1.1 Acute Coronary Syndrome

Prasugrel tablets are indicated to reduce the rate of thrombotic CV events (including stent thrombosis) in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI) as follows:

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Patients with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI).

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Patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI.

Prasugrel tablets have 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 [see Clinical Studies (14)].

4.1 Active Bleeding

Prasugrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage (ICH) [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

4.2 Prior Transient Ischemic Attack or Stroke

Prasugrel tablets are contraindicated in patients with a history of prior transient ischemic attack (TIA) or stroke. In TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN 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 [see Adverse Reactions (6.1) and Clinical Studies (14)].

4.3 Hypersensitivity

Prasugrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product [see Adverse Reactions (6.2)].

5.1 General 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 [see Adverse Reactions (6.1)]. 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 [see Contraindications (4.1, 4.2)].

Other risk factors for bleeding are:

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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 their effect appears to be greater and their use may be considered [see Adverse Reactions (6.1), Use in Specific Populations (8.5), Clinical Pharmacology (12.3), and Clinical Studies (14)].

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CABG or other surgical procedure [see Warnings and Precautions (5.2)].

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Body weight < 60 kg. Consider a lower (5 mg) maintenance dose [see Dosage and Administration (2), Adverse Reactions (6.1), and Use in Specific Populations (8.6)].

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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) [see Adverse Reactions (6.1) and Use in Specific Populations (8.7, 8.8)].

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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 [see Drug Interactions (7.1, 7.2, 7.4) and Clinical Studies (14)].

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.

5.2 Coronary 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 [see Adverse Reactions (6.1)]. 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.

5.3 Discontinuation 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 [see Contraindications (4.1, 4.2) and Warnings and Precautions (5.1)].

5.4 Thrombotic 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 [see Adverse Reactions (6.2)].

5.5 Hypersensitivity Including Angioedema

Hypersensitivity including angioedema has been reported in patients receiving prasugrel tablets, including patients with a history of hypersensitivity reaction to other thienopyridines [see Contraindications (4.3) and Adverse Reactions (6.2)].

6.1 Clinical 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 tablets 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.

6.2 Postmarketing 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) [see Warnings and Precautions (5.4) and Patient Counseling Information (17)]

Immune System Disorders: hypersensitivity reactions including anaphylaxis [see Contraindications (4.3)]

7.1 Warfarin

Coadministration of prasugrel tablets and warfarin increases the risk of bleeding [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

7.2 Nonsteroidal Anti-Inflammatory Drugs

Coadministration of prasugrel tablets and NSAIDs (used chronically) may increase the risk of bleeding [see Warnings and Precautions (5.1)].

7.3 Opioids

As with other oral P2Y12 inhibitors, coadministration of opioid agonists delay and reduce the absorption of prasugrel’s 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 coadministration of morphine or other opioid agonists.

7.4 Other Concomitant Medications

Prasugrel tablets can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes [see Clinical Pharmacology (12.3)].

Prasugrel tablets can be administered with aspirin (75 mg to 325 mg per day), heparin, GPIIb/IIIa inhibitors, statins, digoxin, and drugs that elevate gastric pH, including proton pump inhibitors and H2 blockers [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

In a randomized, placebo-controlled trial, the primary objective of reducing the rate of vaso-occlusive crisis (painful crisis or acute chest syndrome) in pediatric patients, aged 2 to less than 18 years, with sickle cell anemia was not met.

8.5 Geriatric Use

In TRITON-TIMI 38, 38.5% of patients were ≥ 65 years of age and 13.2% were ≥ 75 years of age. The risk of bleeding increased with advancing age in both treatment groups, although the relative risk of bleeding (prasugrel tablets compared with clopidogrel) was similar across age groups.

