Prasugrel: uses, appearance and warnings

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) ( 1.1 ). Patients with ST-elevation myocardial infarction (STEMI) when managed with either primary or delayed PCI ( 1.1 ). 1.1 Acute 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 [see Clinical Studies ( 14 )] .

Prasugrel tablets USP, 5 mg is available as a yellow, round, biconvex, film-coated, non-scored tablet debossed with "P" on one side and "5" on the other side. Prasugrel tablets USP, 10 mg is available as a beige, round, biconvex, film-coated, non-scored tablet; debossed with "PL" on one side and "10" on the other side. 5 mg and 10 mg tablets ( 3 )

16.1 How Supplied Prasugrel tablet USP is available as round, biconvex, film- coated, non-scored tablets in the following strengths, colors, imprints, and presentations: Features Strengths 5 mg 10 mg Tablet color yellow beige Tablet imprint 5 10 Tablet imprint P PL Presentations and NDC Codes Bottles of 30 60505-4642-3 60505-4856-3 16.2 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]. Keep and dispense only in original container. Keep container closed and do not remove desiccant from bottle. Do not break the tablet. 16.1 How Supplied Prasugrel tablet USP is available as round, biconvex, film- coated, non-scored tablets in the following strengths, colors, imprints, and presentations: Features Strengths 5 mg 10 mg Tablet color yellow beige Tablet imprint 5 10 Tablet imprint P PL Presentations and NDC Codes Bottles of 30 60505-4642-3 60505-4856-3

Active pathological bleeding ( 4.1 ) Active pathological bleeding ( 4.1 ) Prior transient ischemic attack or stroke ( 4.2 ) Hypersensitivity to prasugrel or any component of the product ( 4.3 ) 4.1 Active Bleeding Prasugrel tablet is 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 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 [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14 )]. 4.3 Hypersensitivity Prasugrel tablet is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product [see Adverse Reactions ( 6.2 )] .

CABG-related bleeding: Risk increases in patients receiving prasugrel tablets who undergo CABG ( 5.2 ). CABG-related bleeding: Risk increases in patients receiving prasugrel tablets who undergo CABG ( 5.2 ). Discontinuation of prasugrel tablets: Premature discontinuation increases risk of stent thrombosis, MI, and death ( 5.3 ). Thrombotic thrombocytopenic purpura (TTP): TTP has been reported with prasugrel tablets ( 5.4 ). Hypersensitivity: Hypersensitivity including angioedema has been reported with prasugrel tablets including in patients with a history of hypersensitivity reaction to other thienopyridines ( 5.5 ). 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: 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 [see Adverse Reactions ( 6.1 ), Use in Specific Populations ( 8.5 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14 )]. CABG or other surgical procedure [see Warnings and Precautions ( 5.2 )]. 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 )]. 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 )]. 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. Image 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). …

The following serious adverse reactions are also discussed elsewhere in the labeling: Bleeding [see Boxed Warning and Warnings and Precautions ( 5.1 , 5.2 )] Thrombotic thrombocytopenic purpura [see Warnings and Precautions ( 5.4 )] Hypersensitivity including Angioedema [see Warnings and Precautions ( 5.5 )] Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. …

Opioids: Decreased exposure to prasugrel. Consider use of parenteral anti-platelet agent ( 7.3 ). 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 P2Y 12 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 )] . …