KENGREAL

1 INDICATIONS AND USAGE KENGREAL is indicated as an adjunct to percutaneous coronary intervention (PCI) to reduce the risk of periprocedural myocardial infarction (MI), repeat coronary revascularization, and stent thrombosis (ST) in patients who have not been treated with a P2Y 12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor [see Clinical Studies ( 14.1 )]. 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. ( 1 )

2 DOSAGE AND ADMINISTRATION KENGREAL is intended for administration via a dedicated IV line, only after reconstitution and dilution. ( 2.3 ) Administer 30 mcg/kg intravenous (IV) bolus prior to PCI followed immediately by a 4 mcg/kg/min IV infusion for at least 2 hours or duration of procedure, whichever is longer. ( 2.1 ) To maintain platelet inhibition after discontinuation of KENGREAL infusion, administer an oral P2Y 12 platelet inhibitor. ( 2.2 ) 2.1 Recommended Dosing The recommended dosage of KENGREAL is a 30 mcg/kg IV bolus followed immediately by a 4 mcg/kg/min IV infusion. Initiate the bolus infusion prior to PCI. The maintenance infusion should ordinarily be continued for at least 2 hours or for the duration of PCI, whichever is longer. 2.2 Transitioning Patients to Oral P2Y 12 Therapy To maintain platelet inhibition after discontinuation of KENGREAL infusion, administer an oral P2Y 12 platelet inhibitor, as described below: Ticagrelor: 180 mg at any time during KENGREAL infusion or immediately after discontinuation [see Clinical Pharmacology ( 12.2 )] . Prasugrel: 60 mg immediately after discontinuation of KENGREAL [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )] . Clopidogrel: 600 mg immediately after discontinuation of KENGREAL [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )] . 2.3 Preparation and Administration KENGREAL is intended for IV administration, after reconstitution and dilution. Preparation Reconstitute the vial prior to dilution in a bag. For each 50 mg/vial, reconstitute by adding 5 mL of Sterile Water for Injection. Swirl gently until all material is dissolved. Avoid vigorous mixing. Allow any foam to settle. Ensure that the contents of the vial are fully dissolved and the reconstituted material is a clear, colorless to pale yellow solution. Parenteral drug products should be inspected visually for particulate matter after reconstitution. Before administration, each reconstituted vial must be diluted further with Normal Saline (Sodium Chloride Injection 0.9% USP) or 5% Dextrose Injection USP. Withdraw the contents from one reconstituted vial and add to one 250 mL saline bag. Mix the bag thoroughly. This dilution will result in a concentration of 200 mcg/mL and should be sufficient for at least 2 hours of dosing. Patients 100 kg and over will require a minimum of 2 bags. Reconstituted KENGREAL should be diluted immediately. Diluted KENGREAL is stable for up to 12 hours in 5% Dextrose Injection and 24 hours in Normal Saline at Room Temperature. Discard any unused portion of reconstituted solution remaining in the vial. Administration Administer KENGREAL via a dedicated IV line. Administer the bolus volume rapidly (<1 minute), from the diluted bag via manual IV push or pump. Ensure the bolus is completely administered before the start of PCI. Start the infusion immediately after administration of the bolus [see Dosage and Administration ( 2.1 )] . 2.1 Recommended Dosing The recommended dosage of KENGREAL is a 30 mcg/kg IV bolus followed immediately by a 4 mcg/kg/min IV infusion. Initiate the bolus infusion prior to PCI. The maintenance infusion should ordinarily be continued for at least 2 hours or for the duration of PCI, whichever is longer. 2.2 Transitioning Patients to Oral P2Y 12 Therapy To maintain platelet inhibition after discontinuation of KENGREAL infusion, administer an oral P2Y 12 platelet inhibitor, as described below: Ticagrelor: 180 mg at any time during KENGREAL infusion or immediately after discontinuation [see Clinical Pharmacology ( 12.2 )] . Prasugrel: 60 mg immediately after discontinuation of KENGREAL [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )] . Clopidogrel: 600 mg immediately after discontinuation of KENGREAL [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )] . 2.3 Preparation and Administration KENGREAL is intended for IV administration, after reconstitution and dilution. Preparation Reconstitute the vial prior to dilution in a bag. For each 50 mg/vial, reconstitute by adding 5 mL of Sterile Water for Injection. Swirl gently until all material is dissolved. Avoid vigorous mixing. Allow any foam to settle. Ensure that the contents of the vial are fully dissolved and the reconstituted material is a clear, colorless to pale yellow solution. Parenteral drug products should be inspected visually for particulate matter after reconstitution. Before administration, each reconstituted vial must be diluted further with Normal Saline (Sodium Chloride Injection 0.9% USP) or 5% Dextrose Injection USP. Withdraw the contents from one reconstituted vial and add to one 250 mL saline bag. Mix the bag thoroughly. This dilution will result in a concentration of 200 mcg/mL and should be sufficient for at least 2 hours of dosing. Patients 100 kg and over will require a minimum of 2 bags. Reconstituted KENGREAL should be diluted immediately. Diluted KENGREAL is stable for up to 12 hours in 5% Dextrose Injection and 24 hours in Normal Saline at Room Temperature. Discard any unused portion of reconstituted solution remaining in the vial. Administration Administer KENGREAL via a dedicated IV line. Administer the bolus volume rapidly (<1 minute), from the diluted bag via manual IV push or pump. Ensure the bolus is completely administered before the start of PCI. Start the infusion immediately after administration of the bolus [see Dosage and Administration ( 2.1 )] .

