Kcentra

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Kcentra

Classes

Blood Coagulation Factors

Administration
Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The reconstituted solution should be colorless, clear to slightly opalescent (Kcentra) or colorless to slightly blue, clear (Balfaxar), and free from visible particles. Do not use solutions that are cloudy, discolored, or have deposits.
Inspect all components for physical integrity prior to use. Do not use products or components that appear damaged or broken.
The actual potency per vial of Factor IX is stated on the carton. The actual potencies of Factors II, VII, IX, and X, and Proteins C and S are stated on the carton (Kcentra) or indicated as ranges (Balfaxar).

Intravenous Administration

Reconstitution
Ensure vials of prothrombin complex concentrate (PCC) and diluent (provided) are at room temperature of 20 to 25 degrees C (68 to 77 degrees F) prior to and during reconstitution. Use aseptic technique to reconstitute.
Open the transfer device package (i.e., Mix2Vial transfer set or Nextaro transfer device), but do not remove from the package or touch the spike.
Place diluent vial on a flat surface and hold tightly. Grip the transfer device with the clear package and push the spike at the blue end of the transfer device firmly through the center of the stopper of the diluent vial. Do not twist while attaching.
While holding the diluent vial, carefully remove the clear package from the transfer device by pulling vertically upwards. Leave the transfer device attached firmly to the diluent vial.
Place the lyophilized PCC vial on flat surface and hold tightly. Invert diluent vial with transfer device attached and push the other end of the transfer device firmly through the center of the stopper of the PCC vial. Do not twist while attaching. The diluent will automatically transfer into the vial.
Gently swirl (do not shake) the vial until fully dissolved then unscrew the transfer set into 2 pieces. Do not touch the luer lock connector.
While the reconstituted PCC vial is upright, screw a syringe to the transfer device. Invert the system upside down; draw the concentrate into the syringe.
Unscrew the syringe from the transfer device.
To administer, attach the syringe to a suitable intravenous administration set.
If patient is to receive more than 1 vial, the contents of multiple vials may be pooled together; however, use a separate unused transfer device for each product vial.
Storage of Kcentra after reconstitution: After reconstitution, administer immediately or within 4 hours. Reconstituted Kcentra can be stored at 2 to 25 degrees C (36 to 77 degrees F). If cooled, warm to 20 to 25 degrees C (68 to 77 degrees F) prior to administration. Do not freeze. Each vial contains no preservatives and is for single use only. Discard partially used vials.
Storage of Balfaxar after reconstitution: After reconstitution, administer immediately or within 8 hours (provided sterility is maintained). The reconstituted solution can be stored for up to 8 hours at room temperature of 20 to 25 degrees C (68 to 77 degrees F). Each vial contains no preservatives and is for single use only. Discard partially used vials.
 
Intermittent IV Infusion
Do not mix with other medicinal products; administer through a separate infusion line. The infusion line may be flushed with normal saline before and after administration.
Administer at room temperature using aseptic technique.
Administer by intravenous infusion at a rate of 0.12 mL/kg/minute (approximately 3 units/kg/minute), up to a maximum rate of 8.4 mL/minute (approximately 210 units/minute).
Do not allow blood to enter the syringe as there is a possibility of fibrin clot formation.

Adverse Reactions
Severe

atrial fibrillation / Early / 4.2-4.2
pleural effusion / Delayed / 4.2-4.2
heart failure / Delayed / 2.6-2.6
stroke / Early / 1.1-1.9
pulmonary edema / Early / 1.6-1.6
thromboembolism / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
thrombosis / Delayed / Incidence not known
disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
respiratory failure / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known
anaphylactic shock / Rapid / Incidence not known
cardiac arrest / Early / Incidence not known
bradycardia / Rapid / Incidence not known

Moderate

hypotension / Rapid / 7.3-7.3
anemia / Delayed / 5.7-5.8
hypertension / Early / 4.9-4.9
dysuria / Early / 1.9-4.8
sinus tachycardia / Rapid / 4.7-4.7
hypokalemia / Delayed / 4.7-4.7
dyspnea / Early / 3.7-3.7
hypoxia / Early / 3.7-3.7
angina / Early / 1.0-1.0
wheezing / Rapid / Incidence not known
tachypnea / Early / Incidence not known

Mild

asthenia / Delayed / 12.4-17.5
headache / Early / 7.3-7.3
nausea / Early / 6.3-6.3
vomiting / Early / 6.3-6.3
abdominal pain / Early / 2.9-4.9
insomnia / Early / 4.7-4.7
anxiety / Delayed / Incidence not known
pruritus / Rapid / Incidence not known
rash / Early / Incidence not known
flushing / Rapid / Incidence not known
urticaria / Rapid / Incidence not known
infection / Delayed / Incidence not known
tremor / Early / Incidence not known
paresthesias / Delayed / Incidence not known
fever / Early / Incidence not known
chills / Rapid / Incidence not known

