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) ] Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Cosette Pharmaceuticals, Inc. at 1-800-922-1038 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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 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 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 Bleeding Patients may be counted in more than one row.
(TRITON-TIMI 38) Effient (%) (N=6741) Clopidogrel (%) (N=6716) TIMI Major or Minor bleeding 4.5
3.4TIMI
Major bleeding See 5.1 for definition. 2.2
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
0.5TIMI
Minor bleeding 2.4
1.9Figure
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 Effient 10 mg Effient maintenance dose (%) Clopidogrel 75 mg clopidogrel maintenance dose (%) 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
0.1Bleeding Related to CABG In TRITON-TIMI 38,
437 patients who received a thienopyridine underwent CABG during the course of the study. The rate of CABG-related TIMI Major or Minor bleeding was 14.1% for the Effient group and 4.5% in the clopidogrel group (see Table 3 ). The higher risk for bleeding adverse reactions in patients treated with Effient persisted up to 7 days from the most recent dose of study drug. Table 3: CABG-Related Bleeding Patients may be counted in more than one row.
(TRITON-TIMI 38) Effient (%) (N=213) Clopidogrel (%) (N=224) TIMI Major or Minor bleeding 14.1
4.5TIMI
Major bleeding 11.3
3.6 Fatal 0.9 0 Reoperation 3.8
0.5Transfusion
of ≥5 units 6.6
2.2 Intracranial hemorrhage 0 0 TIMI Minor bleeding 2.8
0.9Bleeding Reported as Adverse Reactions
Hemorrhagic events reported as adverse reactions in TRITON-TIMI 38 were, for Effient and clopidogrel, respectively: epistaxis (6.2%, 3.3%), gastrointestinal hemorrhage (1.5%, 1.0%), hemoptysis (0.6%, 0.5%), subcutaneous hematoma (0.5%, 0.2%), post-procedural hemorrhage (0.5%, 0.2%), retroperitoneal hemorrhage (0.3%, 0.2%), pericardial effusion/hemorrhage/tamponade (0.3%, 0.2%), and retinal hemorrhage (0.0%, 0.1%). Malignancies During TRITON-TIMI 38, newly diagnosed malignancies were reported in 1.6% and 1.2% of patients treated with prasugrel and clopidogrel, respectively.
The sites contributing to the differences were primarily colon and lung. In 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 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
4.8 Noncardiac chest pain 3.1
3.5 Atrial fibrillation 2.9
2.4Leukopenia
(<4 × 10 9 WBC WBC = white blood cell /L) 2.8
6.2Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Effient. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders — thrombocytopenia, thrombotic thrombocytopenic purpura (TTP) [see Warnings and Precautions (5.4) and Patient Counseling Information (17) ] Immune system disorders — hypersensitivity reactions including anaphylaxis [see Contraindications (4.3) ]
