIN11YEAR YEARPOST POSTMI MI

NEARLY NEARLY11OUT OUTOF OF55MEN MEN** DIED DIEDWITHIN WITHIN11YEAR YEARPOST POSTMI MI

MI=myocardial infarction.

* These numbers represent pooled data from 3 cardiovascular registries: The Framingham Heart Study, The Atherosclerosis Risk in Communities Study, and the Cardiovascular Health Study, of the National Heart, Lung, and Blood Institute. These data include patients who died within 1 year of their first MI, aged â&#x2030;Ľ45 years, from 1986-2007. The incidence of post-MI mortality rates may be higher or lower in different populations. American Heart Association (AHA) Heart Disease and Stroke Statistics 2013 Update, a publication of statistics on heart disease, stroke, other vascular disease, and their risk factors from the AHA, Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies.

Key risk factors for death post MI may include Patient Age6 | Medical history 6 | Comorbidities7 | Severity of the ACS event6

POST-MI RISK

AHA statiSTIcs for post mi death rates5

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Antiplatelet therapy decisions can help make an impact post MI8-11

Platelets play a key role in atherothrombosis post MI8,9 US ACS Guidelines recommend Dual antiplatelet therapy for up to OR AT LEAST 1 year post MI10-11*

*The Class I/Grade 1B recommended length of therapy as per the following US ACS guidelines are: 2013 ACCF/AHA guidelines for STEMI management: for 1 year in STEMI patients who received a stent during primary PCI; 2012 ACCF/AHA guidelines for UA/NSTEMI management: for up to 12 months in UA/NSTEMI patients in whom an initial conservative (ie, noninvasive) strategy is selected, and for at least 12 months for UA/NSTEMI patients who have undergone PCI. ACCF=American College of Cardiology Foundation.

INDICATIONS BRILINTA is indicated to reduce the rate of thrombotic cardiovascular (CV) events in patients with acute coronary syndrome (ACS) (unstable angina [UA], nonâ&#x20AC;&#x201C;ST-elevation myocardial infarction [NSTEMI], or ST-elevation myocardial infarction [STEMI]). BRILINTA has been shown to reduce the rate of a combined end point of CV death, myocardial infarction (MI), or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with percutaneous coronary intervention (PCI), it also reduces the rate of stent thrombosis. BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin >100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin >100 mg daily. â&#x20AC;˘ Patients in PLATO were treated for up to 12 months

Please read additional Important Safety Information on adjacent pages and on page 16 and accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide. 4

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BRILINTA Is the First and Only CPTP Oral Antiplatelet12

ACTIVE WITHOUT METABOLISM

METABOLISM INDEPENDENT OF CYP2C19 GENOTYPE

PRIMARY CYP ENZYME FOR METABOLISM

CPTP

YES

3A4

THIENOPYRIDINE

2C19

THIENOPYRIDINE

YES

3A4 AND 2B6

F HN

N HO

F S

CLOPIDOGREL14 H N

C - OCH3 CI H2SO4

PRASUGREL15 O

O H3C

O S

HC1 F

CPTP=cyclo-pentyl-triazolo-pyrimidine.

• It is not known how pharmacology or chemical class correlate to clinical efficacy or safety results • Ticagrelor and its active metabolite are approximately equipotent IMPORTANT SAFETY INFORMATION WARNING: BLEEDING RISK • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding (See page 9 for full Boxed WARNING on bleeding risk)

WARNING: ASPIRIN DOSE AND BRILINTA EFFECTIVENESS • Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin 75 mg–100 mg per day • BRILINTA is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure; it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins • Moderate Hepatic Impairment: Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor • BRILINTA is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors and potent CYP3A inducers • Avoid simvastatin and lovastatin doses >40 mg • Monitor digoxin levels with initiation of, or any change in, BRILINTA therapy

PHARMACOLOGY

BRILINTA

CHEMICAL CLASS

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BRILINTA Provided Rapid Onset and High Inhibition of Platelet Aggregation (IPA)16,17 ASSESSMENT OF IPA OVER 8 HOURS AFTER 180-MG LOADING DOSE13,17

88% BRILINTA + aspirin

IPA (%) INDUCED BY 20 µmol/L ADP

100

180-mg loading dose

79%

(n=54)

80 70 60 50

CLOPIDOGREL + aspirin

41%

(n=50)

600-mg loading dose

40 30 20

PLACEBO + aspirin

(n=12)

0 0

LOADING DOSE

TIME (HOURS)

In a multicenter, randomized, double-blind study, patients with stable coronary artery disease (CAD) who were taking aspirin therapy (75 mg to 100 mg per day) received BRILINTA (180-mg loading dose, 90-mg twice daily maintenance dose), clopidogrel (600-mg loading dose, 75-mg once daily maintenance dose), or placebo for 6 weeks. ADP=adenosine diphosphate.

