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KENGREAL is a direct-acting P2Y12 platelet receptor inhibitor that blocks adenosine diphosphate (ADP)-induced platelet activation and aggregation. The chemical structure is similar to adenosine triphosphate (ATP).
The chemical name of KENGREAL is tetrasodium salt of N6-[2-(methylthio)ethyl]-2-[(3,3,3,trifluoropropyl)-5'-adenylic acid, monanhydride with (dichloromethylene) bisphosphonic acid.
The empirical formula of KENGREAL is C17H21N5Cl2F3Na4O12P3S2 and the molecular weight is 864.3 g/mol.
The chemical structure is represented below:
Cangrelor for Injection is a sterile white to off-white lyophilized powder for IV infusion. In addition to the active ingredient, cangrelor, each single use vial contains mannitol, sorbitol, and sodium hydroxide to adjust the pH.
Indications & Dosage
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 P2Y12 platelet
inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor [see Clinical
DOSAGE AND ADMINISTRATION
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.
Transitioning Patients To Oral P2Y12 Therapy
To maintain platelet inhibition after discontinuation of
KENGREAL infusion, an oral P2Y12 platelet inhibitor should be administered.
Administer one as described below:
Ticagrelor: 180 mg at any time during KENGREAL infusion
or immediately after discontinuation [see CLINICAL PHARMACOLOGY].
Prasugrel: 60 mg immediately after discontinuation of
KENGREAL. Do not administer prasugrel prior to discontinuation of KENGREAL [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
Clopidogrel: 600 mg immediately after discontinuation of
KENGREAL. Do not administer clopidogrel prior to discontinuation of KENGREAL [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
Preparation And Administration
KENGREAL is intended for IV administration, after
reconstitution and dilution.
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. Reconstitute the vial prior to dilution in a
bag. Parenteral drug products should be inspected visually for particulate
matter after reconstitution.
Do not use without dilution. 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.
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 Recommended Dosing].
Dosage Forms And Strengths
For Injection: 50 mg of KENGREAL lyophilized powder in a
single-use 10 mL glass vial for reconstitution.
Storage And Handling
KENGREAL is supplied as a
sterile lyophilized powder in single use 10 mL vials.
NDC # 65293-003-01: 10 mL vial containing 50 mg cangrelor NDC # 65293-003-10: 10 count of
10 mL vials containing 50 mg cangrelor
Vials of KENGREAL should be
stored at USP Controlled Room Temperature, [20°C to 25°C (68°F to 77°F) with
excursions between 15°C and 30°C (59°F and
Distributed by: The Medicines Company Parsippany, NJ 07054. Revised: June 2015.
Heart Disease: Symptoms, Signs, and CausesSee Slideshow
Side Effects & Drug Interactions
The following adverse reactions are also discussed
elsewhere in the labeling:
Bleeding [see WARNINGS AND PRECAUTIONS]
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
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
Any GUSTO bleeding, n (%)
Any TIMI bleeding, n (%)
Abbreviations: GUSTO: Global
Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded
Arteries; TIMI: Thrombolysis in Myocardial Infarction
Â a Safety population is all randomized subjects who received at
least one dose of study drug
Â b intracranial hemorrhage or bleeding resulting in substantial
hemodynamic compromise requiring treatment
Â c requiring blood transfusion but not resulting in hemodynamic
Â d all other bleeding not included in severe or moderate
Â 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%)
Â 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
Studya (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.
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
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 was reported more frequently in patients treated
with KENGREAL (1.3%) than with control (0.4%).
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 and
Warnings & Precautions
Included as part of the PRECAUTIONS section.
Drugs that inhibit platelet P2Y12 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].
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].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No carcinogenicity studies were conducted.
Cangrelor was non-mutagenic and non-clastogenic in
genetic toxicology studies, including in vitro bacterial gene mutation assay,
mouse lymphoma thymidine kinase assay, chromosome aberration assay in human
peripheral lymphocytes, and in vivo bone marrow micronucleus assay in mice.
Impairment of Fertility
Cangrelor had no significant effect on male or female
rats fertility treated for 28 days, or on early embryonic development at steady
state plasma concentration (Css) of approximately the same as that achieved in
the PCI setting at the MRHD.