Patients ≥ 75 years of age who received prasugrel tablets 10 mg had an increased risk of fatal bleeding events (1.0%) compared to patients who received clopidogrel (0.1%). In patients ≥ 75 years of age, symptomatic intracranial hemorrhage occurred in 7 patients (0.8%) who received prasugrel tablets and in 3 patients (0.3%) who received clopidogrel. Because of the risk of bleeding, and because effectiveness is uncertain in patients ≥ 75 years of age [see Clinical Studies (14)], use of prasugrel tablets is generally not recommended in these patients, except in high-risk situations (diabetes and past history of myocardial infarction) where their effect appears to be greater and their use may be considered [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

8.6 Low Body Weight

In TRITON-TIMI 38, 4.6% of patients treated with prasugrel tablets had body weight < 60 kg. Individuals with body weight < 60 kg had an increased risk of bleeding and an increased exposure to the active metabolite of prasugrel [see Dosage and Administration (2), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]. 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 [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dosage adjustment is necessary for patients with renal impairment. There is limited experience in patients with end-stage renal disease, but such patients are generally at higher risk of bleeding [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

8.8 Hepatic Impairment

No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B). The pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic disease have not been studied, but such patients are generally at higher risk of bleeding [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

8.9 Metabolic Status

In healthy subjects, patients with stable atherosclerosis, and patients with ACS receiving prasugrel, there was no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation.

10.1 Signs and Symptoms

Platelet inhibition by prasugrel is rapid and irreversible, lasting for the life of the platelet, and is unlikely to be increased in the event of an overdose. In rats, lethality was observed after administration of 2000 mg/kg. Symptoms of acute toxicity in dogs included emesis, increased serum alkaline phosphatase, and hepatocellular atrophy. Symptoms of acute toxicity in rats included mydriasis, irregular respiration, decreased locomotor activity, ptosis, staggering gait, and lacrimation.

10.2 Recommendations about Specific Treatment

Platelet transfusion may restore clotting ability. The prasugrel active metabolite is not likely to be removed by dialysis.

12.1 Mechanism of Action

Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.

12.2 Pharmacodynamics

Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry. Following a 60 mg loading dose of prasugrel tablets, approximately 90% of patients had at least 50% inhibition of platelet aggregation by 1 hour. Maximum platelet inhibition was about 80% (see Figure 2). Mean steady-state inhibition of platelet aggregation was about 70% following 3 to 5 days of dosing at 10 mg daily after a 60 mg loading dose of prasugrel tablets.

Figure 2: Inhibition (Mean ± SD) of 20 μM ADP-induced Platelet Aggregation (IPA) Measured by Light Transmission Aggregometry after Prasugrel 60 mg

Platelet aggregation gradually returns to baseline values over 5-9 days after discontinuation of prasugrel, this time course being a reflection of new platelet production rather than pharmacokinetics of prasugrel. Discontinuing clopidogrel 75 mg and initiating a prasugrel 10 mg maintenance dose with or without a prasugrel 60 mg loading dose results in a decrease of 14 percentage points in maximum platelet aggregation (MPA) by Day 7. This decrease in MPA is not greater than that typically produced by a 10 mg maintenance dose of prasugrel alone. The relationship between inhibition of platelet aggregation and clinical activity has not been established.

12.3 Pharmacokinetics

Prasugrel is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites. The active metabolite has an elimination half-life of about 7 hours (range 2-15 hours). Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics.

12.5 Pharmacogenomics

There is no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

Prasugrel Tablets, USP are available containing prasugrel hydrochloride, USP equivalent to 5 mg or 10 mg prasugrel, respectively.

The 5 mg tablets are yellow, film-coated, capsule shaped, unscored tablets debossed with M on one side of the tablet and PH1 on the other side. They are available as follows:

NDC 0378-5185-93
bottles of 30 tablets

The 10 mg tablets are brown, film-coated, capsule shaped, unscored tablets debossed with M on one side of the tablet and PH2 on the other side. They are available as follows:

NDC 0378-5186-93
bottles of 30 tablets

16.2 Storage and Handling

Store at 20º to 25ºC (68º to 77ºF). [See USP Controlled Room Temperature.]

Protect from moisture.

Keep and dispense only in original container. Keep container closed and do not remove desiccant from bottle. Do not break the tablet.

PHARMACIST: Dispense a Medication Guide with each prescription.