4 CONTRAINDICATIONS Significant active bleeding ( 4.1 ) Hypersensitivity to KENGREAL or any component of the product ( 4.2 ) 4.1 Significant Active Bleeding KENGREAL is contraindicated in patients with significant active bleeding [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )] . 4.2 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 )] . 4.1 Significant Active Bleeding KENGREAL is contraindicated in patients with significant active bleeding [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )] . 4.2 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 )] .

5 WARNINGS AND PRECAUTIONS Bleeding: Like other drugs that inhibit platelet P2Y 12 function, KENGREAL can increase the risk of bleeding ( 5.1 ) 5.1 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 )] . 5.1 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 )] .

7 DRUG INTERACTIONS Clopidogrel: Do not administer during KENGREAL infusion. ( 7.1 ) Prasugrel: Do not administer during KENGREAL infusion. ( 7.1 ) 7.1 Thienopyridines Clopidogrel or prasugrel administered during KENGREAL infusion will have no antiplatelet effect until the next dose is administered. Therefore, administer clopidogrel or prasugrel after KENGREAL infusion is discontinued [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )]. 7.1 Thienopyridines Clopidogrel or prasugrel administered during KENGREAL infusion will have no antiplatelet effect until the next dose is administered. Therefore, administer clopidogrel or prasugrel after KENGREAL infusion is discontinued [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )].

6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling: Bleeding [see Warnings and Precautions ( 5.1 )] The most common adverse reaction is bleeding. ( 5.1 , 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 CHAMPION PHOENIX KENGREAL (N=5529) Clopidogrel (N=5527) Any GUSTO bleeding, n (%) 857 (15.5) 602 (10.9) Severe/life-threatening b 11 (0.2) 6 (0.1) Moderate c 21 (0.4) 14 (0.3) Mild d 825 (14.9) 582 (10.5) Any TIMI bleeding, n (%) 45 (0.8) 17 (0.3) Major e 12 (0.2) 6 (0.1) Minor f 33 (0.6) 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%) Figure 1 : Bleeding Results in the CHAMPION PHOENIX Study a (All Non-CABG related) a 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%). Figure 1: Bleeding Results in the CHAMPION PHOENIX Studya (All Non-CABG related) 6.1 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 CHAMPION PHOENIX KENGREAL (N=5529) Clopidogrel (N=5527) Any GUSTO bleeding, n (%) 857 (15.5) 602 (10.9) Severe/life-threatening b 11 (0.2) 6 (0.1) Moderate c 21 (0.4) 14 (0.3) Mild d 825 (14.9) 582 (10.5) Any TIMI bleeding, n (%) 45 (0.8) 17 (0.3) Major e 12 (0.2) 6 (0.1) Minor f 33 (0.6) 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%) Figure 1 : Bleeding Results in the CHAMPION PHOENIX Study a (All Non-CABG related) a 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%). Figure 1: Bleeding Results in the CHAMPION PHOENIX Studya (All Non-CABG related)

8.1 Pregnancy Risk Summary There are no available data on cangrelor use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Untreated myocardial infarction can be fatal to the pregnant women and fetus ( see Clinical Considerations ). In animal reproduction studies, continuous infusion of cangrelor in pregnant rats and rabbits throughout organogenesis at dose approximately 2-times the maximum recommended human dose (MRHD) did not result in fetal malformations ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Myocardial infarction is a medical emergency in pregnancy which can be fatal to the pregnant woman and fetus if left untreated. Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of cangrelor on the fetus. Labor or delivery Cangrelor use during labor and delivery may increase the risk for maternal bleeding and hemorrhage. Performance of neuraxial blockade procedures is not advised during cangrelor use due to potential risk of spinal hematoma. When possible, discontinue cangrelor 1 hour prior to labor, delivery, or neuraxial blockade [see Clinical Pharmacology ( 12.2 )]. Data Animal Data A prenatal and postnatal development study in female rats demonstrated a slight increase in the incidence of maternal mortality in dams treated at doses up to 30 mcg/kg/min (approximately 7.5 times the MRHD) cangrelor continuous infusion from Day 6 of gestation up to Day 23 post-partum. Pregnancy rates, gestation index, length of gestation, numbers of live, dead and malformed pups, sex ratio, live birth index, and lactation of the maternal animals were unaffected. Cangrelor administered at dose levels of ≥ 3 mcg/kg/min in pregnant rats from Day 6 to 17 post-coitum resulted in dose-related fetal growth retardation characterized by increased incidences of incomplete ossification and unossified hind limb metatarsals. An embryo-fetal development study in rabbits administered 4, 12, or 36 mcg/kg/min cangrelor continuous IV infusion from Day 6 to Day 19 post-coitum resulted in increased incidences of abortion and intrauterine losses at ≥12 mcg/kg/min (3 times the MRHD). Fetal growth retardation occurred at 36 mcg/kg/min (9 times the MRHD) and was characterized by decreased fetal weights, slight reduction in ossification, and a slight increase in skeletal variants. Cangrelor did not produce malformations in either the rat or rabbit embryo-fetal development studies and is not considered to be a teratogen.