Use In Specific Populations
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.
It is not known whether KENGREAL is excreted in human
Safety and effectiveness in pediatric patients have not
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].
No dosage adjustment is required for patients with mild,
moderate, or severe renal impairment [see CLINICAL PHARMACOLOGY].
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].
Overdosage & Contraindications
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.
Significant Active Bleeding
KENGREAL is contraindicated in patients with significant
active bleeding [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
KENGREAL is contraindicated in patients with known
hypersensitivity (e.g., anaphylaxis) to KENGREAL or any component of the
product [see ADVERSE REACTIONS].
Mechanism Of Action
Cangrelor is a direct P2Y12 platelet
receptor inhibitor that blocks ADP-induced platelet activation and aggregation.
Cangrelor binds selectively and reversibly to the P2Y12 receptor to prevent
further signaling and platelet activation.
Cangrelor inhibits activation
and aggregation of platelets. After administration of a 30 mcg/kg IV bolus
followed by a 4 mcg/kg/min IV infusion, platelet inhibition occurs within 2
Figure 2 shows the effect on
platelet activity, and its relation to cangrelor plasma concentration, of
administering a 30 mcg/kg IV bolus, followed by a 1-hour 4 mcg/kg/min IV
infusion, of cangrelor. The anti-platelet effect is maintained for the duration
of the infusion. After discontinuation of the infusion, the anti-platelet
effect decreases rapidly and platelet function returns to normal within 1 hour.
Figure 2: Cangrelor PD Characteristics
intravenously has linear pharmacokinetics in both healthy volunteers and
patients. KENGREAL is rapidly distributed and metabolized, reaching Cmax within
2 minutes after administration of an intravenous bolus followed by infusion.
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%.
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.
Following IV administration of
[3H] 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.
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].
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
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
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].
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.
As shown in Figure 3,
discontinuation of cangrelor infusion, followed by administration of the
irreversible P2Y12 platelet inhibitors clopidogrel and 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 P2Y12 platelet
inhibitor, during the cangrelor infusion led to minimal decrease in platelet
inhibition for approximately 0.5 hours 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.
Champion Phoenix Trial
The CHAMPION PHOENIX trial was intended to test whether
faster platelet inhibition with cangrelor at the time of PCI would reduce the
rate of periprocedural thrombotic events compared to a drug with a slower
antiplatelet effect, clopidogrel, given at about the time of PCI. It was a
randomized, double-blind study in which patients with coronary artery disease
(stable angina, UA/NSTEMI, STEMI) requiring PCI and receiving standard therapy
including aspirin and heparin or bivalirudin were randomized 1:1 to KENGREAL
(n=5472) or to clopidogrel 300 or 600 mg (n=5470). Patients who had already
taken an oral P2Y12 platelet inhibitor were not eligible to enroll. Patients
administered glycoprotein IIb/IIIa inhibitors (GPI) or for whom GPI use was
planned were also not eligible to enroll. PHOENIX was thus a study of people
undergoing PCI who had not been previously treated with anti-platelet therapy
other than aspirin.
The primary outcome measure was 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 populationa)
KENGREAL (N=5470) n (%)
Clopidogrel (N=5469) n (%)
KENGREAL vs. clopidogrel
OR (95% CI)
Primary Endpoint Death/MI/IDR/ST
0.78 (0.66,0.93) b
Note: if a subject had more
than one event at 48 hours, then worst outcome counted (death > MI > IDR
Â 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
KENGREAL vs. clopidogrel OR (95% CI)
Supplementary Endpoint Death/SCAI-MI/IDR/ARC-ST
Note: if a subject had more
than one event at 48 hours, then worst outcome counted (death > SCAI-MI
> IDR > ARCST)
Â a SCAI MI: CK-MB ≥ 10X ULN, or CK-MB ≥ 5X ULN with new Q
waves or new LBBB
Â b ARC-ST defined according to the ARC definition [Cutlip et al.
The effect of KENGREAL appeared to be consistent in a
variety of pre-specified and other clinically important subgroups (see Figure
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
CHAMPION PCI And PLATFORM
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
Subjects Randomized (% of planned enrollment)
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 (%)
No information provided. Please refer to the WARNINGS AND PRECAUTIONS section.