Prasugrel can cause significant, sometimes fatal, bleeding
[see
5.1 General Risk of Bleeding
Thienopyridines, including prasugrel, 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 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 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 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 to 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.
Figure 1: Non-CABG-Related TIMI Major or Minor Bleeding Events.
The risk of bleeding is increased in patients receiving prasugrel who undergo CABG. If possible, prasugrel 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 group and 4.5% in the clopidogrel group
[see Adverse Reactions (6.1)]
. The higher risk for bleeding events in patients treated with prasugrel 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 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 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.
and
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.
*Patients may be counted in more than one row. †See 5.1for 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)
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 group and 4.5% in the clopidogrel group (see Table 3). The higher risk for bleeding adverse reactions in patients treated with prasugrel persisted up to 7 days from the most recent dose of study drug.
Table 3: CABG-Related Bleeding*(TRITON-TIMI 38)
*Patients may be counted in more than one row.
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
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 109WBC*/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
]
.
Do not use prasugrel in patients with active pathological bleeding or a history of transient ischemic attack (TIA) or stroke
[see
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 (
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
In patients ≥75 years of age, prasugrel 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 myocardial infarction [MI]) where its effect appears to be greater and its use may be considered
[see
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 compared with clopidogrel) was similar across age groups.
Patients ≥75 years of age who received prasugrel 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 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 is generally not recommended in these patients, except in high-risk situations (diabetes and past history of myocardial infarction) where its effect appears to be greater and its use may be considered
[see Warnings and Precautions (5.1), Clinical Pharmacology (12.3), and Clinical Studies (14)]
.
]
.
Do not start prasugrel in patients likely to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue prasugrel at least 7 days prior to any surgery
The risk of bleeding is increased in patients receiving prasugrel who undergo CABG. If possible, prasugrel 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 group and 4.5% in the clopidogrel group
[see Adverse Reactions (6.1)]
. The higher risk for bleeding events in patients treated with prasugrel 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 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 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.
]
.
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 nonsteroidal anti-inflammatory drugs [NSAIDs])
[see
5.1 General Risk of Bleeding
Thienopyridines, including prasugrel, 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 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 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 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 to 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.
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, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of prasugrel
[see
5.1 General Risk of Bleeding
Thienopyridines, including prasugrel, 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 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 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 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 to 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.
Figure 1: Non-CABG-Related TIMI Major or Minor Bleeding Events.
]
.
If possible, manage bleeding without discontinuing prasugrel. Discontinuing prasugrel, particularly in the first few weeks after acute coronary syndrome, increases the risk of subsequent cardiovascular (CV) events
[see
5.3 Discontinuation of Prasugrel
Discontinue thienopyridines, including prasugrel, 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)]
.
]
.
Prasugrel tablets are a P2Y12 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 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 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)
]
.
.
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
7.4 Other Concomitant Medications
Prasugrel can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes
[see Clinical Pharmacology (12.3)]
.
Prasugrel 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 H2blockers
[see Clinical Pharmacology (12.3)]
.
and
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 to 15 hours). Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics.
Absorption and Binding
Following oral administration, ≥79% of the dose is absorbed. The absorption and metabolism are rapid, with peak plasma concentrations (Cmax) of the active metabolite occurring approximately 30 minutes after dosing. The active metabolite’s exposure (AUC) increases slightly more than proportionally over the dose range of 5 to 60 mg. Repeated daily doses of 10 mg do not lead to accumulation of the active metabolite. In a study of healthy subjects given a single 15 mg dose, the AUC of the active metabolite was unaffected by a high-fat, high-calorie meal, but Cmaxwas decreased by 49% and Tmaxwas increased from 0.5 to 1.5 hours. Prasugrel can be administered without regard to food. The active metabolite is bound about 98% to human serum albumin.
Metabolism and Elimination
Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The estimates of apparent volume of distribution of prasugrel’s active metabolite ranged from 44 to 68 L and the estimates of apparent clearance ranged from 112 to 166 L/hr in healthy subjects and patients with stable atherosclerosis. The active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to human plasma proteins. Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolites.
Specific Populations
Geriatric Patients
In a study of 32 healthy subjects between the ages of 20 and 80 years, age had no significant effect on pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation. In TRITON-TIMI 38, the mean exposure (AUC) of the active metabolite was 19% higher in patients ≥75 years of age than in patients <75 years of age. In a study in subjects with stable atherosclerosis, the mean exposure (AUC) to the active metabolite of prasugrel in subjects ≥75 years old taking a 5 mg maintenance dose was approximately half that seen in subjects 45 to 64 years old taking a 10 mg maintenance dose
[see
Warnings and Precautions (5.1)
and
Use in Specific Populations (8.5)
]
.
Body Weight
The mean exposure (AUC) to the active metabolite is approximately 30 to 40% higher in subjects with a body weight of <60 kg than in those weighing ≥60 kg. In a study in subjects with stable atherosclerosis, the AUC of the active metabolite on average was 38% lower in subjects <60 kg taking 5 mg (N=34) than in subjects ≥60 kg taking 10 mg (N=38)
[see
Dosage and Administration (2)
,
Warnings and Precautions (5.1)
,
Adverse Reactions (6.1)
, and
Use in Specific Populations (8.6)
]
.
Male and Female Patients
Pharmacokinetics of prasugrel’s active metabolite is similar in men and women.
Racial or Ethnic Groups
Exposure in subjects of African and Hispanic descent is similar to that in Caucasians. In clinical pharmacology studies, after adjusting for body weight, the AUC of the active metabolite was approximately 19% higher in Chinese, Japanese, and Korean subjects than in Caucasian subjects.
Smoking
Pharmacokinetics of prasugrel’s active metabolite is similar in smokers and nonsmokers.
