Kengreal

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 86°F) permitted].

Distributed by: The Medicines Company Parsippany, NJ 07054. Revised: June 2015.

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.

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.

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.
• Prasugrel: 60 mg immediately after discontinuation of KENGREAL. Do not administer prasugrel prior to discontinuation of KENGREAL.
• Clopidogrel: 600 mg immediately after discontinuation of KENGREAL. Do not administer clopidogrel prior to discontinuation of KENGREAL.

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.

Significant Active Bleeding

KENGREAL is contraindicated in patients with significant active bleeding.

Hypersensitivity

KENGREAL is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to KENGREAL or any component of the product.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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. 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

No carcinogenicity studies were conducted.

Mutagenesis

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

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.

Renal Impairment

No dosage adjustment is required for patients with mild, moderate, or severe renal impairment.

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.

SIDE EFFECTS

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

• Bleeding

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)

^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%).

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.

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.

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

• Bleeding

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)

^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%).

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.

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 minutes.

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

KENGREAL administered 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.

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 [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.