sion 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 )] .

uire 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 )] .

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)

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)

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. 8.2 lactation risk summary there are no data on the presence of cangrelor in human milk or animal milk, the effects on the breastfed infant, or the effects on milk production. however, due to its short-half life, cangrelor exposure is expected to be very low in the breastfed infant. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 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 )] . 8.6 renal impairment no dosage adjustment is required for patients with mild, moderate, or severe renal impairment [see clinical pharmacology ( 12.3 )] . 8.7 hepatic impairment kengreal has not been studied in patients with hepatic impairment. however, the metabolism of kengreal is not dependent of hepatic function, so dosage adjustment is not required for patients with hepatic impairment [see clinical pharmacology ( 12.3 )] .

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.

cokinetics kengreal administered intravenously has linear pharmacokinetics in both healthy volunteers and patients. kengreal is rapidly distributed and metabolized, reaching c max within 2 minutes after administration of an intravenous bolus followed by infusion. distribution in a study in healthy volunteers, kengreal administration at a dose of 30 mcg/kg bolus plus 4 mcg/kg/min showed a volume of distribution of 3.9 l. plasma protein binding of kengreal is about 97-98%. metabolism kengreal is deactivated rapidly in the circulation by dephosphorylation to its primary metabolite, a nucleoside, which has negligible anti-platelet activity. kengreal’s metabolism is independent of hepatic function and it does not interfere with other drugs metabolized by hepatic enzymes. elimination following iv administration of [ 3 h] kengreal 58% of radioactivity was recovered in urine. the remaining 35% of radioactivity was in feces, presumably following biliary excretion. the average elimination half-life of kengreal is about 3-6 minutes. specific populations kengreal pharmacokinetics are not affected by sex, age, renal status or hepatic function. no dose adjustment is needed for these factors [see use in specific populations ( 8 )] . weight although weight was a significant covariate for pk with higher clearance in heavier patients, the impact of weight on drug exposure is accounted by the use of weight-based dosing. drug-drug interactions co-administration of cangrelor with unfractionated heparin, aspirin, and nitroglycerin was formally studied in healthy subjects, with no evidence of an effect on the pk/pd of cangrelor. in clinical trials cangrelor has been co-administered with bivalirudin, low molecular weight heparin, clopidogrel, prasugrel, and ticagrelor without clinically detectable interactions. the expected antiplatelet effect of a 600 mg loading dose of clopidogrel or a 60 mg loading dose of prasugrel was blocked when clopidogrel or prasugrel was administered during a cangrelor infusion [see drug interactions ( 7.1 )] . in contrast, the antiplatelet effect of a 180 mg ticagrelor loading dose was not altered significantly when ticagrelor was administered during cangrelor infusion [see drug interactions ( 7.1 )] . figure 3: inhibition (mean) of 20 µm adp-induced platelet aggregation (ipa) measured by light transmission aggregometry after cangrelor 30 mcg/kg bolus and 120-minute 4 mcg/kg infusion with transition to other oral p2y 12 platelet inhibitors. as shown in figure 3, discontinuation of cangrelor infusion, followed by administration of the irreversible p2y 12 platelet inhibitors clopidogrel or prasugrel led to a 1-hour decrease in ipa followed by an increase in inhibition of platelet aggregation beginning at about one hour. this time course of platelet inhibition reflects the pharmacokinetics of cangrelor (offset) followed by the absorption and metabolism of clopidogrel and prasugrel to active metabolites (onset). administration of ticagrelor, a reversible p2y 12 platelet inhibitor, during the cangrelor infusion led to minimal decrease in platelet inhibition for approximately 0.5 hour following discontinuation of the cangrelor infusion. administering ticagrelor during cangrelor infusion does not attenuate the anti-platelet effect of ticagrelor. in vitro studies suggest that neither cangrelor nor its major metabolites inhibit the activity of the hepatic cyp isoenzymes at therapeutic concentrations. therefore, cangrelor administration is not expected to interfere with the hepatic metabolism of other concomitantly administered therapeutic agents. figure 3: inhibition (mean) of 20 µm adp-induced platelet aggregation (ipa) measured by light transmission aggregometry after cangrelor 30 mcg/kg bolus and 120-minute 4 mcg/kg infusion with transition to other oral p2y12 platelet inhibitors.