Patients with Renal Impairment
Pharmacokinetics of prasugrel’s active metabolite and its inhibition of platelet aggregation is similar in patients with moderate renal impairment (CrCL=30 to 50 mL/min) and healthy subjects. In patients with end-stage renal disease, exposure to the active metabolite (both Cmaxand AUC (0-tlast)) was about half that in healthy controls and patients with moderate renal impairment
[see
Warnings and Precautions (5.1)
and
Use in Specific Populations (8.7)
]
.
Patients with Hepatic Impairment
Pharmacokinetics of prasugrel’s active metabolite and inhibition of platelet aggregation was similar in patients with mild to moderate hepatic impairment compared to healthy subjects. The pharmacokinetics and pharmacodynamics of prasugrel’s active metabolite in patients with severe hepatic disease have not been studied
[see
Warnings and Precautions (5.1)
and
Use in Specific Populations (8.8)
]
.
Drug Interaction Studies
Potential for Other Drugs to Affect Prasugrel
Inhibitors of CYP3A
- Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4 and CYP3A5, did not affect prasugrel-mediated inhibition of platelet aggregation or the active metabolite’s AUC and Tmax, but decreased the Cmaxby 34% to 46%. Therefore, CYP3A inhibitors such as verapamil, diltiazem, indinavir, ciprofloxacin, clarithromycin, and grapefruit juice are not expected to have a significant effect on the pharmacokinetics of the active metabolite of prasugrel
[see
Drug Interactions (7.4)
]
.
Inducers of Cytochromes P450
- Rifampicin (600 mg daily), a potent inducer of CYP3A and CYP2B6 and an inducer of CYP2C9, CYP2C19, and CYP2C8, did not significantly change the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation. Therefore, known CYP3A inducers such as rifampicin, carbamazepine, and other inducers of cytochromes P450 are not expected to have significant effect on the pharmacokinetics of the active metabolite of prasugrel
[see
Drug Interactions (7.4)
]
.
Drugs that Elevate Gastric pH
- Daily coadministration of ranitidine (an H2blocker) or lansoprazole (a proton pump inhibitor) decreased the Cmaxof the prasugrel active metabolite by 14% and 29%, respectively, but did not change the active metabolite’s AUC and Tmax. In TRITON-TIMI 38, prasugrel was administered without regard to coadministration of a proton pump inhibitor or H2blocker
[see
Drug Interactions (7.4)
]
.
Statins
- Atorvastatin (80 mg daily), a drug metabolized by CYP450 3A4, did not alter the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation
[see
Drug Interactions (7.4)
]
.
Heparin
- A single intravenous dose of unfractionated heparin (100 units/kg) did not significantly alter coagulation or the prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone
[see
Drug Interactions (7.4)
]
.
Aspirin
- Aspirin 150 mg daily did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone
[see
Drug Interactions (7.4)
]
.
Warfarin
- A significant prolongation of the bleeding time was observed when prasugrel was coadministered with 15 mg of warfarin
[see
Drug Interactions (7.1)
]
.
Potential for Prasugrel to Affect Other Drugs
In vitro
metabolism studies demonstrate that prasugrel’s main circulating metabolites are not likely to cause clinically significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A, or induction of CYP1A2 or CYP3A.
Drugs Metabolized by CYP2B6 -
Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel decreased exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%, an amount not considered clinically significant. Prasugrel is not anticipated to have significant effect on the pharmacokinetics of drugs that are primarily metabolized by CYP2B6, such as halothane, cyclophosphamide, propofol, and nevirapine.
Effect on Digoxin
- The potential role of prasugrel as a Pgp substrate was not evaluated. Prasugrel is not an inhibitor of Pgp, as digoxin clearance was not affected by prasugrel coadministration
[see
Drug Interactions (7.4)
]
.
Morphine
- Coadministration of 5 mg intravenous morphine with 60 mg loading dose of prasugrel in healthy adults decreased the Cmaxof prasugrel’s active metabolite by 31% with no change in AUC, Tmax, or inhibition of ADP-induced platelet aggregation. ADP-induced platelet aggregation was higher up to 2 hours following 60 mg loading dose of prasugrel in stable patients more than 1 year after an ACS who were coadministered morphine. In the patients with a 2-hour delay in the onset of platelet aggregation (5 of 11), Tmaxwas delayed and prasugrel active metabolite levels were significantly lower at 30 min (5 vs 120 ng/mL) following coadministration with morphine.
]
. Prasugrel tablets may be administered with or without food
[see
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 to 15 hours). Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics.
Absorption and Binding
Following oral administration, ≥79% of the dose is absorbed. The absorption and metabolism are rapid, with peak plasma concentrations (Cmax) of the active metabolite occurring approximately 30 minutes after dosing. The active metabolite’s exposure (AUC) increases slightly more than proportionally over the dose range of 5 to 60 mg. Repeated daily doses of 10 mg do not lead to accumulation of the active metabolite. In a study of healthy subjects given a single 15 mg dose, the AUC of the active metabolite was unaffected by a high-fat, high-calorie meal, but Cmaxwas decreased by 49% and Tmaxwas increased from 0.5 to 1.5 hours. Prasugrel can be administered without regard to food. The active metabolite is bound about 98% to human serum albumin.
Metabolism and Elimination
Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The estimates of apparent volume of distribution of prasugrel’s active metabolite ranged from 44 to 68 L and the estimates of apparent clearance ranged from 112 to 166 L/hr in healthy subjects and patients with stable atherosclerosis. The active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to human plasma proteins. Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolites.
Specific Populations
Geriatric Patients
In a study of 32 healthy subjects between the ages of 20 and 80 years, age had no significant effect on pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation. In TRITON-TIMI 38, the mean exposure (AUC) of the active metabolite was 19% higher in patients ≥75 years of age than in patients <75 years of age. In a study in subjects with stable atherosclerosis, the mean exposure (AUC) to the active metabolite of prasugrel in subjects ≥75 years old taking a 5 mg maintenance dose was approximately half that seen in subjects 45 to 64 years old taking a 10 mg maintenance dose
[see
Warnings and Precautions (5.1)
and
Use in Specific Populations (8.5)
]
.