• It is not known how bleeding or thrombotic risk track with IPA for either BRILINTA or clopidogrel13 • The maximum IPA effect of BRILINTA was 88% at around 2 hours, and was maintained for at least 8 hours13,16* • IPA was higher in the BRILINTA group at all time points13 • Patients can be transitioned from clopidogrel to BRILINTA without interruption of antiplatelet effect13 — The transition from clopidogrel to BRILINTA resulted in an absolute IPA increase of 26.4%, and the transition from BRILINTA to clopidogrel resulted in an absolute IPA decrease of 24.5% *Demonstrated in patients with stable CAD.

Please read additional Important Safety Information on adjacent pages and on page 16 and accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide. 6

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BRILINTA loading in the ed or cath lab is NOT Restricted By 13: Patient Age Or Weight

intent of Medical or Invasive Management*

Prior TIA / ischemic Stroke

CYP2C19 Genotype

Concomitant PPI Use

Other important treatment considerations include contraindications, patient bleeding risk, comorbid conditions, other concomitant medications, and overall health status ED=emergency department; TIA=transient ischemic attack; PPI=proton pump inhibitor. *PLATO included both medical and invasive (percutaneous coronary intervention [PCI] or coronary artery bypass graft surgery [CABG]) treatment approaches. Patients who received fibrinolytic therapy within the previous 24 hours or who had a need for chronic oral anticoagulation therapy were excluded.18

• In the PLATelet Inhibition and Patient Outcomes (PLATO) study, 43% of patients were ≥65 years of age and 15% were ≥75 years of age. The relative risk of bleeding was similar among treatment groups and age groups; however, greater sensitivity of some older individuals cannot be ruled out13 • Initial aspirin loading dose is usually 325 mg, followed by a maintenance dose of 75 mg–100 mg daily. Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA. Avoid maintenance doses of aspirin >100 mg daily13

IMPORTANT SAFETY INFORMATION • Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery • BRILINTA is contraindicated in patients with a history of intracranial hemorrhage and active pathological bleeding such as peptic ulcer or intracranial hemorrhage. BRILINTA is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure; it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins. BRILINTA is also contraindicated in patients with hypersensitivity (e.g. angioedema) to ticagrelor or any component of the product • Moderate Hepatic Impairment: Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor • BRILINTA is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors and potent CYP3A inducers. Avoid simvastatin and lovastatin doses >40 mg. Monitor digoxin levels with initiation of, or any change in, BRILINTA therapy • In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias. PLATO excluded patients at increased risk of bradycardic events. Consider the risks and benefits of treatment

INITIATION

Previous Clopidogrel Loading Or Maintenance Dose

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PLATO trial design was Different From TRITON TIMI-3813,18,19

TRIAL

PATIENT POPULATION

COMPARATORS

ACS MANAGEMENT STRATEGY

PRERANDOMIZATION CLOPIDOGREL USE

CLOPIDOGREL LOADING DOSE

BRILINTA

PRASUGREL

PLATO

TRITON TIMI-38

38% STEMI 43% NSTEMI 17% UA

26% STEMI 74% UA/NSTEMI

BRILINTA + ASPIRIN VS CLOPIDOGREL + ASPIRIN

PRASUGREL + ASPIRIN VS CLOPIDOGREL + ASPIRIN

INVASIVE (INCLUDING PCI OR CABG) OR MEDICAL*

PCI

YES† (46%)

300 MG OR HIGHER

300 MG

YES‡

NO§

(N=18,624)

RANDOMIZATION PRIOR TO CORONARY ANGIOGRAPHY

(N=13,608)

• The PLATO study compared BRILINTA (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter) for the prevention of CV events in 18,624 patients with ACS (UA, NSTEMI, STEMI). Patients were treated for at least 6 months and up to 12 months. BRILINTA and clopidogrel were studied with aspirin and other standard therapies * Patients who received fibrinolytic therapy within the previous 24 hours or who had a need for chronic oral anticoagulation therapy were excluded. † In-hospital load prior to randomization. ‡ Patients could have been randomized at any point prior to PCI, including post-angiography.20 § Except for STEMI patients presenting within 12 hours of symptom onset and primary PCI planned.