imination half-life of kengreal is about 3-6 minutes. specific populations kengreal pharmacokinetics are not affected by sex, age, renal status or hepatic function. no dose adjustment is needed for these factors [see use in specific populations ( 8 )] . weight although weight was a significant covariate for pk with higher clearance in heavier patients, the impact of weight on drug exposure is accounted by the use of weight-based dosing. drug-drug interactions co-administration of cangrelor with unfractionated heparin, aspirin, and nitroglycerin was formally studied in healthy subjects, with no evidence of an effect on the pk/pd of cangrelor. in clinical trials cangrelor has been co-administered with bivalirudin, low molecular weight heparin, clopidogrel, prasugrel, and ticagrelor without clinically detectable interactions. the expected antiplatelet effect of a 600 mg loading dose of clopidogrel or a 60 mg loading dose of prasugrel was blocked when clopidogrel or prasugrel was administered during a cangrelor infusion [see drug interactions ( 7.1 )] . in contrast, the antiplatelet effect of a 180 mg ticagrelor loading dose was not altered significantly when ticagrelor was administered during cangrelor infusion [see drug interactions ( 7.1 )] . figure 3: inhibition (mean) of 20 µm adp-induced platelet aggregation (ipa) measured by light transmission aggregometry after cangrelor 30 mcg/kg bolus and 120-minute 4 mcg/kg infusion with transition to other oral p2y 12 platelet inhibitors. as shown in figure 3, discontinuation of cangrelor infusion, followed by administration of the irreversible p2y 12 platelet inhibitors clopidogrel or prasugrel led to a 1-hour decrease in ipa followed by an increase in inhibition of platelet aggregation beginning at about one hour. this time course of platelet inhibition reflects the pharmacokinetics of cangrelor (offset) followed by the absorption and metabolism of clopidogrel and prasugrel to active metabolites (onset). administration of ticagrelor, a reversible p2y 12 platelet inhibitor, during the cangrelor infusion led to minimal decrease in platelet inhibition for approximately 0.5 hour following discontinuation of the cangrelor infusion. administering ticagrelor during cangrelor infusion does not attenuate the anti-platelet effect of ticagrelor. in vitro studies suggest that neither cangrelor nor its major metabolites inhibit the activity of the hepatic cyp isoenzymes at therapeutic concentrations. therefore, cangrelor administration is not expected to interfere with the hepatic metabolism of other concomitantly administered therapeutic agents. figure 3: inhibition (mean) of 20 µm adp-induced platelet aggregation (ipa) measured by light transmission aggregometry after cangrelor 30 mcg/kg bolus and 120-minute 4 mcg/kg infusion with transition to other oral p2y12 platelet inhibitors.

s the first occurrence of any one of the composite endpoint of all-cause mortality, myocardial infarction (mi), ischemia-driven revascularization (idr), and stent thrombosis (st) within 48 hours after randomization. kengreal was administered as 30 mcg/kg bolus followed by 4 mcg/kg/min infusion for 2 to 4 hours. clopidogrel 600 mg was administered immediately at the end of the kengreal infusion in patients randomized to kengreal. clopidogrel 300 mg or 600 mg was administered shortly before pci or shortly afterward, in patients randomized to clopidogrel. kengreal significantly reduced the occurrence of primary composite endpoint events compared to clopidogrel (relative risk reduction [rrr] 22%). most of the effect was a reduction in post-procedural mis detected solely by elevations in ck-mb (type 4a mi). kengreal did not reduce the risk of death. table 2 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint. table 2: primary endpoint and its component events at 48 hours in champion phoenix (mitt population a ) kengreal (n=5470) n (%) clopidogrel (n=5469) n (%) kengreal vs. clopidogrel or (95% ci) p-value primary endpoint death/mi/idr/st 257 (4.7) 322 (5.9) 0.78 (0.66,0.93) b 0.005 death 18 (0.3) 18 (0.3) mi 202 (3.7) 254 (4.6) idr 10 (0.2) 14 (0.3) st 27 (0.5) 36 (0.7) note: if a subject had more than one event at 48 hours, then worst outcome counted (death >mi >idr >st) a the mitt population is all randomized subjects who received at least one dose of study drug and underwent the index pci procedure b based on logistic model adjusted for loading dose and baseline patient status for primary endpoint a supplementary analysis was also performed omitting two subcomponent events of the primary endpoint that were of lesser clinical significance: intraprocedural stent thrombosis (defined as a new or increasing thrombus within or adjacent to a deployed stent occurring during the index pci procedure), and myocardial infarction with less than a 10-fold increase in ck-mb, or with less than a 5-fold increase in ck-mb in the presence of new q waves or new left bundle branch block (lbbb). these results are shown in table 3. table 3: supplementary endpoint and its component events at 48 hours in champion phoenix (mitt population) n (%) kengreal ( n=5470 ) clopidogrel ( n=5469 ) kengreal vs. clopidogrel or (95% ci) supplementary endpoint death/scai-mi/idr/arc-st 79 (1.4) 114 (2.1) 0.69 (0.52,0.92) death 18 (0.3) 18 (0.3) scai-mi a 48 (0.9) 80 (1.5) idr 13 (0.2) 16 (0.3) arc-st b 0 (0.0) 0 (0.0) note: if a subject had more than one event at 48 hours, then worst outcome counted (death >scai-mi >idr >arc-st) a scai mi: ck-mb ≥10x uln, or ck-mb ≥5x uln with new q waves or new lbbb b arc-st defined according to the arc definition [cutlip et al. 2007] the effect of kengreal appeared to be consistent in a variety of pre-specified and other clinically important subgroups (see figure 4). figure 4: champion phoenix study: primary efficacy endpoint by subgroup ( mitt population a ) a the mitt population is all randomized subjects who received at least one dose of study drug and underwent the index pci procedure. 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. figure 4: champion phoenix study: primary efficacy endpoint by subgroup (mitt populationa) 14.2 champion pci and platform trials two additional concurrent clinical trials of the effect of kengreal in patients undergoing percutaneous coronary intervention, champion pci and champion platform were conducted and terminated early for futility. they were completed prior to the design and conduct of champion phoenix. the comparative characteristics and outcomes of each trial are shown in table 4. table 4: summary of the champion trials pci platform phoenix subjects randomized (% of planned enrollment) 8,846 (99%) 5,346 (84%) 11,145 (100%) primary endpoint at 48 hours death, mi, or idr death, mi, or idr death, mi, idr, or st outcome of primary analysis, or (95% ci) 1.05 (0.88, 1.24) 0.87 (0.71, 1.07) 0.78 (0.66, 0.93) clopidogrel dose and time in clopidogrel arm 600 mg immediately before pci 600 mg immediately after pci 300 or 600 mg shortly before or shortly after pci population enrolled (%) stable angina 15% 5% 58% ua/nstemi 74% 95% 26% stemi 11% excluded 16%