diagnose a disease that you have never seen, or
perhaps even read about, and you have to combine
your memory with it. That’s why my trainees are
called unicorns, because I used to tell them that
there’s this imaginary animal that nobody had ever
seen but if you saw one in the ward, you’d recognize it. Without the ability to imagine, I’m not sure
you would quite know what was going on.”
WARNING: BLEEDING RISK
• Effient can cause significant, sometimes fatal, bleeding [see Warnings and
Precautions (5.1, 5.2) and Adverse Reactions (6.1)].
• Do not use Effient in patients with active pathological bleeding or a history of
transient ischemic attack or stroke [see Contraindications (4.1, 4.2)].
• In patients ≥75 years of age, Effient is generally not recommended, because
of the increased risk of fatal and intracranial bleeding and uncertain benefit,
except in high-risk situations (patients with diabetes or a history of prior MI)
where its effect appears to be greater and its use may be considered [see Use
in Specific Populations (8.5)].
• Do not start Effient in patients likely to undergo urgent coronary artery
bypass graft surgery (CABG). When possible, discontinue Effient at least
7 days prior to any surgery [see Warnings and Precautions (5.2)].
• Additional risk factors for bleeding include: body weight <60 kg; propensity
to bleed; concomitant use of medications that increase the risk of bleeding
(e.g., warfarin, heparin, fibrinolytic therapy, chronic use of non-steroidal
anti-inflammatory drugs [NSAIDs]) [see Warnings and Precautions (5.1)].
• Suspect bleeding in any patient who is hypotensive and has recently
undergone coronary angiography, percutaneous coronary intervention (PCI),
CABG, or other surgical procedures in the setting of Effient [see Warnings and
Precautions (5.1)].
• If possible, manage bleeding without discontinuing Effient. Discontinuing
Effient, particularly in the first few weeks after acute coronary syndrome,
increases the risk of subsequent cardiovascular events [see Warnings and
Precautions (5.3)].
1 INDICATIONS AND USAGE
1.1 Acute Coronary Syndrome: Effient® is indicated to reduce the rate of thrombotic
cardiovascular (CV) events (including stent thrombosis) in patients with acute coronary
syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI)
as follows:
• Patients with unstable angina (UA) or non–ST-elevation myocardial infarction
(NSTEMI).
• Patients with ST-elevation myocardial infarction (STEMI) when managed with
primary or delayed PCI.
Effient has been shown to reduce the rate of a combined endpoint of cardiovascular
death, nonfatal myocardial infarction (MI), or nonfatal stroke compared to clopidogrel.
The difference between treatments was driven predominantly by MI, with no difference
on strokes and little difference on CV death [see Clinical Studies (14) in full Prescribing
Information].
2 DOSAGE AND ADMINISTRATION
Initiate Effient treatment as a single 60-mg oral loading dose and then continue at
10-mg orally once daily. Patients taking Effient should also take aspirin (75-mg to
325-mg) daily [see Drug Interactions (7.3) and Clinical Pharmacology (12.3) in full
Prescribing Information]. Effient may be administered with or without food [see Clinical
Pharmacology (12.3) in full Prescribing Information and Clinical Studies (14) in full
Prescribing Information].
Timing of Loading Dose
In the clinical trial that established the efficacy and safety of Effient, the loading dose
of Effient was not administered until coronary anatomy was established in UA/NSTEMI
patients and in STEMI patients presenting more than 12 hours after symptom onset. In
STEMI patients presenting within 12 hours of symptom onset, the loading dose of Effient
was administered at the time of diagnosis, although most received Effient at the time
of PCI [see Clinical Studies (14) in full Prescribing Information]. For the small fraction of
patients that required urgent CABG after treatment with Effient, the risk of significant
bleeding was substantial.