Body Weight
The mean exposure (AUC) to the active metabolite is approximately 30 to 40% higher in subjects with a body weight of <60 kg than in those weighing ≥60 kg. In a study in subjects with stable atherosclerosis, the AUC of the active metabolite on average was 38% lower in subjects <60 kg taking 5 mg (N=34) than in subjects ≥60 kg taking 10 mg (N=38)
[see
Dosage and Administration (2)
,
Warnings and Precautions (5.1)
,
Adverse Reactions (6.1)
, and
Use in Specific Populations (8.6)
]
.
Male and Female Patients
Pharmacokinetics of prasugrel’s active metabolite is similar in men and women.
Racial or Ethnic Groups
Exposure in subjects of African and Hispanic descent is similar to that in Caucasians. In clinical pharmacology studies, after adjusting for body weight, the AUC of the active metabolite was approximately 19% higher in Chinese, Japanese, and Korean subjects than in Caucasian subjects.
Smoking
Pharmacokinetics of prasugrel’s active metabolite is similar in smokers and nonsmokers.
Patients with Renal Impairment
Pharmacokinetics of prasugrel’s active metabolite and its inhibition of platelet aggregation is similar in patients with moderate renal impairment (CrCL=30 to 50 mL/min) and healthy subjects. In patients with end-stage renal disease, exposure to the active metabolite (both Cmaxand AUC (0-tlast)) was about half that in healthy controls and patients with moderate renal impairment
[see
Warnings and Precautions (5.1)
and
Use in Specific Populations (8.7)
]
.
Patients with Hepatic Impairment
Pharmacokinetics of prasugrel’s active metabolite and inhibition of platelet aggregation was similar in patients with mild to moderate hepatic impairment compared to healthy subjects. The pharmacokinetics and pharmacodynamics of prasugrel’s active metabolite in patients with severe hepatic disease have not been studied
[see
Warnings and Precautions (5.1)
and
Use in Specific Populations (8.8)
]
.
Drug Interaction Studies
Potential for Other Drugs to Affect Prasugrel
Inhibitors of CYP3A
- Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4 and CYP3A5, did not affect prasugrel-mediated inhibition of platelet aggregation or the active metabolite’s AUC and Tmax, but decreased the Cmaxby 34% to 46%. Therefore, CYP3A inhibitors such as verapamil, diltiazem, indinavir, ciprofloxacin, clarithromycin, and grapefruit juice are not expected to have a significant effect on the pharmacokinetics of the active metabolite of prasugrel
[see
Drug Interactions (7.4)
]
.
Inducers of Cytochromes P450
- Rifampicin (600 mg daily), a potent inducer of CYP3A and CYP2B6 and an inducer of CYP2C9, CYP2C19, and CYP2C8, did not significantly change the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation. Therefore, known CYP3A inducers such as rifampicin, carbamazepine, and other inducers of cytochromes P450 are not expected to have significant effect on the pharmacokinetics of the active metabolite of prasugrel
[see
Drug Interactions (7.4)
]
.
Drugs that Elevate Gastric pH
- Daily coadministration of ranitidine (an H2blocker) or lansoprazole (a proton pump inhibitor) decreased the Cmaxof the prasugrel active metabolite by 14% and 29%, respectively, but did not change the active metabolite’s AUC and Tmax. In TRITON-TIMI 38, prasugrel was administered without regard to coadministration of a proton pump inhibitor or H2blocker
[see
Drug Interactions (7.4)
]
.
Statins
- Atorvastatin (80 mg daily), a drug metabolized by CYP450 3A4, did not alter the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation
[see
Drug Interactions (7.4)
]
.
Heparin
- A single intravenous dose of unfractionated heparin (100 units/kg) did not significantly alter coagulation or the prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone
[see
Drug Interactions (7.4)
]
.
Aspirin
- Aspirin 150 mg daily did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone
[see
Drug Interactions (7.4)
]
.
Warfarin
- A significant prolongation of the bleeding time was observed when prasugrel was coadministered with 15 mg of warfarin
[see
Drug Interactions (7.1)
]
.
Potential for Prasugrel to Affect Other Drugs
In vitro
metabolism studies demonstrate that prasugrel’s main circulating metabolites are not likely to cause clinically significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A, or induction of CYP1A2 or CYP3A.
Drugs Metabolized by CYP2B6 -
Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel decreased exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%, an amount not considered clinically significant. Prasugrel is not anticipated to have significant effect on the pharmacokinetics of drugs that are primarily metabolized by CYP2B6, such as halothane, cyclophosphamide, propofol, and nevirapine.
Effect on Digoxin
- The potential role of prasugrel as a Pgp substrate was not evaluated. Prasugrel is not an inhibitor of Pgp, as digoxin clearance was not affected by prasugrel coadministration
[see
Drug Interactions (7.4)
]
.
Morphine
- Coadministration of 5 mg intravenous morphine with 60 mg loading dose of prasugrel in healthy adults decreased the Cmaxof prasugrel’s active metabolite by 31% with no change in AUC, Tmax, or inhibition of ADP-induced platelet aggregation. ADP-induced platelet aggregation was higher up to 2 hours following 60 mg loading dose of prasugrel in stable patients more than 1 year after an ACS who were coadministered morphine. In the patients with a 2-hour delay in the onset of platelet aggregation (5 of 11), Tmaxwas delayed and prasugrel active metabolite levels were significantly lower at 30 min (5 vs 120 ng/mL) following coadministration with morphine.
and
14 CLINICAL STUDIES
The clinical evidence for the effectiveness of prasugrel is derived from the TRITON-TIMI 38 (
TR
ial to Assess
I
mprovement in
T
herapeutic Outcomes by
O
ptimizing Platelet Inhibitio
N
with Prasugrel) study, a 13,608 patient, multicenter, international, randomized, double-blind, parallel-group study comparing prasugrel to a regimen of clopidogrel, each added to aspirin and other standard therapy, in patients with ACS (UA, NSTEMI, or STEMI) who were to be managed with PCI. Randomization was stratified for UA/NSTEMI and STEMI.