IMPORTANT SAFETY INFORMATION • Moderate Hepatic Impairment: Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor • Premature discontinuation increases the risk of MI, stent thrombosis, and death • Dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients taking clopidogrel. Dyspnea resulting from BRILINTA is self-limiting. Rule out other causes • The most commonly observed adverse reactions associated with the use of BRILINTA vs clopidogrel were Total Major Bleeding (11.6% vs 11.2%) and dyspnea (14% vs 8%) • In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias. PLATO excluded patients at increased risk of bradycardic events. Consider the risks and benefits of treatment

Please read additional Important Safety Information on adjacent pages and on page 16 and accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide. 8

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BRILINTA Indication in ACS is Different From Prasugrel13,15 INDICATIONS AND USAGE ACUTE CORONARY SYNDROME

PRASUGREL

BRILINTA BRILINTA is a P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic CV events in patients with ACS (UA, STEMI, NSTEMI). BRILINTA has been shown to reduce the rate of a combined end point of CV death, MI, or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with PCI, it also reduces the rate of stent thrombosis.

Prasugrel is indicated to reduce the rate of thrombotic CV events (including stent thrombosis) in patients with ACS who are to be managed with PCI as follows: • Patients with UA or NSTEMI • Patients with STEMI when managed with primary or delayed PCI

BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin above 100 mg daily.

It is generally recommended that antiplatelet therapy be administered promptly in the management of ACS because many cardiovascular events occur within hours of initial presentation. In the clinical trial that established the efficacy of prasugrel, prasugrel and the control drug were not administered to UA/NSTEMI patients until coronary anatomy was established. For the small fraction of patients that required urgent CABG after treatment with prasugrel, the risk of significant bleeding was substantial. Because the large majority of patients are managed without CABG, however, treatment can be considered before determining coronary anatomy if need for CABG is considered unlikely. The advantages of earlier treatment with prasugrel must then be balanced against the increased rate of bleeding in patients who do need to undergo urgent CABG.

• There have been no head-to-head clinical outcomes studies comparing Brilinta and prasugrel IMPORTANT SAFETY INFORMATION WARNING: BLEEDING RISK • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding • Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage • Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery •S uspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures in the setting of BRILINTA • If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events

TRIALS/ INDICATIONS

Prasugrel has been shown to reduce the rate of a combined end point of CV death, nonfatal MI, or nonfatal stroke compared to clopidogrel. The difference between treatments was driven predominantly by MI, with no difference on strokes and little difference on CV death.

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BRILINTA: Proven Superior to Clopidogrel at 12 Months in Reducing Thrombotic CV Events13,21 PLATO Primary Efficacy End Point: Composite of CV Death, MI,* or Stroke at 12 Months13,21 14

COMPOSITE OF CV DEATH, MI,* OR STROKE (K-M%)

12 mos.

11.7%

AT 12 MONTHS

16%

CLOPIDOGREL + aspirin

RRR

(n=9291)

30 days

5.4%

9.8% BRILINTA + aspirin

1.9%

(n=9333)

4.8

Absolute Risk Reduction

Hazard Ratio 0.84

95% Confidence Interval 0.77-0.92

P value <0.001

NNT: 54†

0 0

120

180

240

300

360

DAYS FROM RANDOMIZATION • Difference between treatments was driven by CV death and MI with no difference

in stroke

REDUCTIONS IN THROMBOTIC CV EVENTS SEEN AS EARLY AS 30 DAYS THAT INCREASED OVER 12 MONTHS13,21

* Excluding silent MI. RRR=relative risk reduction. ARR=absolute risk reduction. K-M=Kaplan-Meier. † Number needed to treat (NNT) was 54; NNT=1/ARR; ARR=11.67%–9.8%=1.87%; NNT=1/0.0187=53.5.