Boxed Warning
Angina, coronary artery disease, disseminated intravascular coagulation (DIC), hepatic disease, myocardial infarction, peripheral vascular disease, stroke, thromboembolic disease, thromboembolism

Prothrombin complex concentrate (PCC) is contraindicated in patients with a history of disseminated intravascular coagulation (DIC). Reversing vitamin K antagonist (VKA) therapy with PCC exposes patients to the thromboembolic risk of their underlying disease. Weigh the benefits of reversing VKA therapy against the potential risks of thromboembolism, especially in patients with a history of thromboembolic disease. Because of the increased risk of thromboembolic events, PCC may not be suitable for use in patients with a thromboembolic disease event in the previous 3 months. Patients with a thromboembolic event, myocardial infarction, DIC, stroke, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the previous 3 months were excluded from clinical trials of PCC. Monitor for signs and symptoms of thromboembolism during and after administration of PCC in patients with a history of coronary artery disease, hepatic disease, or patients at risk of thromboembolic events or DIC. Carefully consider resuming anticoagulation after administration of PCC once the risk of thromboembolic events outweighs the risk of acute bleeding.

Common Brand Names

Balfaxar, Kcentra

Dea Class

Rx

Description

Parenteral blood coagulation factor product
Used for the urgent reversal of acquired factor deficiency induced by vitamin K antagonist (VKA) therapy in adults with major bleeding or need for an urgent surgery or invasive procedure
Comprised of factors II, VII, IX and X, and antithrombotic proteins C and S

Dosage And Indications
For vitamin K antagonist reversal in persons with acute major bleeding or need for urgent surgery or invasive procedure.
NOTE: Prothrombin complex concentrate has been designated an orphan drug by the FDA for this indication.
For vitamin K antagonist reversal in persons with an INR of 2 or more and acute non-intracranial major bleeding. Intravenous dosage (Kcentra) Adults

25 units factor IX/kg (Max: 2,500 units factor IX) IV for pre-treatment INR 2 to 3.9; 35 units factor IX/kg (Max: 3,500 units factor IX) IV for pre-treatment INR 4 to 6; and 50 units factor IX/kg (Max: 5,000 units factor IX) IV for pre-treatment INR more than 6. Because coagulation factor concentrations may be unstable in patients with acute major bleeding, measure INR prior to treatment and close to the time of dosing. Administer vitamin K concurrently to maintain vitamin K-dependent clotting factor concentrations once the effects of prothrombin complex concentrate have diminished. Repeat dosing is not recommended.

Intravenous dosage (Kcentra fixed dose†) Adults

1,000 units factor IX IV for pre-treatment INR of 2 or more. Because coagulation factor concentrations may be unstable in patients with acute major bleeding, measure INR prior to treatment and close to the time of dosing. Administer vitamin K concurrently to maintain vitamin K-dependent clotting factor concentrations once the effects of prothrombin complex concentrate have diminished. Repeat dosing is not recommended.

For vitamin K antagonist reversal in persons with an INR of 2 or more and acute intracranial major bleeding. Intravenous dosage (Kcentra) Adults

25 units factor IX/kg (Max: 2,500 units factor IX) IV for pre-treatment INR 2 to 3.9; 35 units factor IX/kg (Max: 3,500 units factor IX) IV for pre-treatment INR 4 to 6; and 50 units factor IX/kg (Max: 5,000 units factor IX) IV for pre-treatment INR more than 6. Because coagulation factor concentrations may be unstable in patients with acute major bleeding, measure INR prior to treatment and close to the time of dosing. Administer vitamin K concurrently to maintain vitamin K-dependent clotting factor concentrations once the effects of prothrombin complex concentrate have diminished. Repeat dosing is not recommended.

Intravenous dosage (Kcentra fixed dose†) Adults

1,500 units factor IX IV for pre-treatment INR of 2 or more. Because coagulation factor concentrations may be unstable in patients with acute major bleeding, measure INR prior to treatment and close to the time of dosing. Administer vitamin K concurrently to maintain vitamin K-dependent clotting factor concentrations once the effects of prothrombin complex concentrate have diminished. Repeat dosing is not recommended.

For vitamin K antagonist reversal in persons with an INR 1.4 to 1.9 and acute intracranial major bleeding†. Intravenous dosage (Kcentra) Adults

25 units factor IX/kg (Max: 2,500 units factor IX) IV for pre-treatment INR 1.4 to 1.9. Because coagulation factor concentrations may be unstable in patients with acute major bleeding, measure INR prior to treatment and close to the time of dosing. Administer vitamin K concurrently to maintain vitamin K-dependent clotting factor concentrations once the effects of prothrombin complex concentrate have diminished. Repeat dosing is not recommended.