Patients with UA/NSTEMI presenting within 72 hours of symptom onset were to be randomized after undergoing coronary angiography. Patients with STEMI presenting within 12 hours of symptom onset could be randomized prior to coronary angiography. Patients with STEMI presenting between 12 hours and 14 days of symptom onset were to be randomized after undergoing coronary angiography. Patients underwent PCI, and for both UA/NSTEMI and STEMI patients, the loading dose was to be administered anytime between randomization and 1 hour after the patient left the catheterization lab. If patients with STEMI were treated with thrombolytic therapy, randomization could not occur until at least 24 hours (for tenecteplase, reteplase, or alteplase) or 48 hours (for streptokinase) after the thrombolytic was given.
Patients were randomized to receive prasugrel (60 mg loading dose followed by 10 mg once daily) or clopidogrel (300 mg loading dose followed by 75 mg once daily), with administration and follow-up for a minimum of 6 months (actual median 14.5 months). Patients also received aspirin (75 mg to 325 mg once daily). Other therapies, such as heparin and intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, were administered at the discretion of the treating physician. Oral anticoagulants, other platelet inhibitors, and chronic NSAIDs were not allowed.
The primary outcome measure was the composite of cardiovascular death, nonfatal MI, or nonfatal stroke in the UA/NSTEMI population. Success in this group allowed analysis of the same endpoint in the overall ACS and STEMI populations. Nonfatal MIs included both MIs detected solely through analysis of creatine kinase muscle-brain (CK-MB) changes and clinically apparent (investigator-reported) MIs.
The patient population was 92% Caucasian, 26% female, and 39% ≥65 years of age. The median time from symptom onset to study drug administration was 7 hours for patients with STEMI and 30 hours for patients with UA/NSTEMI. Approximately 99% of patients underwent PCI. The study drug was administered after the first coronary guidewire was placed in approximately 75% of patients.
Prasugrel significantly reduced total endpoint events compared to clopidogrel (see Figure 3 and Table 5). The reduction of total endpoint events was driven primarily by a decrease in nonfatal MIs, both those occurring early (through 3 days) and later (after 3 days). Approximately 40% of MIs occurred peri-procedurally and were detected solely by changes in CK-MB. Administration of the clopidogrel loading dose in TRITON-TIMI 38 was delayed relative to the placebo-controlled trials that supported its approval for ACS. Prasugrel produced higher rates of clinically significant bleeding than clopidogrel in TRITON-TIMI 38
[see Adverse Reactions (6.1)]
. Choice of therapy requires balancing these differences in outcome.
The treatment effect of prasugrel was apparent within the first few days, and persisted to the end of the study (see Figure 3). The inset shows results over the first 7 days.
Figure 3: Time to First Event of CV Death, MI, or Stroke (TRITON-TIMI 38)
The Kaplan-Meier curves (see Figure 3) show the primary composite endpoint of CV death, nonfatal MI, or nonfatal stroke over time in the UA/NSTEMI and STEMI populations. In both populations, the curves separate within the first few hours. In the UA/NSTEMI population, the curves continue to diverge throughout the 15-month follow-up period. In the STEMI population, the early separation was maintained throughout the 15-month follow-up period, but there was no progressive divergence after the first few weeks.
Prasugrel reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI and STEMI populations (see Table 5). In patients who survived an on-study myocardial infarction, the incidence of subsequent events was also lower in the prasugrel group.
Table 5: Patients with Outcome Events (CV Death, MI, Stroke) in TRITON-TIMI 38
*RRR = (1-Hazard Ratio) x 100%. Values with a negative relative risk reduction indicate a relative risk increase.
Patients with events
From Kaplan-Meier analysis
Prasugrel (%)
Clopidogrel (%)
Relative Risk Reduction (%)*(95% CI)
p-value
UA/NSTEMI
N=5044
N=5030
CV death, nonfatal MI, or nonfatal stroke
9.3
11.2
18.0 (7.3, 27.4)
0.002
CV death
1.8
1.8
2.1 (-30.9, 26.8)
0.885
Nonfatal MI
7.1
9.2
23.9 (12.7, 33.7)
<0.001
Nonfatal Stroke
0.8
0.8
2.1 (-51.3, 36.7)
0.922
STEMI
N=1769
N=1765
CV death, nonfatal MI, or nonfatal stroke
9.8
12.2
20.7 (3.2, 35.1)
0.019
CV death
2.4
3.3
26.2 (-9.4, 50.3)
0.129
Nonfatal MI
6.7
8.8
25.4 (5.2, 41.2)
0.016
Nonfatal Stroke
1.2
1.1
-9.7 (-104.0, 41.0)
0.77
The effect of prasugrel in various subgroups is shown in Figures 4 and 5. Results are generally consistent across pre-specified subgroups, with the exception of patients with a history of TIA or stroke
[see Contraindications (4.2)]
. The treatment effect was driven primarily by a reduction in nonfatal MI. The effect in patients ≥75 years of age was also somewhat smaller, and bleeding risk is higher in these individuals
[see Adverse Reactions (6.1)]
. See below for analyses of patients ≥75 years of age with risk factors.
Figure 4: Subgroup Analyses for Time to First Event of CV Death, MI, or Stroke (HR and 95% CI; TRITON-TIMI 38) – UA/NSTEMI Patients
Figure 5: Subgroup Analyses for Time to First Event of CV Death, MI, or Stroke (HR and 95% CI; TRITON-TIMI 38) – STEMI Patients
Prasugrel is generally not recommended in patients ≥75 years of age, except in high-risk situations (diabetes mellitus or prior MI) where its effect appears to be greater and its use may be considered. These recommendations are based on subgroup analyses (see Table 6) and must be interpreted with caution, but the data suggest that prasugrel reduces ischemic events in such patients.