• AT 30 DAYS BRILINTA plus aspirin reduced the primary composite end point of CV death, MI,* or stroke by 12% RRR (ARR 0.6%) vs clopidogrel plus aspirin (HR 0.88, 95% CI 0.77-1.0)13,21 • BRILINTA and clopidogrel were studied with aspirin and other standard therapies13 • Patients taking clopidogrel (maintenance or loading doses prior to randomization) were permitted13

IMPORTANT SAFETY INFORMATION WARNING: ASPIRIN DOSE AND BRILINTA EFFECTIVENESS • Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin 75 mg–100 mg per day

Please read additional Important Safety Information on adjacent pages and on page 16 and accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide. 10

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BRILINTA: The first and Only OAP FDA Approved to Demonstrate Superior Reductions in CV Death vs Clopidogrel22 PLATO Secondary Efficacy End Point: CV Death at 12 Months13,18 6

CV DEATH (K-M%)

5.1%

AT 12 MONTHS

21%

(n=9291)

4.0%

BRILINTA + aspirin (n=9333)

Hazard Ratio 0.79

95% Confidence Interval 0.69-0.91

P value 0.001

Absolute Risk Reduction

1.1% NNT: 91*

0 0

120

BRILINTA SAVED MORE LIVES THAN CLOPIDOGREL BY REDUCING CV DEATH13

RRR

CLOPIDOGREL + aspirin

180

240

300

360

* Number needed to treat (NNT) was 91; NNT=1/ARR; ARR=5.1%–4.0%=1.1%; NNT=1/0.011=91.

DAYS FROM RANDOMIZATION

BRILINTA + aspirin

CLOPIDOGREL + aspirin

HAZARD RATIO

(n=9333)

(n=9291)

(95% Confidence Interval)

MI (EXCLUDING SILENT 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

OUTCOMES (K-M%)

Includes patients who could have had other nonfatal events or died.

†

• Due to the hierarchical test sequence in PLATO, all-cause mortality was an exploratory analysis and, therefore, the P value is nominal18

IMPORTANT SAFETY INFORMATION • Premature discontinuation increases the risk of MI, stent thrombosis, and death

P value

OVER TIME (12 MONTHS)

additional secondary EFFICACY end points at 12 months13

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There Was No Significant Difference in PLATO-DEFINED Total Major Bleeding With BRILINTA vs Clopidogrel13 PLATO Primary Safety End point: Total Major Bleeding at 12 Months13

PLATO TOTAL MAJOR BLEEDING (K-M%)

11.6%

BRILINTA + aspirin (n=9235)

CLOPIDOGREL + aspirin (n=9186)

11.2%

Hazard Ratio 1.04

95% Confidence Interval 0.95-1.13

P value 0.434

No baseline demographic factor altered the relative risk of Total Major Bleeding with BRILINTA compared with clopidogrel18

0 0

120

K-M=Kaplan Meier.

180

240

300

360

DAYS FROM FIRST DOSE

PLATO used the following bleeding severity categorization: Major Bleed–Fatal/Life threatening. Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells [PRBCs]) for bleeding. Major Bleed–Other. Any one of the following: significantly disabling (eg, intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL; transfusion of 2-3 units (whole blood or PRBCs) for bleeding. Minor Bleed. Requires medical intervention to stop or treat bleeding (eg, epistaxis requiring visit to medical facility for packing). Minimal Bleed. All others (eg, bruising, bleeding gums, oozing from injection sites) not requiring intervention or treatment.

IMPORTANT SAFETY INFORMATION WARNING: BLEEDING RISK • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding • Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage • Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery • Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures in the setting of BRILINTA • If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events • The most commonly observed adverse reactions associated with the use of BRILINTA vs clopidogrel were Total Major Bleeding (11.6% vs 11.2%) and dyspnea (14% vs 8%) • In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias. PLATO excluded patients at increased risk of bradycardic events. Consider the risks and benefits of treatment

Please read additional Important Safety Information on adjacent pages and on page 16 and accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide. 12

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There Was A Somewhat Greater RISK OF PLATO-DEFINED Non–CABG-related Major and Minor Bleeding With BRILINTA vs Clopidogrel13 NON–CABG-RELATED BLEEDING RATES (K-M%)

BRILINTA + aspirin

CLOPIDOGREL + aspirin

TOTAL (MAJOR + MINOR)

8.7

7 .0

MAJOR

4.5

3 .8

FATAL/LIFE-THREATENING

2.1

1 .9

FATAL

0.2

0 .2

INTRACRANIAL (FATAL/LIFE-THREATENING)

