Prasugrel

Prasugrel tablets is a P2Y 12 platelet inhibitor indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with percutaneous coronary intervention (PCI) as follows: Patients with unstable angina or non-ST-elevation myocardial infarction (NSTEMI). Patients with ST-elevation myocardial infarction (STEMI) when managed with either primary or delayed PCI.

1.1Acute Coronary Syndrome Prasugrel

tablet is indicated to reduce the rate of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI) as follows: Patients with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI). Patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI. Prasugrel tablet has been shown to reduce the rate of a combined endpoint of cardiovascular death, nonfatal myocardial infarction (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 .

Initiate prasugrel tablets treatment as a single 60 mg oral loading dose and then continue at 10 mg orally once daily. Patients taking prasugrel tablets should also take aspirin (75 mg to 325 mg) daily . Prasugrel tablets may be administered with or without food . Timing of Loading Dose In the clinical trial that established the efficacy and safety of prasugrel tablets, the loading dose of prasugrel tablets was not administered until coronary anatomy was established in UA/NSTEMI patients and in STEMI patients presenting more than 12 hours after symptom onset. In STEMI patients presenting within 12 hours of symptom onset, the loading dose of prasugrel tablets was administered at the time of diagnosis, although most received prasugrel tablets at the time of PCI . For the small fraction of patients that required urgent CABG after treatment with prasugrel tablets, the risk of significant bleeding was substantial.

Although 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 a trial of 4033 NSTEMI patients, no clear benefit was observed when prasugrel tablets loading dose was administered prior to diagnostic coronary angiography compared to at the time of PCI; however, risk of bleeding was increased with early administration in patients undergoing PCI or early CABG. Dosing in Low Weight Patients Compared to patients weighing ≥60 kg, patients weighing <60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10 mg once daily maintenance dose. Consider lowering the maintenance dose to 5 mg in patients <60 kg. The effectiveness and safety of the 5 mg dose have not been prospectively studied . Initiate treatment with a single 60 mg oral loading dose.

Continue at 10 mg once daily with or without food. Consider 5 mg once daily for patients <60 kg. Patients should also take aspirin (75 mg to 325 mg) daily.

5 WARNINGS AND PRECAUTIONS CABG-related bleeding: Risk increases in patients receiving prasugrel tablets who undergo CABG. CABG-related bleeding: Risk increases in patients receiving prasugrel tablets who undergo CABG. Discontinuation of prasugrel tablets: Premature discontinuation increases risk of stent thrombosis, MI, and death. Thrombotic thrombocytopenic purpura (TTP): TTP has been reported with prasugrel tablets. Hypersensitivity: Hypersensitivity including angioedema has been reported with prasugrel tablets including in patients with a history of hypersensitivity reaction to other thienopyridines.

5.1General Risk of Bleeding Thienopyridines,

including prasugrel tablets, increase the risk of bleeding. With the dosing regimens used in TRITON-TIMI 38, TIMI (Thrombolysis in Myocardial Infarction) Major (clinically overt bleeding associated with a fall in hemoglobin ≥5 g/dL, or intracranial hemorrhage) and TIMI Minor (overt bleeding associated with a fall in hemoglobin of ≥3 g/dL but <5 g/dL) bleeding events were more common on prasugrel tablets than on clopidogrel . The bleeding risk is highest initially, as shown in Figure 1 (events through 450 days; inset shows events through 7 days). Figure 1: Non-CABG-Related TIMI Major or Minor Bleeding Events.

Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures even if the patient does not have overt signs of bleeding. Do not use prasugrel tablets in patients with active bleeding, prior TIA or stroke . Other risk factors for bleeding are: Age ≥ 75 years. Because of the risk of bleeding (including fatal bleeding) and uncertain effectiveness in patients ≥75 years of age, use of prasugrel tablets is generally not recommended in these patients, except in high-risk situations (patients with diabetes or history of myocardial infarction) where its effect appears to be greater and its use may be considered . CABG or other surgical procedure . Body weight <60 kg.