Table 6: Subgroup Analyses for Time to First Event of CV Death, MI, or Stroke: Patients < or ≥75 Years of Age, ± Diabetes, ± Prior History of MI, All ACS Patient Population
Prasugrel
Clopidogrel
Hazard Ratio (95% CI)
N
% with events
N
% with events
Age ≥75
Diabetes –yes
249
14.9
234
21.8
0.64 (0.42, 0.97)
Diabetes - no
652
16.4
674
15.3
1.1 (0.83, 1.43)
Age <75
Diabetes – yes
1327
10.8
1336
14.8
0.72 (0.58, 0.89)
Diabetes – no
4585
7.8
4551
9.5
0.82 (0.71, 0.94)
Age ≥75
Prior MI – yes
220
17.3
212
22.6
0.72 (0.47, 1.09)
Prior MI – no
681
15.6
696
15.2
1.05 (0.80, 1.37)
Age <75
Prior MI – yes
1006
12.2
996
15.4
0.78 (0.62, 0.99)
Prior MI – no
4906
7.7
4891
9.7
0.78 (0.68, 0.90)
There were 50% fewer stent thromboses (95% C.I. 32% to 64%; p<0.001) reported among patients randomized to prasugrel (0.9%) than among patients randomized to clopidogrel (1.8%). The difference manifested early and was maintained through one year of follow-up. Findings were similar with bare metal and drug-eluting stents.
In TRITON-TIMI 38, prasugrel reduced ischemic events (mainly nonfatal MIs) and increased bleeding events
[see Adverse Reactions (6.1)]
relative to clopidogrel. The findings are consistent with the intended greater inhibition of platelet aggregation by prasugrel at the doses used in the study
[see Clinical Pharmacology (12.2)].
There is, however, an alternative explanation: both prasugrel and clopidogrel are prodrugs that must be metabolized to their active moieties. Whereas the pharmacokinetics of prasugrel’s active metabolite is not known to be affected by genetic variations in CYP2B6, CYP2C9, CYP2C19, or CYP3A5, the pharmacokinetics of clopidogrel’s active metabolite is affected by CYP2C19 genotype, and approximately 30% of Caucasians are reduced metabolizers. Moreover, certain proton pump inhibitors, widely used in the ACS patient population and used in TRITON-TIMI 38, inhibit CYP2C19, thereby decreasing formation of clopidogrel’s active metabolite. Thus, reduced-metabolizer status and use of proton pump inhibitors may diminish clopidogrel’s activity in a fraction of the population, and may have contributed to prasugrel’s greater treatment effect and greater bleeding rate in TRITON-TIMI 38. The extent to which these factors were operational, however, is unknown.
Figure 3: Time to first event of CV death, MI, or stroke (TRITON-TIMI 38).
Figure 4: Subgroup analyses for time to first event of CV death, MI, or stroke (HR and 95% CI; TRITON-TIMI 38) – UA/NSTEMI Patients.
Figure5
]
.
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
14 CLINICAL STUDIES
The clinical evidence for the effectiveness of prasugrel is derived from the TRITON-TIMI 38 (
TR
ial to Assess
I
mprovement in
T
herapeutic Outcomes by
O
ptimizing Platelet Inhibitio
N
with Prasugrel) study, a 13,608 patient, multicenter, international, randomized, double-blind, parallel-group study comparing prasugrel to a regimen of clopidogrel, each added to aspirin and other standard therapy, in patients with ACS (UA, NSTEMI, or STEMI) who were to be managed with PCI. Randomization was stratified for UA/NSTEMI and STEMI.
Patients with UA/NSTEMI presenting within 72 hours of symptom onset were to be randomized after undergoing coronary angiography. Patients with STEMI presenting within 12 hours of symptom onset could be randomized prior to coronary angiography. Patients with STEMI presenting between 12 hours and 14 days of symptom onset were to be randomized after undergoing coronary angiography. Patients underwent PCI, and for both UA/NSTEMI and STEMI patients, the loading dose was to be administered anytime between randomization and 1 hour after the patient left the catheterization lab. If patients with STEMI were treated with thrombolytic therapy, randomization could not occur until at least 24 hours (for tenecteplase, reteplase, or alteplase) or 48 hours (for streptokinase) after the thrombolytic was given.
Patients were randomized to receive prasugrel (60 mg loading dose followed by 10 mg once daily) or clopidogrel (300 mg loading dose followed by 75 mg once daily), with administration and follow-up for a minimum of 6 months (actual median 14.5 months). Patients also received aspirin (75 mg to 325 mg once daily). Other therapies, such as heparin and intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, were administered at the discretion of the treating physician. Oral anticoagulants, other platelet inhibitors, and chronic NSAIDs were not allowed.
The primary outcome measure was the composite of cardiovascular death, nonfatal MI, or nonfatal stroke in the UA/NSTEMI population. Success in this group allowed analysis of the same endpoint in the overall ACS and STEMI populations. Nonfatal MIs included both MIs detected solely through analysis of creatine kinase muscle-brain (CK-MB) changes and clinically apparent (investigator-reported) MIs.
The patient population was 92% Caucasian, 26% female, and 39% ≥65 years of age. The median time from symptom onset to study drug administration was 7 hours for patients with STEMI and 30 hours for patients with UA/NSTEMI. Approximately 99% of patients underwent PCI. The study drug was administered after the first coronary guidewire was placed in approximately 75% of patients.
