【药品名称】
通用名：普拉格雷片
商品名：Effient
【生产企业】
Eli Lilly and Company
【成份】
prasugrel
【作用与适应症】
Acute Coronary Syndrome
Effient 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.Effient 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)].【规格】
Initiate Effient treatment as a single 60-mg oral loading dose and then continue at 10-mg orally once daily. Patients taking Effient should also take aspirin (75-mg to 325-mg) daily [see Drug Interactions (7.3) and Clinical Pharmacology(12.3)]. Effient 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 Effient， the loading dose of Effient was not administered until coronary anatomy was established in UA/NSTEMI patients and in STEMI patients presenting more than12 hours after symptom onset. In STEMI patients presenting within 12 hours of symptom onset， the loading dose of Effient was administered at the time of diagnosis， although most received Effient at the time of PCI [see Clinical Studies (14)]. For the small fraction of patients that required urgent CABG after treatment with Effient， 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， noclear benefit was observed when Effient 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 undergoingPCI 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 themaintenance 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)].【用法用量】
Effient 5-mg is available as a yellow， elongated hexagonal， film-coated， non-scored tablet debossed with “5121” on one side and 3 parallel arched lines followed by a “5” on the other side.
Effient 10-mg is available as a beige， elongated hexagonal， film-coated， non-scored tablet debossed with“5123” on one side and 3 parallel arched lines followed by a “10” on the other side.
【副作用与不良反应】
Clinical Trials Experience
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)] Safety in patients with ACS undergoing PCI was evaluated in a clopidogrel-controlled study， TRITON-TIMI 38， in which 6741 patients were treated with Effient (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 Effient 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 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 Effient and 6.3% for clopidogrel.
Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for Effient 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 Effient than onclopidogrel， as shown in Table 1.
Figure 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) [see Warnings and Precautions (5.1)].
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.
Bleeding 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 Effient group and 4.5% in the clopidogrel group (see Table 3). The higher risk for bleeding adverse reactions in patients treated with Effient persisted up to 7 days from the most recent dose of study drug.
Bleeding Reported as Adverse Reactions - Hemorrhagic events reported as adverse reactions in TRITON-TIMI 38 were， for Effient 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 anotherPhase 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 Effient 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.
【禁忌】
Active Bleeding
Effient 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)].
Prior Transient Ischemic Attack or Stroke
Effient is contraindicated in patients with a history of prior transient ischemic attack (TIA) or stroke. In TRITONTIMI 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 Effient (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 Effient 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 strokeor TIA while on Effient generally should have therapy discontinued [see Adverse Reactions (6.1) and Clinical Studies (14)].
Hypersensitivity
Effient is contraindicated in patients with hypersensitivity (e.g.， anaphylaxis) to prasugrel or any component of the product [see Adverse Reactions (6.2)].
【注意事项】
General Risk of Bleeding
Thienopyridines， including Effient， 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 Effient 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).
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 Effient 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 Effient 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 antiinflammatory drugs [NSAIDs]， and fibrinolytic agents). Aspirin and heparin were commonly used in TRITONTIMI38 [see Drug Interactions (7.1， 7.2. 7.3)， 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 halflife 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.
Coronary Artery Bypass Graft Surgery-Related Bleeding
The risk of bleeding is increased in patients receiving Effient who undergo CABG. If possible， Effient 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 Effient group and 4.5% in the clopidogrel group [see Adverse Reactions (6.1)]. The higher risk for bleeding events in patients treated with Effient 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 Effient 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 Effient 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.
Discontinuation of Effient
Discontinue thienopyridines， including Effient， 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， prematurediscontinuation 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)].
Thrombotic Thrombocytopenic Purpura
Thrombotic thrombocytopenic purpura (TTP) has been reported with the use of Effient. 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 [seeAdverse Reactions (6.2)].
Hypersensitivity Including Angioedema
Hypersensitivity including angioedema has been reported in patients receiving Effient， including patients with a history of hypersensitivity reaction to other thienopyridines [see Contraindications (4.3) and Adverse Reactions (6.2)].
【药物相互作用】
Warfarin
Coadministration of Effient and warfarin increases the risk of bleeding [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Non-Steroidal Anti-Inflammatory Drugs
Coadministration of Effient and NSAIDs (used chronically) may increase the risk of bleeding [see Warnings and Precautions (5.1)].
Other Concomitant Medications
Effient can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes [see Clinical Pharmacology (12.3)].
Effient 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)].
【药物分类】
抗凝溶栓及抗血小板药