Although it is generally recommended that antiplatelet therapy be administered promptly
in the management of ACS because many cardiovascular events occur within hours of
initial presentation, in a trial of 4033 NSTEMI patients, no clear benefit was observed when
Effient loading dose was administered prior to diagnostic coronary angiography compared
to at the time of PCI; however, risk of bleeding was increased with early administration in
patients undergoing PCI or early CABG.
Dosing in Low Weight Patients: Compared to patients weighing ≥60 kg, patients weighing
<60 kg have an increased exposure to the active metabolite of prasugrel and an increased
risk of bleeding on a 10-mg once daily maintenance dose. Consider lowering the
maintenance dose to 5-mg in patients <60 kg. The effectiveness and safety of the 5-mg
dose have not been prospectively studied [see Warnings and Precautions (5.1), Adverse
Reactions (6.1), and Clinical Pharmacology (12.3) in full Prescribing Information].
4 CONTRAINDICATIONS
4.1 Active Bleeding: Effient is contraindicated in patients with active pathological bleeding
such as peptic ulcer or intracranial hemorrhage [see Warnings and Precautions (5.1) and
Adverse Reactions (6.1)].
4.2 Prior Transient Ischemic Attack or Stroke: Effient is contraindicated in patients
with a history of prior transient ischemic attack (TIA) or stroke. In TRITON-TIMI 38 (TRial
to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with
Prasugrel), patients with a history of TIA or ischemic stroke (>3 months prior to enrollment)
Back in 2012, Dr. Somerville felt that, overall,
the United States was not providing appropriate
care to patients with ACHD. Her opinion has not
changed in the subsequent 4 years.
“There are a lot of patients out there who are
not being treated and people are having a go at
them -- surgeons, physicians, cardiologists -- and
had a higher rate of stroke on Effient (6.5%; of which 4.2% were thrombotic stroke and
2.3% were intracranial hemorrhage [ICH]) than on clopidogrel (1.2%; all thrombotic).
In patients without such a history, the incidence of stroke was 0.9% (0.2% ICH) and
1.0% (0.3% ICH) with Effient and clopidogrel, respectively. Patients with a history of
ischemic stroke within 3 months of screening and patients with a history of hemorrhagic
stroke at any time were excluded from TRITON-TIMI 38. Patients who experience a stroke
or TIA while on Effient generally should have therapy discontinued [see Adverse Reactions
(6.1) and Clinical Studies (14) in full Prescribing Information].
4.3 Hypersensitivity: Effient is contraindicated in patients with hypersensitivity (e.g.,
anaphylaxis) to prasugrel or any component of the product [see Adverse Reactions (6.2)].
5 WARNINGS AND PRECAUTIONS
5.1 General Risk of Bleeding: Thienopyridines, including Effient, increase the risk
of bleeding. With the dosing regimens used in TRITON-TIMI 38, TIMI (Thrombolysis in
Myocardial Infarction) Major (clinically overt bleeding associated with a fall in hemoglobin
≥5 g/dL, or intracranial hemorrhage) and TIMI Minor (overt bleeding associated with a fall
in hemoglobin of ≥3 g/dL but <5 g/dL) bleeding events were more common on Effient than
on clopidogrel [see Adverse Reactions (6.1)]. The bleeding risk is highest initially, as shown
in Figure 1 (events through 450 days; inset shows events through 7 days).
Figure 1: Non-CABG-Related TIMI Major or Minor Bleeding Events.
Effient
5
Non-CABG-Related TIMI
Major or Minor Bleeding Events (%)
Effient® (prasugrel) tablets
Brief Summary of Prescribing Information
BRIEF SUMMARY. Please see Full Prescribing Information for additional information
about Effient.