0.3

0 .2

BRILINTA + aspirin

CLOPIDOGREL + aspirin

85.8

8 6 .9

48.1

4 7 .9

0.9

1 .1

CABG-RELATED BLEEDING RATES (K-M%)

(n=9235)

(n=770)

TOTAL MAJOR

FATAL/LIFE-THREATENING

FATAL

(n=9186)

(n=814)

No baseline demographic factor altered the relative risk of Non–CABG-related Bleeding with BRILINTA compared with clopidogrel

BLEEDING

• About half of the Non–CABG-related Bleeding events were in the first 30 days • PLATO did not show an advantage for BRILINTA compared with clopidogrel for CABG-related Bleeding • When antiplatelet therapy was stopped 5 days before CABG, Major Bleeding occurred in 75% of patients treated with BRILINTA and 79% of patients on clopidogrel • In general, risk factors for bleeding include older age, a history of bleeding disorders, performance of percutaneous invasive procedures, and concomitant use of medications that increase the risk of bleeding (eg, anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic nonsteroidal anti-inflamatory drugs [NSAIDs])

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Load BRILINTA Whether or Not a Clopidogrel Loading Dose Has Been Given13 administer loading dose regardless of previous clopidogrel use

begin maintenance dose 12 hours after loading dose23

LOADING DOSE

MAINTENANCE DOSE

BRILINTA + aspirin

TWO 90-MG TABLETS

INITIAL LOADING DOSE OF ASPIRIN

ONE 90-MG TABLET TWICE DAILY

(USUALLY 325 MG)

81-MG ASPIRIN ONCE DAILY

Tablet images are not actual size.

BRILINTA can be administered with or without food

A patient who misses a dose of BRILINTA should take one 90-mg tablet (the next dose) at its scheduled time BRILINTA is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. No dosage adjustment is needed in patients with mild hepatic impairment. BRILINTA has not been studied in moderate to severe hepatic impairment. For patients with moderate hepatic impairment, consider the risks and benefits of treatment and carefully consider use. For patients with severe hepatic impairment, BRILINTA is contraindicated No dosage adjustment is needed in patients with renal impairment. Patients on dialysis have not been studied

Please read additional Important Safety Information on adjacent pages and on page 16 and accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide. 14

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administration with other drugs13 BRILINTA can be coadministered with proton pump inhibitors (such as omeprazole), unfractionated heparin, low-molecular-weight heparin, GPIIb/IIIa inhibitors, beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin-receptor blockers

DRUGS

RECOMMENDATIONS AND/OR IMPACT ON SIMILAR DRUGS

STRONG CYP3A INHIBITORS

Ticagrelor is metabolized by CYP3A4/5. Avoid use with strong inhibitors of CYP3A (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin).

POTENT CYP3A INDUCERS

Ticagrelor is metabolized by CYP3A4/5. Avoid use with potent inducers of CYP3A (eg, rifampin, dexamethasone, phenytoin, carbamazepine, and phenobarbital).

ASPIRIN

Use BRILINTA with a daily maintenance dose of aspirin of 75 mg–100 mg. Avoid use with aspirin over 100 mg per day.

SIMVASTATIN AND LOVASTATIN

Avoid simvastatin and lovastatin doses >40 mg.

DIGOXIN

Monitor digoxin levels with initiation of, or any change in, BRILINTA therapy.

• In general, risk factors for bleeding include concomitant use of medications that increase the risk of bleeding (eg, anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic NSAIDs)

11. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA Focused Update incorporated into the ACCF/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e663-e828. 12. Husted S, van Giezen JJJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther. 2009;27(4):259-274. 13. BRILINTA® [package insert]. Wilmington, DE: AstraZeneca LP; 2013. 14. Plavix® [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2011. 15. Effient® [package insert]. Indianapolis, IN: Daiichi Sankyo, Inc. and Eli Lilly and Company; 2012. 16. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009;120(25):2577-2585. 17. Data on file, 1766201, AstraZeneca. 18. Wallentin L, Becker RC, Budaj A, et al; for the PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057 and Appendix. 19. Wiviott SD, Braunwald E, McCabe CH, et al; for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015. 20. Data on file, 2379807, AstraZeneca. 21. Data on file, 1755503, AstraZeneca. 22. Data on file, 1795500, AstraZeneca. 23. Data on file, 1397901, AstraZeneca. 24. Fingertip Formulary®. [[March 13, 2013]].