Prasugrel significantly reduced total endpoint events compared to clopidogrel (see Figure 3 and Table 5). The reduction of total endpoint events was driven primarily by a decrease in nonfatal MIs, both those occurring early (through 3 days) and later (after 3 days). Approximately 40% of MIs occurred peri-procedurally and were detected solely by changes in CK-MB. Administration of the clopidogrel loading dose in TRITON-TIMI 38 was delayed relative to the placebo-controlled trials that supported its approval for ACS. Prasugrel produced higher rates of clinically significant bleeding than clopidogrel in TRITON-TIMI 38
[see Adverse Reactions (6.1)]
. Choice of therapy requires balancing these differences in outcome.
The treatment effect of prasugrel was apparent within the first few days, and persisted to the end of the study (see Figure 3). The inset shows results over the first 7 days.
Figure 3: Time to First Event of CV Death, MI, or Stroke (TRITON-TIMI 38)
The Kaplan-Meier curves (see Figure 3) show the primary composite endpoint of CV death, nonfatal MI, or nonfatal stroke over time in the UA/NSTEMI and STEMI populations. In both populations, the curves separate within the first few hours. In the UA/NSTEMI population, the curves continue to diverge throughout the 15-month follow-up period. In the STEMI population, the early separation was maintained throughout the 15-month follow-up period, but there was no progressive divergence after the first few weeks.
Prasugrel reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI and STEMI populations (see Table 5). In patients who survived an on-study myocardial infarction, the incidence of subsequent events was also lower in the prasugrel group.
Table 5: Patients with Outcome Events (CV Death, MI, Stroke) in TRITON-TIMI 38
*RRR = (1-Hazard Ratio) x 100%. Values with a negative relative risk reduction indicate a relative risk increase.
Patients with events
From Kaplan-Meier analysis
Prasugrel (%)
Clopidogrel (%)
Relative Risk Reduction (%)*(95% CI)
p-value
UA/NSTEMI
N=5044
N=5030
CV death, nonfatal MI, or nonfatal stroke
9.3
11.2
18.0 (7.3, 27.4)
0.002
CV death
1.8
1.8
2.1 (-30.9, 26.8)
0.885
Nonfatal MI
7.1
9.2
23.9 (12.7, 33.7)
<0.001
Nonfatal Stroke
0.8
0.8
2.1 (-51.3, 36.7)
0.922
STEMI
N=1769
N=1765
CV death, nonfatal MI, or nonfatal stroke
9.8
12.2
20.7 (3.2, 35.1)
0.019
CV death
2.4
3.3
26.2 (-9.4, 50.3)
0.129
Nonfatal MI
6.7
8.8
25.4 (5.2, 41.2)
0.016
Nonfatal Stroke
1.2
1.1
-9.7 (-104.0, 41.0)
0.77
The effect of prasugrel in various subgroups is shown in Figures 4 and 5. Results are generally consistent across pre-specified subgroups, with the exception of patients with a history of TIA or stroke
[see Contraindications (4.2)]
. The treatment effect was driven primarily by a reduction in nonfatal MI. The effect in patients ≥75 years of age was also somewhat smaller, and bleeding risk is higher in these individuals
[see Adverse Reactions (6.1)]
. See below for analyses of patients ≥75 years of age with risk factors.
Figure 4: Subgroup Analyses for Time to First Event of CV Death, MI, or Stroke (HR and 95% CI; TRITON-TIMI 38) – UA/NSTEMI Patients
Figure 5: Subgroup Analyses for Time to First Event of CV Death, MI, or Stroke (HR and 95% CI; TRITON-TIMI 38) – STEMI Patients
Prasugrel is generally not recommended in patients ≥75 years of age, except in high-risk situations (diabetes mellitus or prior MI) where its effect appears to be greater and its use may be considered. These recommendations are based on subgroup analyses (see Table 6) and must be interpreted with caution, but the data suggest that prasugrel reduces ischemic events in such patients.
Table 6: Subgroup Analyses for Time to First Event of CV Death, MI, or Stroke: Patients < or ≥75 Years of Age, ± Diabetes, ± Prior History of MI, All ACS Patient Population
Prasugrel
Clopidogrel
Hazard Ratio (95% CI)
N
% with events
N
% with events
Age ≥75
Diabetes –yes
249
14.9
234
21.8
0.64 (0.42, 0.97)
Diabetes - no
652
16.4
674
15.3
1.1 (0.83, 1.43)
Age <75
Diabetes – yes
1327
10.8
1336
14.8
0.72 (0.58, 0.89)
Diabetes – no
4585
7.8
4551
9.5
0.82 (0.71, 0.94)
Age ≥75
Prior MI – yes
220
17.3
212
22.6
0.72 (0.47, 1.09)
Prior MI – no
681
15.6
696
15.2
1.05 (0.80, 1.37)
Age <75
Prior MI – yes
1006
12.2
996
15.4
0.78 (0.62, 0.99)
Prior MI – no
4906
7.7
4891
9.7
0.78 (0.68, 0.90)
There were 50% fewer stent thromboses (95% C.I. 32% to 64%; p<0.001) reported among patients randomized to prasugrel (0.9%) than among patients randomized to clopidogrel (1.8%). The difference manifested early and was maintained through one year of follow-up. Findings were similar with bare metal and drug-eluting stents.
In TRITON-TIMI 38, prasugrel reduced ischemic events (mainly nonfatal MIs) and increased bleeding events
[see Adverse Reactions (6.1)]
relative to clopidogrel. The findings are consistent with the intended greater inhibition of platelet aggregation by prasugrel at the doses used in the study
[see Clinical Pharmacology (12.2)].
There is, however, an alternative explanation: both prasugrel and clopidogrel are prodrugs that must be metabolized to their active moieties. Whereas the pharmacokinetics of prasugrel’s active metabolite is not known to be affected by genetic variations in CYP2B6, CYP2C9, CYP2C19, or CYP3A5, the pharmacokinetics of clopidogrel’s active metabolite is affected by CYP2C19 genotype, and approximately 30% of Caucasians are reduced metabolizers. Moreover, certain proton pump inhibitors, widely used in the ACS patient population and used in TRITON-TIMI 38, inhibit CYP2C19, thereby decreasing formation of clopidogrel’s active metabolite. Thus, reduced-metabolizer status and use of proton pump inhibitors may diminish clopidogrel’s activity in a fraction of the population, and may have contributed to prasugrel’s greater treatment effect and greater bleeding rate in TRITON-TIMI 38. The extent to which these factors were operational, however, is unknown.
