Brief Summary KENGREAL ® (cangrelor) for injection, for intravenous use Brief Summary of Prescribing Information SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE KENGREAL is a P2Y 12 platelet inhibitor indicated as an adjunct to percutaneous coronary intervention (PCI) for reducing the risk of periprocedural myocardial infarction (MI), repeat coronary revascularization, and stent thrombosis (ST) in patients in who have not been treated with a P2Y 12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor. CONTRAINDICATIONS Significant Active Bleeding -KENGREAL is contraindicated in patients with significant active bleeding [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Hypersensitivity -KENGREAL is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to KENGREAL or any component of the product [see Adverse Reactions (6.1)]. WARNINGS AND PRECAUTIONS Bleeding -Drugs that inhibit platelet P2Y 12 function, including KENGREAL, increase the risk of bleeding. In CHAMPION PHOENIX bleeding events of all severities were more common with KENGREAL than with clopidogrel [see Adverse Reactions (6.1)]. Bleeding complications with KENGREAL were consistent across a variety of clinically important subgroups (see Figure 1). Once KENGREAL is discontinued, there is no antiplatelet effect after an hour [see Clinical Pharmacology (12.3)]. ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling: Bleeding [see Warnings and Precautions (5.1)]. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of KENGREAL has been evaluated in 13,301 subjects in controlled trials, in whom, 5,529 were in the CHAMPION PHOENIX trial. Bleeding There was a greater incidence of bleeding with KENGREAL than with clopidogrel. No baseline demographic factor altered the relative risk of bleeding with KENGREAL (see Table 1 and Figure 1). Table 1. Major Bleeding Results in the CHAMPION PHOENIX Study (Non-CABG related bleeding) a Figure 1. Bleeding Results in the CHAMPION PHOENIX Study a (All Non-CABG related) Subgroup All Patients Age [yrs] <75 (82%) ≥75 (18%) Gender Male (72%) Female (28%) Race Non-white (6%) White (94%) Weight <60 Kg (5%) ≥60 Kg (95%) Patient Presentation SA (58%) ACS (42%) UA/NSTEMI (26%) STEMI (15%) Prior TIA/Stroke No (95%) Yes (5%) Diabetes No (72%) Yes (28%) 0.1 0.5 1 2 10 Kengreal Clopidogrel OR (95% CI) n/N (%) n/N (%) 857/5529 (15.5) 602/5527 (10.9) 1.50 (1.34, 1.68) 653/4504 (14.5) 204/1025 (19.9) 440/4531 (9.7) 162/996 (16.3) 1.58 (1.39, 1.79) 1.28 (1.02, 1.61) 517/3946 (13.1) 394/4018 (9.8) 1.39 (1.21, 1.59) 340/1583 (21.5) 208/1509 (13.8) 1.71 (1.42, 2.07) 46/338 (13.6) 38/345 (11.0) 1.27 (0.80, 2.01) 810/5188 (15.6) 564/5175 (10.9) 1.51 (1.35, 1.70) 67/319 (21.0) 36/272 (13.2) 1.74 (1.12, 2.71) 790/5210 (15.2) 566/5255 (10.8) 1.48 (1.32, 1.66) 479/3201 (15.0) 326/3184 (10.2) 1.54 (1.33, 1.79) 378/2328 (16.2) 276/2343 (11.8) 1.45 (1.23, 1.72) 227/1468 (15.5) 163/1433 (11.4) 1.43 (1.15, 1.77) 151/860 (17.6) 113/910 (12.4) 1.50 (1.15, 1.96) 811/5236 (15.5) 559/5256 (10.6) 1.54 (1.37, 1.73) 43/275 (15.6) 41/252 (16.3) 0.95 (0.60, 1.52) 610/3986 (15.3) 431/3972 (10.9) 1.48 (1.30, 1.69) 246/1535 (16.0) 169/1547 (10.9) 1.56 (1.26, 1.92) Kengreal better a Clopidogrel better CHAMPION PHOENIX Any GUSTO bleeding, n (%) Severe/life-threatening Moderate Mild d Any TIMI bleeding, n (%) Major Minor e f c b KENGREAL (N=5529) 857 (15.5) 11 (0.2) 21 (0.4) 825 (14.9) 45 (0.8) 12 (0.2) 33 (0.6) CLOPIDOGREL (N=5527) 602 (10.9) 6 (0.1) 14 (0.3) 582 (10.5) 17 (0.3) 6 (0.1) 11 (0.2) Abbreviations: GUSTO: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries; TIMI: Thrombolysis in Myocardial Infarction a Safety population is all randomized subjects who received at least one dose of study drug b intracranial hemorrhage or bleeding resulting in substantial hemodynamic compromise requiring treatment c requiring blood transfusion but not resulting in hemodynamic compromise d all other bleeding not included in severe or moderate e any intracranial hemorrhage, or any overt bleeding associated with a reduction in hemoglobin of ≥5 g/dL (or, when hemoglobin is not available, an absolute reduction in hematocrit ≥15%) f any overt sign of bleeding (including observation by imaging techniques) that is associated with a reduction in hemoglobin of ≥3 g/dL and <5 g/dL (or, when hemoglobin is not available, an absolute reduction in hematocrit of ≥9% and <15%) Please see Full Prescribing Information at www.kengreal.com. Reference: KENGREAL ® (cangrelor) Prescribing Information. 