DOSING

References 1. Newby LK, Jess RL, Babb JD, et al. ACCF 2012 Expert Consensus Document on Practical Clinical Considerations in the Interpretation of Troponin Elevations: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2012;60(23):2427-2463. 2. Antman EM, Tanasijevic MJ, Thompson B, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med. 1996;335:1342-1349. 3. Dokainish H, Pillai M, Murphy SA, et al; for the TACTICS-TIMI-18 Investigators. Prognostic implications of elevated troponin in patients with suspected acute coronary syndrome but no critical epicardial coronary disease: a TACTICS-TIMI-18 substudy. J Am Coll Cardiol. 2005;45:19-24. 4. Ohman EM, Armstrong PW, Christenson RH, et al. Cardiac troponin T levels for risk stratification in acute myocardial ischemia. GUSTO IIA Investigators. N Engl J Med. 1996;335(18):1333-1341. 5. Go AS, Mozaffarian D, Roger VL, et al; on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127(1):e6-e245. 6. Fox KAA , Dabbous OH, Goldberg RJ, et al; for the GRACE Investigators. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). BMJ. 2006;333:1091-1094. 7. McManus DD, Nguyen HL, Saczynski JS, et al. Multiple cardiovascular comorbidities and acute myocardial infarction: temporal trends (1990-2007) and impact on death rates at 30 days and 1 year. Clin Epidemiol. 2012;4:115-123. 8. Gitt AK, Betriu A. Antiplatelet therapy in acute coronary syndromes. Eur Heart J Suppl. 2008;10(suppl A):A4-A12. 9. Davi G, Patrono C. Mechanisms of disease: Platelet activation and atherothrombosis. N Engl J Med. 2007;357:2482-2494. 10. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation. 2013; 127:e362-e425.

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INDICATIONS AND IMPORTANT SAFETY INFORMATION

INDICATIONS

CONTRAINDICATIONS

BRILINTA is indicated to reduce the rate of thrombotic cardiovascular (CV) events in patients with acute coronary syndrome (ACS) (unstable angina [UA], non–ST-elevation myocardial infarction [NSTEMI], or ST-elevation myocardial infarction [STEMI]). BRILINTA has been shown to reduce the rate of a combined end point of CV death, myocardial infarction (MI), or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with percutaneous coronary intervention (PCI), it also reduces the rate of stent thrombosis. BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin >100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin >100 mg daily.

• BRILINTA is contraindicated in patients with a history of intracranial hemorrhage and active pathological bleeding such as peptic ulcer or intracranial hemorrhage • BRILINTA is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure; it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins • BRILINTA is also contraindicated in patients with hypersensitivity (e.g. angioedema) to ticagrelor or any component of the product

IMPORTANT SAFETY INFORMATION ABOUT BRILINTA WARNING: BLEEDING RISK • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding • Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage • Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery • Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures in the setting of BRILINTA • If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events

WARNINGS AND PRECAUTIONS • Moderate Hepatic Impairment: Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor • Premature discontinuation increases the risk of MI, stent thrombosis, and death • Dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients taking clopidogrel. Dyspnea resulting from BRILINTA is self-limiting. Rule out other causes • BRILINTA is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors and potent CYP3A inducers. Avoid simvastatin and lovastatin doses >40 mg • Monitor digoxin levels with initiation of, or any change in, BRILINTA therapy

ADVERSE REACTIONS • The most commonly observed adverse reactions associated with the use of BRILINTA vs clopidogrel were Total Major Bleeding (11.6% vs 11.2%) and dyspnea (14% vs 8%) • In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias. PLATO excluded patients at increased risk of bradycardic events. Consider the risks and benefits of treatment

Please read accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide. 16

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BRILINTA Is Covered Without Prior Authorization For 85% of Medicare Part D and Commercially Insured Patients Nationwide24*†

MEDICARE PART D

BRILINTA HAS THE MOST PREFERRED MEDICARE PART D FORMULARY ACCESS COVERAGE OF ANY BRANDED ORAL ANTIPLATELET NATIONWIDE‡ Formulary comparisons do not imply comparable efficacy, safety, or FDA-approved indications.

