PRASUGREL- prasugrel hydrochloride tablet, film coated
Panacea Biotec Limited
WARNING: BLEEDING RISK
- Prasugrel tablets can cause significant, sometimes fatal, bleeding [see Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].
- Do not use Prasugrel tablets in patients with active pathological bleeding or a history of transient ischemic attack or stroke [see Contraindications (4.1, 4.2)].
- In patients ≥ 75 years of age, Prasugrel tablets is generally not recommended, because of the increased risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of prior MI) where its effect appears to be greater and its use may be considered [see Use in Specific Populations (8.5)].
- Do not start Prasugrel tablets in patients likely to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue Prasugrel tablets at least 7 days prior to any surgery. [see Warnings and Precautions (5.2)].
- Additional risk factors for bleeding include: body weight <60 kg; propensity to bleed; concomitant use of medications that increase the risk of bleeding (e.g., warfarin, heparin, fibrinolytic therapy, chronic use of non-steroidal anti-inflammatory drugs [NSAIDs]) [see Warnings and Precautions (5.1)].
- Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of Prasugrel tablets [see Warnings and Precautions (5.1)].
- If possible, manage bleeding without discontinuing Prasugrel tablets. Discontinuing Prasugrel tablets, particularly in the first few weeks after acute coronary syndrome, increases the risk of subsequent cardiovascular events [see Warnings and Precautions (5.3)]
1 INDICATIONS AND USAGE
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)].
2 DOSAGE AND ADMINISTRATION
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 [see Drug Interactions (7.4) and Clinical Pharmacology (12.3)]. Prasugrel tablets may be administered with or without food [see Clinical Pharmacology (12.3) and Clinical Studies (14)].
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 [see Clinical Studies (14)]. 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 [see Warnings and Precautions (5.1), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].
3 DOSAGE FORMS AND STRENGTHS
Prasugrel tablets 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 10-mg is available as a beige, round, biconvex, film-coated, non-scored tablet: debossed with “P” on one side and “10” on the other side.
4.1 Active Bleeding
Prasugrel tablet 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)].
4.2 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 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing 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)].
Prasugrel tablet is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product [see Adverse Reactions (6.2)].
5 WARNINGS AND PRECAUTIONS
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 Trials (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 non-steroidal 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.
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