Consider a lower (5 mg) maintenance dose . Propensity to bleed (e.g., recent trauma, recent surgery, recent or recurrent gastrointestinal (GI) bleeding, active peptic ulcer disease, severe hepatic impairment, or moderate to severe renal impairment) . Medications that increase the risk of bleeding (e.g., oral anticoagulants, chronic use of nonsteroidal anti-inflammatory drugs [NSAIDs], and fibrinolytic agents). Aspirin and heparin were commonly used in TRITON-TIMI 38 . Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7-10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of prasugrel's active metabolite is short relative to the lifetime of the platelet, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.

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5.2Coronary Artery Bypass Graft Surgery-Related

Bleeding The risk of bleeding is increased in patients receiving prasugrel tablets who undergo CABG. If possible, prasugrel tablets should be discontinued at least 7 days prior to CABG. Of the 437 patients who underwent CABG during TRITON-TIMI 38, the rates of CABG-related TIMI Major or Minor bleeding were 14.1% in the prasugrel tablets group and 4.5% in the clopidogrel group . The higher risk for bleeding events in patients treated with prasugrel tablets persisted up to 7 days from the most recent dose of study drug. For patients receiving a thienopyridine within 3 days prior to CABG, the frequencies of TIMI Major or Minor bleeding were 26.7% (12 of 45 patients) in the prasugrel tablets group, compared with 5.0% (3 of 60 patients) in the clopidogrel group. For patients who received their last dose of thienopyridine within 4 to 7 days prior to CABG, the frequencies decreased to 11.3% (9 of 80 patients) in the prasugrel group and 3.4% (3 of 89 patients) in the clopidogrel group.

Do not start Prasugrel tablets in patients likely to undergo urgent CABG. CABG-related bleeding may be treated with transfusion of blood products, including packed red blood cells and platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.

5.3Discontinuation of Prasugrel

tablets Discontinue thienopyridines, including prasugrel tablets, for active bleeding, elective surgery, stroke, or TIA. The optimal duration of thienopyridine therapy is unknown. In patients who are managed with PCI and stent placement, premature discontinuation of any antiplatelet medication, including thienopyridines, conveys an increased risk of stent thrombosis, myocardial infarction, and death. Patients who require premature discontinuation of a thienopyridine will be at increased risk for cardiac events.

Lapses in therapy should be avoided, and if thienopyridines must be temporarily discontinued because of an adverse event(s), they should be restarted as soon as possible .

5.4Thrombotic Thrombocytopenic Purpura

(TTP) TTP has been reported with the use of prasugrel tablets. TTP can occur after a brief exposure (<2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment, including plasmapheresis (plasma exchange). TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragment red blood cells] seen on peripheral smear), neurological findings, renal dysfunction, and fever .

5.5Hypersensitivity Including Angioedema Hypersensitivity

including angioedema has been reported in patients receiving prasugrel tablets, including patients with a history of hypersensitivity reaction to other thienopyridines .

Active pathological bleeding Active pathological bleeding Prior transient ischemic attack or stroke Hypersensitivity to prasugrel or any component of the product

4.1Active Bleeding Prasugrel

tablet is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage (ICH) .

4.2Prior Transient Ischemic Attack or Stroke

Prasugrel tablet is contraindicated in patients with a history of prior transient ischemic attack (TIA) or stroke. In TRITON-TIMI 38 ( TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet Inhibitio N with prasugrel), patients with a history of TIA or ischemic stroke (>3 months prior to enrollment) had a higher rate of stroke on prasugrel tablets (6.5%; of which 4.2% were thrombotic stroke and 2.3% were intracranial hemorrhage [ICH]) than on clopidogrel (1.2%; all thrombotic). In patients without such a history, the incidence of stroke was 0.9% (0.2% ICH) and 1.0% (0.3% ICH) with Prasugrel tablets and clopidogrel, respectively.

Patients with a history of ischemic stroke within 3 months of screening and patients with a history of hemorrhagic stroke at any time were excluded from TRITON-TIMI 38. Patients who experience a stroke or TIA while on Prasugrel tablets generally should have therapy discontinued .

4.3Hypersensitivity Prasugrel

tablet is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product .