A CRITIQUE FROM A LEGEND
4
Clopidogrel
3
3
2
2
1
1
0
0
0
Number at risk:
Effient
6741
Clopidogrel 6716
90
6042
6023
0
1
2
3
4
5
6
7
180
270
360
450
5707
5764
4813
4883
4078
4138
2747
2792
Days from Randomization
Suspect bleeding in any patient who is hypotensive and has recently undergone coronary
angiography, PCI, CABG, or other surgical procedures even if the patient does not have
overt signs of bleeding. Do not use Effient in patients with active bleeding, prior TIA or
stroke [see Contraindications (4.1, 4.2)].
Other risk factors for bleeding are:
• Age ≥75 years. Because of the risk of bleeding (including fatal bleeding) and uncertain
effectiveness in patients ≥75 years of age, use o f Effient is generally not recommended
in these patients, except in high-risk situations (patients with diabetes or history
of myocardial infarction) where its effect appears to be greater and its use may be
considered [see Adverse Reactions (6.1), Use in Specific Populations (8.5), Clinical
Pharmacology (12.3) in full Prescribing Information, and Clinical Studies (14) in full
Prescribing Information].
• CABG or other surgical procedure [see Warnings and Precautions (5.2)].
• Body weight <60 kg. Consider a lower (5-mg) maintenance dose
[see Dosage and Administration (2), Adverse Reactions (6.1), and Use in Specific
Populations (8.6)].
• Propensity to bleed (e.g., recent trauma, recent surgery, recent or recurrent
gastrointestinal (GI) bleeding, active peptic ulcer disease, severe hepatic impairment, or
moderate to severe renal impairment) [see Adverse Reactions (6.1) and Use in Specific
Populations (8.7, 8.8)].
• Medications that increase the risk of bleeding (e.g., oral anticoagulants, chronic use of
non-steroidal anti-inflammatory drugs [NSAIDs], and fibrinolytic agents). Aspirin and
heparin were commonly used in TRITON-TIMI 38 [see Drug Interactions (7.1, 7.2, 7.3),
and Clinical Studies (14) in full Prescribing Information].
Thienopyridines inhibit platelet aggregation for the lifetime of the platelet
(7-10 days), so withholding a dose will not be useful in managing a bleeding event or
the risk of bleeding associated with an invasive procedure. Because the half-life of
prasugrel’s active metabolite is short relative to the lifetime of the platelet, it may be
possible to restore hemostasis by administering exogenous platelets; however, platelet
transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may
be less effective.
5.2 Coronary Artery Bypass Graft Surgery-Related Bleeding: The risk of bleeding is
increased in patients receiving Effient who undergo CABG. If possible, Effient should be
discontinued at least 7 days prior to CABG.
Of the 437 patients who underwent CABG during TRITON-TIMI 38, the rates of CABGrelated TIMI Major or Minor bleeding were 14.1% in the Effient group and 4.5% in the
clopidogrel group [see Adverse Reactions (6.1)]. The higher risk for bleeding events in
patients treated with Effient persisted up to 7 days from the most recent dose of study
drug. For patients receiving a thienopyridine within 3 days prior to CABG, the frequencies
of TIMI Major or Minor bleeding were 26.7% (12 of 45 patients) in the Effient group,
compared with 5.0% (3 of 60 patients) in the clopidogrel group. For patients who received
their last dose of thienopyridine within 4 to 7 days prior to CABG, the frequencies
decreased to 11.3% (9 of 80 patients) in the prasugrel group and 3.4% (3 of 89 patients)
in the clopidogrel group.
Do not start Effient in patients likely to undergo urgent CABG. CABG-related bleeding
may be treated with transfusion of blood products, including packed red blood cells and
platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of
the maintenance dose may be less effective.
5.3 Discontinuation of Effient: Discontinue thienopyridines, including Effient, for active
bleeding, elective surgery, stroke, or TIA. The optimal duration of thienopyridine therapy
is unknown. In patients who are managed with PCI and stent placement, premature
it’s a bad reflection on your (US) health service,”
said Dr. Somerville. “The first thing you have to do
is establish more centers of care. There is no reason to force these patients to live more than half of
their lives being badly cared for.”