2016. KENGREAL ® is a registered trademark of Chiesi Farmaceutici S.p.A. ©2017 Chiesi USA, Inc. All rights reserved. Printed in the USA. 3/17 PP-K-0118 V2.0 Safety population is all randomized subjects who received at least one dose of study drug Note: The figure above presents effects in various subgroups most of which are baseline characteristics and most of which were pre-specified (patient presentation and weight were not pre-specified subgroups). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Drug Discontinuation In CHAMPION PHOENIX the rate of discontinuation for bleeding events was 0.3% for KENGREAL and 0.1% for clopidogrel. Discontinuation for non-bleeding adverse events was low and similar for KENGREAL (0.6%) and for clopidogrel (0.4%). Coronary artery dissection, coronary artery perforation, and dyspnea were the most frequent events leading to discontinuation in patients treated with KENGREAL. Non-Bleeding Adverse Reactions Hypersensitivity -Serious cases of hypersensitivity were more frequent with KENGREAL (7/13301) than with control (2/12861). These included anaphylactic reactions, anaphylactic shock, bronchospasm, angioedema, and stridor. Decreased renal function -Worsening renal function was reported in 3.2% of KENGREAL patients with severe renal impairment (creatinine clearance <30 mL/min) compared to 1.4% of clopidogrel patients with severe renal impairment. Dyspnea -Dyspnea was reported more frequently in patients treated with KENGREAL (1.3%) than with control (0.4%). DRUG INTERACTIONS Thienopyridines -If clopidogrel or prasugrel are administered during KENGREAL infusion, they will have no antiplatelet effect until the next dose is administered. Clopidogrel and prasugrel, therefore, should not be administered until KENGREAL infusion is discontinued [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C -There are no adequate and well-controlled studies of KENGREAL in pregnant women. Cangrelor did not produce malformations in either the rat or rabbit reproductive studies, and is not considered to be a teratogen. In embryo-fetal development studies in rats, cangrelor produced dose-related fetal growth retardation characterized by increased incidences of incomplete ossification and unossified hind limb metatarsals at plasma concentration of approximately 5 times lower than that achieved in the PCI setting at the maximum recommended human dose (MRHD). In rabbits, cangrelor was associated with increased incidences of abortion and intrauterine losses, as well as fetal growth retardation at plasma concentrations of approximately 12 times higher than the PCI setting at the MRHD. Nursing Mothers: It is not known whether KENGREAL is excreted in human milk. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: In CHAMPION PHOENIX, 18% of patients were ≥75 years. No overall differences in safety or effectiveness were observed between these patients and those patients <75 years [see Clinical Studies (14.1)]. Renal Impairment: No dosage adjustment is required for patients with mild, moderate, or severe renal impairment [see Clinical Pharmacology (12.3)]. Hepatic Impairment: KENGREAL has not been studied in patients with hepatic impairment. However, the metabolism of KENGREAL is not dependent of hepatic function, so that dosage adjustment is not required for patients with hepatic impairment [see Clinical Pharmacology (12.3)]. OVERDOSAGE There is no specific treatment to reverse the antiplatelet effect of KENGREAL but the effect is gone within one hour after the drug is discontinued. In clinical trials, 36 patients received an overdose of KENGREAL, ranging from 36 to 300 mcg/kg (bolus dose) or 4.8 to 13.7 mcg/kg/min (infusion dose). The maximum overdose received was 10 times the PCI bolus dose or 3.5 times the PCI infusion dose in 4 patients. No clinical sequela were noted as a result of overdose following completion of KENGREAL therapy.