8.1Pregnancy Risk Summary There

are no data with prasugrel tablets use in pregnant women to inform a drug-associated risk. No structural malformations were observed in animal reproductive and developmental toxicology studies when rats and rabbits were administered prasugrel during organogenesis at doses of up to 30 times the recommended therapeutic exposures in humans . Due to the mechanism of action of prasugrel tablets, and the associated identified risk of bleeding, consider the benefits and risks of prasugrel tablets and possible risks to the fetus when prescribing Prasugrel tablets to a pregnant woman . The background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Data Animal Data In embryo fetal developmental toxicology studies, pregnant rats and rabbits received prasugrel at maternally toxic oral doses equivalent to more than 40 times the human exposure.A slight decrease in fetal body weight was observed; but, there were no structural malformations in either species. In prenatal and postnatal rat studies, maternal treatment with prasugrel had no effect on the behavioral or reproductive development of the offspring at doses greater than 150 times the human exposure.

The following serious adverse reactions are also discussed elsewhere in the labeling: Bleeding Thrombotic thrombocytopenic purpura Hypersensitivity including Angioedema Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1Clinical Trials Experience Safety in

patients with ACS undergoing PCI was evaluated in a clopidogrel-controlled study, TRITON-TIMI 38, in which 6741 patients were treated with prasugrel tablets (60 mg loading dose and 10 mg once daily) for a median of 14.5 months (5802 patients were treated for over 6 months; 4136 patients were treated for more than 1 year). The population treated with prasugrel tablet was 27 to 96 years of age, 25% female, and 92% Caucasian. All patients in the TRITON-TIMI 38 study were to receive aspirin.

The dose of clopidogrel in this study was a 300 mg loading dose and 75 mg once daily. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with the rates observed in other clinical trials of another drug and may not reflect the rates observed in practice. Drug Discontinuation The rate of study drug discontinuation because of adverse reactions was 7.2% for Prasugrel tablets and 6.3% for clopidogrel.

Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for prasugrel tablets and 1.4% for clopidogrel). Bleeding Bleeding Unrelated to CABG Surgery - In TRITON-TIMI 38, overall rates of TIMI Major or Minor bleeding adverse reactions unrelated to coronary artery bypass graft surgery (CABG) were significantly higher on prasugrel tablets than on clopidogrel, as shown in Table 1 . Table 1: Non-CABG-Related Bleeding * (TRITON-TIMI 38) * Patients may be counted in more than one row. † See 5.1 for definition. Prasugrel tablets (%) (N=6741) Clopidogrel (%) (N=6716) TIMI Major or Minor bleeding 4.5

3.4TIMI Major

bleeding † 2.2

1.7Life-threatening

1.3

0.8Fatal

0.3

0.1Symptomatic

intracranial hemorrhage (ICH) 0.3

0.3Requiring

inotropes 0.3

0.1Requiring

surgical intervention 0.3

0.3Requiring

transfusion (≥4 units) 0.7

0.5TIMI Minor

bleeding † 2.4

1.9Figure

1 demonstrates non-CABG related TIMI Major or Minor bleeding. The bleeding rate is highest initially, as shown in Figure 1 (inset: Days 0 to 7) . Bleeding by Weight and Age - In TRITON –TIMI 38, non –CABG-related TIMI Major or Minor bleeding rates in patients with the risk factors of age ≥75 years and weight <60 kg are shown in Table 2 . Table 2: Bleeding Rates for Non-CABG-Related Bleeding by Weight and Age (TRITON-TIMI 38) * 10 mg Prasugrel tablets maintenance dose † 75 mg clopidogrel maintenance dose Major/Minor Fatal Prasugrel tablets * (%) Clopidogrel † (%) Prasugrel tablets * (%) Clopidogrel † (%) Weight <60 kg (N=308 Prasugrel tablets, N=356 clopidogrel) 10.1 6.5 0.0