She continued, “When money is attached to a
patient, doctors don’t want to transfer them, they
think they know best. Education is being directed at
discontinuation of any antiplatelet medication, including thienopyridines, conveys an
increased risk of stent thrombosis, myocardial infarction, and death. Patients who
require premature discontinuation of a thienopyridine will be at increased risk for
cardiac events. Lapses in therapy should be avoided, and if thienopyridines must be
temporarily discontinued because of an adverse event(s), they should be restarted as soon
as possible [see Contraindications (4.1, 4.2) and Warnings and Precautions (5.1)].
5.4 Thrombotic Thrombocytopenic Purpura: Thrombotic thrombocytopenic purpura
(TTP) has been reported with the use of Effient. TTP can occur after a brief exposure
(<2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment,
including plasmapheresis (plasma exchange). TTP is characterized by thrombocytopenia,
microangiopathic hemolytic anemia (schistocytes [fragment red blood cells] seen on
peripheral smear), neurological findings, renal dysfunction, and fever [see Adverse
Reactions (6.2)].
5.5 Hypersensitivity Including Angioedema: Hypersensitivity including angioedema
has been reported in patients receiving Effient, including patients with a history of
hypersensitivity reaction to other thienopyridines [see Contraindications (4.3) and Adverse
Reactions (6.2)].
6 ADVERSE REACTIONS
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 Effient (60-mg loading dose and 10-mg once daily) for a median of 14.5 months
(5802 patients were treated for over 6 months; 4136 patients were treated for more than
1 year). The population treated with Effient was 27 to 96 years of age, 25% female, and
92% Caucasian. All patients in the TRITON-TIMI 38 study were to receive aspirin. The dose
of clopidogrel in this study was a 300-mg loading dose and 75-mg once daily.
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates obse rved in the clinical trials cannot be directly compared with the rates observed in
other clinical trials of another drug and may not reflect the rates observed in practice.
Drug Discontinuation: The rate of study drug discontinuation because of adverse reactions
was 7.2% for Effient and 6.3% for clopidogrel. Bleeding was the most common adverse
reaction leading to study drug discontinuation for both drugs (2.5% for Effient and 1.4%
for clopidogrel).
Bleeding: Bleeding Unrelated to CABG Surgery – In TRITON-TIMI 38, overall rates of
TIMI Major or Minor bleeding adverse reactions unrelated to coronary artery bypass
graft surgery (CABG) were significantly higher on Effient than on clopidogrel, as shown
in Table 1.
Table 1: Non-CABG-Related Bleedinga (TRITON-TIMI 38)
Effient (%)
(N=6741)
4.5
2.2
1.3
0.3
0.3
0.3
0.3
0.7
2.4
Clopidogrel (%)
(N=6716)
3.4
1.7
0.8
0.1
0.3
0.1
0.3
0.5
1.9
TIMI Major or Minor bleeding
TIMI Major bleedingb
Life-threatening
Fatal
Symptomatic intracranial hemorrhage (ICH)
Requiring inotropes
Requiring surgical intervention
Requiring transfusion (≥4 units)
TIMI Minor bleedingb
a
Patients may be counted in more than one row.
b
See 5.1 for definition.
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)
Major/Minor
Fatal
Effienta Clopidogrelb Effienta Clopidogrelb
(%)
(%)
(%)
(%)
Weight <60 kg (N=308 Effient, 10.1
N=356 clopidogrel)
Weight ≥60 kg (N=6373 Effient, 4.2
N=6299 clopidogrel)
Age <75 years (N=5850 Effient, 3.8
N=5822 clopidogrel)
Age ≥75 years (N=891 Effient, 9.0
N=894 clopidogrel)
a
10-mg Effient maintenance dose.
b
75-mg clopidogrel maintenance dose.
6.5
0.0
0.3
3.3
0.3
0.1
2.9
0.2
0.1
6.9
1.0
0.1