COMMERCIAL

• THE MAJORITY OF COMMERCIALLY INSURED PATIENTS HAVE PREFERRED FORMULARY ACCESS FOR BRILINTA NATIONWIDE‡§ • WITH THE BRILINTA SAVINGS CARD, MOST COMMERCIALLY INSURED PATIENTS WILL PAY ONLY $8 MORE PER MONTH THAN THE COPAY OF GENERIC CLOPIDOGREL§II —Eligible patients can receive savings on out-of-pocket costs that exceed $18 (up to a $75 savings limit) on each of their next 11 prescriptions for 30-day supplies of BRILINTA. See eligibility below¶ —Pricing comparisons do not imply comparable efficacy, safety, or FDA-approved indications

*“Covered without prior authorization” means that additional information is not required to be provided to the health plan in order for BRILINTA to be covered. Step edits may apply. † “Patients” means covered lives (Commercial, Commercial [BCBS], Employer, Medicare MA, Medicare PDP, Medicare SN, Municipal Plan, PBM, Union) at Tiers 1-7 in the US, as calculated by Fingertip Formulary. ‡ “Preferred” means Tier 2 or lowest branded copay tier (or better) formulary placement. Individual costs and benefit design may vary. Please consult with individual plan for specific information. AstraZeneca does not endorse any individual, commercial, Medicare Part D, or Medicaid plan or plans. § “Patients” means covered lives (Commercial, Commercial [BCBS], Employer, Municipal Plan, PBM, Union) at Tiers 1-7 in the US, as calculated by Fingertip Formulary. II Based on the ‘average Tier 1 copay for Commercial covered lives’ for generic clopidogrel from Fingertip Formulary as of March 13, 2013. ¶ Patient Eligibility for Savings Card: This offer is good for eligible patients purchasing up to a 30-day supply (up to 60 tablets) of BRILINTA (ticagrelor) tablets and may not be used for any other product. This offer is good for the purchase of BRILINTA manufactured for AstraZeneca Pharmaceuticals LP and lawfully purchased from an authorized retailer or distributor in the United States or its territories. This offer is not insurance and is not valid for mail order or prescriptions purchased under Medicaid, Medicare or similar federal or state programs or for patients who are Medicare eligible and enrolled in an employer-sponsored group waiver health plan or government-subsidized prescription drug benefit program for retirees; or for patients under 18 years of age. Offer not valid where prohibited by law, taxed or restricted. Offer is not transferable, is limited to one per person and may not be combined with any other offer. Offer must be presented along with a valid prescription for BRILINTA at the time of purchase. If you have commercial insurance, you may receive up to 100% off of your first prescription for BRILINTA. If you pay cash for your prescriptions, you may receive your first prescription free. On each of your next 11 refills of BRILINTA, you may receive up to $75 in savings on your out-of-pocket costs that exceed $18 for each prescription up to 11 prescription fills. This offer expires 14 months from date of first use. If you have any questions regarding this offer, please call 1-888-912-7454. AstraZeneca reserves the right to change or discontinue this offer at any time without notice.

ISI/ACCESS

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IN THE TREATMENT OF ACS

HELP MAKE AN IMPACT WITH BRILINTA PROVEN TO SAVE MORE LIVES THAN CLOPIDOGREL BY REDUCING CV DEATH AT 12 MONTHS13 AT 12 MONTHS, BRILINTA plus aspirin significantly reduced the primary composite end point of CV death, MI, or stroke by 16% RRR (ARR 1.9%) vs clopidogrel plus aspirin. The difference between treatments was driven by CV death and MI with no difference in stroke AT 12 MONTHS, BRILINTA plus aspirin significantly reduced the secondary end point of CV death by 21% RRR (ARR 1.1%) vs clopidogrel plus aspirin

BLEEDING AT 12 MONTHS • There was no significant difference in Total Major Bleeding (which includes Fatal and Life-threatening bleeding) for BRILINTA plus aspirin vs clopidogrel plus aspirin (11.6% vs 11.2%) • There was somewhat greater risk of Non–CABG-related Major plus Minor Bleeding for BRILINTA plus aspirin vs clopidogrel plus aspirin (8.7% vs 7.0%) and Non–CABG-related Major Bleeding (4.5% vs 3.8%), respectively • PLATO trial did not show an advantage for BRILINTA compared with clopidogrel for CABG-related Bleeding (Total Major 85.8% vs 86.9% and Fatal/life-threatening 48.1% vs 47.9%, respectively)

WARNING: ASPIRIN DOSE AND BRILINTA EFFECTIVENESS • Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin 75 mg–100 mg per day Please read additional Important Safety Information on adjacent pages and on page 16 and accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.