Figure 3: Time to first event of CV death, MI, or stroke (TRITON-TIMI 38).
Figure 4: Subgroup analyses for time to first event of CV death, MI, or stroke (HR and 95% CI; TRITON-TIMI 38) – UA/NSTEMI Patients.
Figure5
]
. 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
5.1 General Risk of Bleeding
Thienopyridines, including prasugrel, 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 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 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 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 to 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.
Figure 1: Non-CABG-Related TIMI Major or Minor Bleeding Events.
,
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.
*Patients may be counted in more than one row. †See 5.1for 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)
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 group and 4.5% in the clopidogrel group (see Table 3). The higher risk for bleeding adverse reactions in patients treated with prasugrel persisted up to 7 days from the most recent dose of study drug.
Table 3: CABG-Related Bleeding*(TRITON-TIMI 38)
*Patients may be counted in more than one row.
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
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 109WBC*/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
, and
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 to 15 hours). Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics.
Absorption and Binding
Following oral administration, ≥79% of the dose is absorbed. The absorption and metabolism are rapid, with peak plasma concentrations (Cmax) of the active metabolite occurring approximately 30 minutes after dosing. The active metabolite’s exposure (AUC) increases slightly more than proportionally over the dose range of 5 to 60 mg. Repeated daily doses of 10 mg do not lead to accumulation of the active metabolite. In a study of healthy subjects given a single 15 mg dose, the AUC of the active metabolite was unaffected by a high-fat, high-calorie meal, but Cmaxwas decreased by 49% and Tmaxwas increased from 0.5 to 1.5 hours. Prasugrel can be administered without regard to food. The active metabolite is bound about 98% to human serum albumin.
Metabolism and Elimination
Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The estimates of apparent volume of distribution of prasugrel’s active metabolite ranged from 44 to 68 L and the estimates of apparent clearance ranged from 112 to 166 L/hr in healthy subjects and patients with stable atherosclerosis. The active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to human plasma proteins. Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolites.
Specific Populations
Geriatric Patients
In a study of 32 healthy subjects between the ages of 20 and 80 years, age had no significant effect on pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation. In TRITON-TIMI 38, the mean exposure (AUC) of the active metabolite was 19% higher in patients ≥75 years of age than in patients <75 years of age. In a study in subjects with stable atherosclerosis, the mean exposure (AUC) to the active metabolite of prasugrel in subjects ≥75 years old taking a 5 mg maintenance dose was approximately half that seen in subjects 45 to 64 years old taking a 10 mg maintenance dose
[see
Warnings and Precautions (5.1)
and
Use in Specific Populations (8.5)
]
.
Body Weight
The mean exposure (AUC) to the active metabolite is approximately 30 to 40% higher in subjects with a body weight of <60 kg than in those weighing ≥60 kg. In a study in subjects with stable atherosclerosis, the AUC of the active metabolite on average was 38% lower in subjects <60 kg taking 5 mg (N=34) than in subjects ≥60 kg taking 10 mg (N=38)
[see
Dosage and Administration (2)
,
Warnings and Precautions (5.1)
,
Adverse Reactions (6.1)
, and
Use in Specific Populations (8.6)
]
.
Male and Female Patients
Pharmacokinetics of prasugrel’s active metabolite is similar in men and women.
Racial or Ethnic Groups
Exposure in subjects of African and Hispanic descent is similar to that in Caucasians. In clinical pharmacology studies, after adjusting for body weight, the AUC of the active metabolite was approximately 19% higher in Chinese, Japanese, and Korean subjects than in Caucasian subjects.
Smoking
Pharmacokinetics of prasugrel’s active metabolite is similar in smokers and nonsmokers.
Patients with Renal Impairment
Pharmacokinetics of prasugrel’s active metabolite and its inhibition of platelet aggregation is similar in patients with moderate renal impairment (CrCL=30 to 50 mL/min) and healthy subjects. In patients with end-stage renal disease, exposure to the active metabolite (both Cmaxand AUC (0-tlast)) was about half that in healthy controls and patients with moderate renal impairment
[see
Warnings and Precautions (5.1)
and
Use in Specific Populations (8.7)
]
.
Patients with Hepatic Impairment
Pharmacokinetics of prasugrel’s active metabolite and inhibition of platelet aggregation was similar in patients with mild to moderate hepatic impairment compared to healthy subjects. The pharmacokinetics and pharmacodynamics of prasugrel’s active metabolite in patients with severe hepatic disease have not been studied
[see
Warnings and Precautions (5.1)
and
Use in Specific Populations (8.8)
]
.
Drug Interaction Studies
Potential for Other Drugs to Affect Prasugrel
Inhibitors of CYP3A
- Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4 and CYP3A5, did not affect prasugrel-mediated inhibition of platelet aggregation or the active metabolite’s AUC and Tmax, but decreased the Cmaxby 34% to 46%. Therefore, CYP3A inhibitors such as verapamil, diltiazem, indinavir, ciprofloxacin, clarithromycin, and grapefruit juice are not expected to have a significant effect on the pharmacokinetics of the active metabolite of prasugrel
[see
Drug Interactions (7.4)
]
.
Inducers of Cytochromes P450
- Rifampicin (600 mg daily), a potent inducer of CYP3A and CYP2B6 and an inducer of CYP2C9, CYP2C19, and CYP2C8, did not significantly change the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation. Therefore, known CYP3A inducers such as rifampicin, carbamazepine, and other inducers of cytochromes P450 are not expected to have significant effect on the pharmacokinetics of the active metabolite of prasugrel
[see
Drug Interactions (7.4)
]
.