0.3Weight

≥60 kg (N=6373 Prasugrel tablets, N=6299 clopidogrel) 4.2 3.3 0.3

0.1Age

<75 years (N=5850 Prasugrel tablets, N=5822 clopidogrel) 3.8 2.9 0.2

0.1Age

≥75 years (N=891 Prasugrel tablets, N=894 clopidogrel) 9.0 6.9 1.0

0.1Bleeding Related to

CABG - In TRITON-TIMI 38, 437 patients who received a thienopyridine underwent CABG during the course of the study. The rate of CABG-related TIMI Major or Minor bleeding was 14.1% for the prasugrel tablets group and 4.5% in the clopidogrel group . The higher risk for bleeding adverse reactions in patients treated with prasugrel tablets persisted up to 7 days from the most recent dose of study drug. Table 3: CABG-Related Bleeding * (TRITON-TIMI 38) * Patients may be counted in more than one row.

Prasugrel tablets (%) (N=213) Clopidogrel (%) (N=224) TIMI Major or Minor bleeding 14.1

4.5TIMI Major

bleeding 11.3

3.6Fatal

0.9 0 Reoperation 3.8

0.5Transfusion of

≥5 units 6.6

2.2Intracranial

hemorrhage 0 0 TIMI Minor bleeding 2.8

0.9Bleeding Reported as Adverse Reactions

- Hemorrhagic events reported as adverse reactions in TRITON-TIMI 38 were, for Prasugrel tablets and clopidogrel, respectively: epistaxis (6.2%, 3.3%), gastrointestinal hemorrhage (1.5%, 1.0%), hemoptysis (0.6%, 0.5%), subcutaneous hematoma (0.5%, 0.2%), post-procedural hemorrhage (0.5%, 0.2%), retroperitoneal hemorrhage (0.3%, 0.2%), pericardial effusion/hemorrhage/tamponade (0.3%, 0.2%), and retinal hemorrhage (0.0%, 0.1%). Malignancies During TRITON-TIMI 38, newly-diagnosed malignancies were reported in 1.6% and 1.2% of patients treated with prasugrel and clopidogrel, respectively. The sites contributing to the differences were primarily colon and lung.

In another Phase 3 clinical study of ACS patients not undergoing PCI, in which data for malignancies were prospectively collected, newly-diagnosed malignancies were reported in 1.8% and 1.7% of patients treated with prasugrel and clopidogrel, respectively. The site of malignancies was balanced between treatment groups except for colorectal malignancies. The rates of colorectal malignancies were 0.3% prasugrel, 0.1% clopidogrel and most were detected during investigation of GI bleed or anemia.

It is unclear if these observations are causally-related, are the result of increased detection because of bleeding, or are random occurrences. Other Adverse Events In TRITON-TIMI 38, common and other important non-hemorrhagic adverse events were, for prasugrel tablets and clopidogrel, respectively: severe thrombocytopenia (0.06%, 0.04%), anemia (2.2%, 2.0%), abnormal hepatic function (0.22%, 0.27%), allergic reactions (0.36%, 0.36%), and angioedema (0.06%, 0.04%). Table 4 summarizes the adverse events reported by at least 2.5% of patients.

Table 4: Non-Hemorrhagic Treatment Emergent Adverse Events Reported by at Least 2.5% of Patients in Either Group * WBC=white blood cell Prasugrel tablets (%) (N=6741) Clopidogrel (%) (N=6716) Hypertension 7.5

7.1Hypercholesterolemia/Hyperlipidemia

7.0

7.4Headache

5.5

5.3Back

pain 5.0

4.5Dyspnea

4.9

4.5Nausea

4.6

4.3Dizziness

4.1

4.6Cough

3.9

4.1Hypotension

3.9

3.8Fatigue

3.7

4.8Non-cardiac

chest pain 3.1

3.5Atrial

fibrillation 2.9

3.1Bradycardia

2.9

2.4Leukopenia

(<4 x 10 9 WBC * /L) 2.8

3.5Rash

2.8

2.4Pyrexia

2.7

2.2Peripheral

edema 2.7

3.0Pain in

extremity 2.6

2.6Diarrhea

2.3 2.6

6.2Postmarketing Experience The

following adverse reactions have been identified during post approval use of prasugrel tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders - thrombocytopenia, thrombotic thrombocytopenic purpura (TTP) Immune system disorders - hypersensitivity reactions including anaphylaxis