ADVERSE REACTIONS
Clinical Trials Experience
The following serious adverse reactions are also discussed elsewhere in the labeling:
-
Bleeding [see Boxed Warning and Warnings and Precautions (5.1, 5.2)]
-
Thrombotic thrombocytopenic purpura [see Warnings and Precautions ]
Safety in patients with ACS undergoing PCI was evaluated in a clopidogrel-controlled study, TRITON-TIMI 38, in which 6741 patients were treated with Effient (60 mg loading dose and 10 mg once daily) for a median of 14.5 months (5802 patients were treated for over 6 months; 4136 patients were treated for more than 1 year). The population treated with Effient was 27 to 96 years of age, 25% female, and 92% Caucasian. All patients in the TRITON-TIMI 38 study were to receive aspirin. The dose of clopidogrel in this study was a 300 mg loading dose and 75 mg once daily.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials cannot be directly compared with the rates observed in other clinical trials of another drug and may not reflect the rates observed in practice.
Drug Discontinuation
The rate of study drug discontinuation because of adverse reactions was 7.2% for Effient and 6.3% for clopidogrel. Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for Effient and 1.4% for clopidogrel).
Bleeding
Bleeding Unrelated to CABG Surgery - In TRITON-TIMI 38, overall rates of TIMI Major or Minor bleeding adverse reactions unrelated to coronary artery bypass graft surgery (CABG) were significantly higher on Effient than on clopidogrel, as shown in Table 1.
Table 1: Non-CABG-Related Bleedinga (TRITON-TIMI 38)
|
Effient
(%)
(N=6741)
|
Clopidogrel
(%)
(N=6716)
|
p-value
|
|
a Patients may be counted in more than one row.
|
|
b See 5.1 for definition.
|
|
TIMI Major or Minor bleeding
|
4.5
|
3.4
|
p=0.002
|
|
TIMI Major bleedingb
|
2.2
|
1.7
|
p=0.029
|
|
Life-threatening
|
1.3
|
0.8
|
p=0.015
|
|
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 bleedingb
|
2.4
|
1.9
|
p=0.022
|
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].
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
|
Effient
(%)
|
Clopidogrel
(%)
|
Effient
(%)
|
Clopidogrel
(%)
|
|
Weight < 60 kg (N=308 Effient, N=356 clopidogrel)
|
10.1
|
6.5
|
0.0
|
0.3
|
|
Weight ≥ 60 kg (N=6373 Effient, N=6299 clopidogrel)
|
4.2
|
3.3
|
0.3
|
0.1
|
|
Age < 75 years (N=5850 Effient, N=5822 clopidogrel)
|
3.8
|
2.9
|
0.2
|
0.1
|
|
Age ≥ 75 years (N=891 Effient, 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 Effient group and 4.5% in the clopidogrel group (Table 3). The higher risk for bleeding adverse reactions in patients treated with Effient persisted up to 7 days from the most recent dose of study drug.
Table 3: CABG-Related Bleedinga (TRITON-TIMI 38)
|
Effient (%)
(N=213)
|
Clopidogrel (%)
(N=224)
|
|
a Patients may be counted in more than one row.
|
|
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 Effient and clopidogrel, respectively: epistaxis (6.2%, 3.3%), gastrointestinal hemorrhage (1.5%, 1.0%), hemoptysis (0.6%, 0.5%), subcutaneous hematoma (0.5%, 0.2%), post-procedural hemorrhage (0.5%, 0.2%), retroperitoneal hemorrhage (0.3%, 0.2%), 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. It is unclear if these observations are causally-related or are random occurrences.
Other Adverse Events
In TRITON-TIMI 38, common and other important non-hemorrhagic adverse events were, for Effient and clopidogrel, respectively: severe thrombocytopenia (0.06%, 0.04%), anemia (2.2%, 2.0%), abnormal hepatic function (0.22%, 0.27%), allergic reactions (0.36%, 0.36%), and angioedema (0.06%, 0.04%). Table 4 summarizes the adverse events reported by at least 2.5% of patients.
Table 4: Non-Hemorrhagic Treatment Emergent Adverse Events Reported by at Least 2.5% of Patients in Either Group
|
|
Effient (%)
(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
|
|
Non-cardiac chest pain
|
3.1
|
3.5
|
|
Atrial fibrillation
|
2.9
|
3.1
|
|
Bradycardia
|
2.9
|
2.4
|
|
Leukopenia (< 4 x 109 WBC/L)
|
2.8
|
3.5
|
|
Rash
|
2.8
|
2.4
|
|
Pyrexia
|
2.7
|
2.2
|
|
Peripheral edema
|
2.7
|
3.0
|
|
Pain in extremity
|
2.6
|
2.6
|
|
Diarrhea
|
2.3
|
2.6
|
|
REPORTS OF SUSPECTED EFFIENT SIDE EFFECTS / ADVERSE REACTIONS
Below is a sample of reports where side effects / adverse reactions may be related to Effient. The information is not vetted and should not be considered as verified clinical evidence.
Possible Effient side effects / adverse reactions in 67 year old female
Reported by a pharmacist from United States on 2011-10-06
Patient: 67 year old female weighing 85.2 kg (187.4 pounds)
Reactions: Haemorrhagic Anaemia, Upper Gastrointestinal Haemorrhage, Gastric Ulcer
Adverse event resulted in: hospitalization
Suspect drug(s):
Aspirin
Dosage: po chronic
Administration route: Oral
Indication: Coronary Artery Disease
Effient
Dosage: po chronic
Administration route: Oral
Indication: Coronary Artery Disease
Possible Effient side effects / adverse reactions in 50 year old male
Reported by a physician from United States on 2011-10-07
Patient: 50 year old male weighing 83.0 kg (182.6 pounds)
Reactions: Intracranial Aneurysm
Adverse event resulted in: death
Suspect drug(s):
Effient
Other drugs received by patient: Coumadin; Aspirin
Possible Effient side effects / adverse reactions in 65 year old male
Reported by a consumer/non-health professional from United States on 2011-10-07
Patient: 65 year old male
Reactions: Transient Ischaemic Attack
Suspect drug(s):
Effient
|