Drugs that Elevate Gastric pH
- Daily coadministration of ranitidine (an H2blocker) or lansoprazole (a proton pump inhibitor) decreased the Cmaxof the prasugrel active metabolite by 14% and 29%, respectively, but did not change the active metabolite’s AUC and Tmax. In TRITON-TIMI 38, prasugrel was administered without regard to coadministration of a proton pump inhibitor or H2blocker
[see
Drug Interactions (7.4)
]
.
Statins
- Atorvastatin (80 mg daily), a drug metabolized by CYP450 3A4, did not alter the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation
[see
Drug Interactions (7.4)
]
.
Heparin
- A single intravenous dose of unfractionated heparin (100 units/kg) did not significantly alter coagulation or the prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone
[see
Drug Interactions (7.4)
]
.
Aspirin
- Aspirin 150 mg daily did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone
[see
Drug Interactions (7.4)
]
.
Warfarin
- A significant prolongation of the bleeding time was observed when prasugrel was coadministered with 15 mg of warfarin
[see
Drug Interactions (7.1)
]
.
Potential for Prasugrel to Affect Other Drugs
In vitro
metabolism studies demonstrate that prasugrel’s main circulating metabolites are not likely to cause clinically significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A, or induction of CYP1A2 or CYP3A.
Drugs Metabolized by CYP2B6 -
Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel decreased exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%, an amount not considered clinically significant. Prasugrel is not anticipated to have significant effect on the pharmacokinetics of drugs that are primarily metabolized by CYP2B6, such as halothane, cyclophosphamide, propofol, and nevirapine.
Effect on Digoxin
- The potential role of prasugrel as a Pgp substrate was not evaluated. Prasugrel is not an inhibitor of Pgp, as digoxin clearance was not affected by prasugrel coadministration
[see
Drug Interactions (7.4)
]
.
Morphine
- Coadministration of 5 mg intravenous morphine with 60 mg loading dose of prasugrel in healthy adults decreased the Cmaxof prasugrel’s active metabolite by 31% with no change in AUC, Tmax, or inhibition of ADP-induced platelet aggregation. ADP-induced platelet aggregation was higher up to 2 hours following 60 mg loading dose of prasugrel in stable patients more than 1 year after an ACS who were coadministered morphine. In the patients with a 2-hour delay in the onset of platelet aggregation (5 of 11), Tmaxwas delayed and prasugrel active metabolite levels were significantly lower at 30 min (5 vs 120 ng/mL) following coadministration with morphine.
]
.
Prasugrel Tablets USP, 5 mg are available as yellow, elongated hexagonal, film-coated, non-scored tablets debossed with ‘I’ on one side and ‘23’ on the other side.
Prasugrel Tablets USP, 10 mg are available as beige, elongated hexagonal, film-coated, non-scored tablets debossed with ‘I’ on one side and ‘24’ on the other side.
Risk Summary
There are no data with prasugrel use in pregnant women to inform a drug-associated risk. No structural malformations were observed in animal reproductive and developmental toxicology studies when rats and rabbits were administered prasugrel during organogenesis at doses of up to 30 times the recommended therapeutic exposures in humans
[see Data]
. Due to the mechanism of action of prasugrel, and the associated identified risk of bleeding, consider the benefits and risks of prasugrel and possible risks to the fetus when prescribing prasugrel to a pregnant woman
[see
WARNING: BLEEDING RISK
Prasugrel can cause significant, sometimes fatal, bleeding
[see Warnings and Precautions (5.1, 5.2)and Adverse Reactions (6.1)]
.
Do not use prasugrel in patients with active pathological bleeding or a history of transient ischemic attack (TIA) or stroke
[see Contraindications (4.1, 4.2)]
.
In patients ≥75 years of age, prasugrel 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 myocardial infarction [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 in patients likely to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue prasugrel 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 nonsteroidal 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
[see Warnings and Precautions (5.1)]
.
If possible, manage bleeding without discontinuing prasugrel. Discontinuing prasugrel, particularly in the first few weeks after acute coronary syndrome, increases the risk of subsequent cardiovascular (CV) events
[see Warnings and Precautions (5.3)]
.
WARNING: BLEEDING RISK
See full prescribing information for complete boxed warning.
Prasugrel can cause significant, sometimes fatal, bleeding (5.1, 5.2, 6.1).
Do not use prasugrel in patients with active pathological bleeding or a history of transient ischemic attack or stroke (4.1, 4.2).
In patients
≥75 years of age, prasugrel is generally not recommended, except in high-risk patients (diabetes or prior
myocardial infarction [MI]
), where its use may be considered
(8.5)
.
Do not start prasugrel in patients likely to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue prasugrel at least 7 days prior to any surgery
(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
(5.1)
.
Suspect bleeding in any patient who is hypotensive and has recently undergone
invasive or surgical procedures
(5.1)
.
If possible, manage bleeding without discontinuing prasugrel. Stopping prasugrel increases the risk of subsequent cardiovascular events
(5.3)
.
and
5.1 General Risk of Bleeding
Thienopyridines, including prasugrel, 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 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 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 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 to 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.
Figure 1: Non-CABG-Related TIMI Major or Minor Bleeding Events.
,
5.3 Discontinuation of Prasugrel
Discontinue thienopyridines, including prasugrel, 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)]
.
].
The background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.
Data
Animal Data
In embryo-fetal developmental toxicology studies, pregnant rats and rabbits received prasugrel at maternally toxic oral doses equivalent to more than 40 times the human exposure. A slight decrease in fetal body weight was observed, but there were no structural malformations in either species. In prenatal and postnatal rat studies, maternal treatment with prasugrel had no effect on the behavioral or reproductive development of the offspring at doses greater than 150 times the human exposure.
Active pathological bleeding
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)]
.
Prior transient ischemic attack or stroke
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 (
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
