Prasugrel
Generic: PRASUGREL
Basic Information
Manufacturer
Accord Healthcare Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
cd6bf899-06b7-4f52-96c5-ffc94a7288ff
Indications & Usage
1 INDICATIONS AND USAGE Prasugrel 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 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: 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 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 )] .
Patients with ST-elevation myocardial infarction (STEMI) when managed with either primary or delayed PCI ( 1.1 ).
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: 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 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 )] .
Adverse Reactions
6 ADVERSE REACTIONS Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction ( 6.1 ).
To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc.
at 1-866-941-7875or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 )] 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 (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 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 and 6.3% for clopidogrel.
Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for prasugrel 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 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 (%) (N=6741) Clopidogrel (%) (N=6716) TIMI Major or Minor bleeding 4.5 3.4 TIMI Major bleeding † 2.2 1.7 Life-threatening 1.3 0.8 Fatal 0.3 0.1 Symptomatic intracranial hemorrhage (ICH) 0.3 0.3 Requiring inotropes 0.3 0.1 Requiring surgical intervention 0.3 0.3 Requiring transfusion (≥4 units) 0.7 0.5 TIMI Minor bleeding † 2.4 1.9 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 .
Table 2: Bleeding Rates for Non-CABG-Related Bleeding by Weight and Age (TRITON-TIMI 38) * 10 mg prasugrel maintenance dose † 75 mg clopidogrel maintenance dose Major/Minor Fatal Prasugrel * (%) Clopidogrel † (%) Prasugrel * (%) Clopidogrel † (%) Weight <60 kg (N=308 prasugrel, N=356 clopidogrel) 10.1 6.5 0.0 0.3 Weight ≥60 kg (N=6373 prasugrel, N=6299 clopidogrel) 4.2 3.3 0.3 0.1 Age <75 years (N=5850 prasugrel, N=5822 clopidogrel) 3.8 2.9 0.2 0.1 Age ≥75 years (N=891 prasugrel, N=894 clopidogrel) 9.0 6.9 1.0 0.1 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 prasugrel tablets group and 4.5% in the clopidogrel group ( see Table 3 ).
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) Prasugrel (%) (N=213) Clopidogrel (%) (N=224) TIMI Major or Minor bleeding 14.1 4.5 TIMI Major bleeding 11.3 3.6 Fatal 0.9 0 Reoperation 3.8 0.5 Transfusion of ≥5 units 6.6 2.2 Intracranial hemorrhage 0 0 TIMI Minor bleeding 2.8 0.9 * Patients may be counted in more than one row.
Bleeding Reported as Adverse Reactions Hemorrhagic events reported as adverse reactions in TRITON-TIMI 38 were, for prasugrel 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 nonhemorrhagic adverse events were, for prasugrel 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 Prasugrel (%) (N=6741) Clopidogrel (%) (N=6716) Hypertension 7.5 7.1 Hypercholesterolemia/Hyperlipidemia 7.0 7.4 Headache 5.5 5.3 Back pain 5.0 4.5 Dyspnea 4.9 4.5 Nausea 4.6 4.3 Dizziness 4.1 4.6 Cough 3.9 4.1 Hypotension 3.9 3.8 Fatigue 3.7 4.8 Noncardiac chest pain 3.1 3.5 Atrial fibrillation 2.9 3.1 Bradycardia 2.9 2.4 Leukopenia (<4 x 10 9 WBC*/L) 2.8 3.5 Rash 2.8 2.4 Pyrexia 2.7 2.2 Peripheral edema 2.7 3.0 Pain in extremity 2.6 2.6 Diarrhea 2.3 2.6 * WBC = white blood cell 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 )]
To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc.
at 1-866-941-7875or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 )] 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 (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 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 and 6.3% for clopidogrel.
Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for prasugrel 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 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 (%) (N=6741) Clopidogrel (%) (N=6716) TIMI Major or Minor bleeding 4.5 3.4 TIMI Major bleeding † 2.2 1.7 Life-threatening 1.3 0.8 Fatal 0.3 0.1 Symptomatic intracranial hemorrhage (ICH) 0.3 0.3 Requiring inotropes 0.3 0.1 Requiring surgical intervention 0.3 0.3 Requiring transfusion (≥4 units) 0.7 0.5 TIMI Minor bleeding † 2.4 1.9 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 .
Table 2: Bleeding Rates for Non-CABG-Related Bleeding by Weight and Age (TRITON-TIMI 38) * 10 mg prasugrel maintenance dose † 75 mg clopidogrel maintenance dose Major/Minor Fatal Prasugrel * (%) Clopidogrel † (%) Prasugrel * (%) Clopidogrel † (%) Weight <60 kg (N=308 prasugrel, N=356 clopidogrel) 10.1 6.5 0.0 0.3 Weight ≥60 kg (N=6373 prasugrel, N=6299 clopidogrel) 4.2 3.3 0.3 0.1 Age <75 years (N=5850 prasugrel, N=5822 clopidogrel) 3.8 2.9 0.2 0.1 Age ≥75 years (N=891 prasugrel, N=894 clopidogrel) 9.0 6.9 1.0 0.1 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 prasugrel tablets group and 4.5% in the clopidogrel group ( see Table 3 ).
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) Prasugrel (%) (N=213) Clopidogrel (%) (N=224) TIMI Major or Minor bleeding 14.1 4.5 TIMI Major bleeding 11.3 3.6 Fatal 0.9 0 Reoperation 3.8 0.5 Transfusion of ≥5 units 6.6 2.2 Intracranial hemorrhage 0 0 TIMI Minor bleeding 2.8 0.9 * Patients may be counted in more than one row.
Bleeding Reported as Adverse Reactions Hemorrhagic events reported as adverse reactions in TRITON-TIMI 38 were, for prasugrel 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 nonhemorrhagic adverse events were, for prasugrel 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 Prasugrel (%) (N=6741) Clopidogrel (%) (N=6716) Hypertension 7.5 7.1 Hypercholesterolemia/Hyperlipidemia 7.0 7.4 Headache 5.5 5.3 Back pain 5.0 4.5 Dyspnea 4.9 4.5 Nausea 4.6 4.3 Dizziness 4.1 4.6 Cough 3.9 4.1 Hypotension 3.9 3.8 Fatigue 3.7 4.8 Noncardiac chest pain 3.1 3.5 Atrial fibrillation 2.9 3.1 Bradycardia 2.9 2.4 Leukopenia (<4 x 10 9 WBC*/L) 2.8 3.5 Rash 2.8 2.4 Pyrexia 2.7 2.2 Peripheral edema 2.7 3.0 Pain in extremity 2.6 2.6 Diarrhea 2.3 2.6 * WBC = white blood cell 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 )]