Prasugrel (Page 2 of 7)

5.2 Coronary Artery Bypass Graft Surgery-Related Bleeding

The risk of bleeding is increased in patients receiving Prasugrel tablets who undergo CABG. If possible, Prasugrel tablets 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 tablets group and 4.5% in the clopidogrel group [see Adverse Reactions (6.1)]. The higher risk for bleeding events in patients treated with Prasugrel tablets 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 tablets 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 tablets 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 Prasugrel tablets

Discontinue thienopyridines, including Prasugrel tablets, 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)].

5.4 Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) has been reported with the use of Prasugrel tablets. 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 Prasugrel tablets, 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 Prasugrel tablets (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 tablet 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 of drug 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 Prasugrel tablets and 6.3% for clopidogrel. Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for Prasugrel tablets 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 tablets than on clopidogrel, as shown in Table 1.

Table 1: Non-CABG-Related Bleeding^a (TRITON-TIMI 38)

			Prasugrel tablets (%) (N=6741)	Clopidogrel (%) (N=6716)
TIMI Major or Minor bleeding			4.5	3.4
TIMI Major bleedingb			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 bleedingb			2.4	1.9

^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
	Prasugrel tabletsa (%)	Clopidogrelb (%)	Prasugrel tabletsa (%)	Clopidogrelb (%)
Weight <60 kg (N=308 Prasugrel tablets, N=356 clopidogrel)	10.1	6.5	0.0	0.3
Weight ≥60 kg (N=6373 Prasugrel tablets, N=6299 clopidogrel)	4.2	3.3	0.3	0.1
Age <75 years (N=5850 Prasugrel tablets, N=5822 clopidogrel)	3.8	2.9	0.2	0.1
Age ≥75 years (N=891 Prasugrel tablets, N=894 clopidogrel)	9.0	6.9	1.0	0.1

^a 10 mg Prasugrel tablets maintenance dose

^b 75 mg clopidogrel maintenance dose

Bleeding Related to CABG — In TRITON-TIMI 38, 437 patients who received a thienopyridine underwent CABG during the course of the study. The rate of CABG-related TIMI Major or Minor bleeding was 14.1% for the Prasugrel tablets group and 4.5% in the clopidogrel group (see Table 3). The higher risk for bleeding adverse reactions in patients treated with Prasugrel tablets persisted up to 7 days from the most recent dose of study drug.

Table 3: CABG-Related Bleeding^a (TRITON-TIMI 38)

	Prasugrel tablets (%) (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

^a Patients may be counted in more than one row.

Bleeding Reported as Adverse Reactions — Hemorrhagic events reported as adverse reactions in TRITON-TIMI 38 were, for Prasugrel tablets 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 non-hemorrhagic adverse events were, for Prasugrel tablets 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 tablets (%) (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