KENGREAL

KENGREAL- cangrelor injection, powder, lyophilized, for solution
The Medicines Company

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 P2Y12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor [see Clinical Studies ( 14.1)].

2 DOSAGE AND ADMINISTRATION

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, 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 ( 12.2)].
  • Prasugrel: 60 mg immediately after discontinuation of KENGREAL. Do not administer prasugrel prior to discontinuation of KENGREAL [see Drug Interactions ( 7.1) and Clinical Pharmacology ( 12.2)].
  • Clopidogrel: 600 mg immediately after discontinuation of KENGREAL. Do not administer clopidogrel prior to 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

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.

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)].

3 DOSAGE FORMS AND STRENGTHS

For Injection: 50 mg of KENGREAL lyophilized powder in a single-use 10 mL glass vial for reconstitution.

4 CONTRAINDICATIONS

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

5.1 Bleeding

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 ( 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)].

6 ADVERSE REACTIONS

The following adverse reactions are also discussed elsewhere in the labeling:

  • Bleeding [see Warnings and Precautions ( 5.1)]

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)

Figure 1: Bleeding Results in the CHAMPION PHOENIX Studya (All Non-CABG related)
(click image for full-size original)

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%).

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