For vitamin K antagonist reversal in persons with an INR of 2 or more and need for urgent surgery or invasive procedure. Intravenous dosage Adults

25 units factor IX/kg (Max: 2,500 units factor IX) IV for pre-treatment INR 2 to 3.9; 35 units factor IX/kg (Max: 3,500 units factor IX) IV for pre-treatment INR 4 to 6; and 50 units factor IX/kg (Max: 5,000 units factor IX) IV for pre-treatment INR more than 6. Because coagulation factor concentrations may be unstable in patients with urgent need for surgery or other invasive procedure, measure INR prior to treatment and close to the time of dosing. Administer vitamin K concurrently to maintain vitamin K-dependent clotting factor concentrations once the effects of prothrombin complex concentrate have diminished. Repeat dosing is not recommended.

For direct thrombin inhibitor reversal†, including dabigatran reversal†, in persons with acute major bleeding or need for urgent surgery or invasive procedure. Intravenous dosage Adults

50 units factor IX/kg (Max: 4,000 units) IV as a single dose as an alternative.

For direct oral anticoagulant reversal†, including apixaban reversal†, edoxaban reversal†, and rivaroxaban reversal†, in persons with acute major bleeding or need for urgent surgery or invasive procedure. Intravenous dosage (weight-based dose) Adults

50 units factor IX/kg IV as a single dose as an alternative.

†Indicates off-label use

Dosing Considerations
Hepatic Impairment

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Drug Interactions

Alteplase: (Major) The concomitant use of protein C concentrate and alteplase, tPA may further increase the risk of bleeding from tPA. In clinical trials, several episodes of bleeding were reported. Concurrent anticoagulant medication may have been responsible for these bleeding episodes.
Aminocaproic Acid: (Major) In general, aminocaproic acid should not be administered simultaneously with factor IX complex, factor IX concentrates, factor IX Fc fusion protein, recombinant, and factor IX albumin fusion protein, recombinant due to the increased risk of thrombosis. Some hematologists recommend separating administration of aminocaproic acid from these clotting factor complexes by 8 hours. Aminocaproic acid has been used concurrently with human factor IX complexes or anti-inhibitor coagulant complex perioperatively in hemophiliac patients. The risk of developing thrombosis, however, is increased. In rare instances, thrombosis leading to acute myocardial infarction or gangrene has been reported in patients with hemophilia receiving combination therapy with factor IX concentrate and aminocaproic acid. Concomitant administration of aminocaproic acid with purer formulations of factor IX may also result in an increased risk of thrombosis.
Apixaban: (Contraindicated) The actions of factor X are likely to be counteracted by direct and indirect factor Xa inhibitors such as apixaban, edoxaban, rivaroxaban, and fondaparinux.
Betrixaban: (Major) The actions of factor X are likely to be counteracted by factor Xa inhibitors such as betrixaban.
Edoxaban: (Major) The actions of factor X are likely to be counteracted by direct and indirect factor Xa inhibitors such as apixaban, edoxaban, rivaroxaban, and fondaparinux.
Fondaparinux: (Major) The actions of factor X are likely to be counteracted by direct and indirect factor Xa inhibitors such as apixaban, edoxaban, rivaroxaban, and fondaparinux.
Protein C Concentrate, Human: (Major) Use factor X cautiously with other plasma products that may contain factor X (e.g., fresh frozen plasma, prothrombin complex concentrate, human).
Rivaroxaban: (Major) The actions of factor X are likely to be counteracted by factor Xa inhibitors such as rivaroxaban.
Tranexamic Acid: (Major) Tranexamic acid should not be administered concomitantly with factor IX complex, Factor IX Fc fusion protein, recombinant, or Factor IX concentrates, due to the increased risk of thrombosis.
Warfarin: (Major) Concomitant administration of vitamin K antagonists (coumarin anticoagulants such as warfarin) and protein C concentrate should be done with close monitoring. Upon initiation of vitamin K antagonists, patients may experience a transient hypercoagulable state before the desired anticoagulant effect becomes apparent. This transient effect may occur because protein C also is a vitamin K-dependent plasma protein with a much shorter half-life than other vitamin K-dependent proteins such as Factor II, IX and X. Upon initiation of treatment, the activity of protein C is more rapidly suppressed than that of the procoagulant factors. Therefore, if a patient is switched to oral anticoagulants, protein C replacement must be continued until stable anticoagulation is established. In addition, patients with severe congenital protein C deficiency are at a higher risk of developing warfarin-induced skin necrosis. Monitor patients closely during treatment.

How Supplied

Kcentra/Prothrombin, Coagulation Factor VII (Pooled Human Plasma), Coagulation Factor IX (Pooled Human Plasma), High Purity, Coagulation Factor X (Pooled Human Plasma), Protein C Concentrate (Human), Protein S Concentrate (Human) Intravenous Inj Pwd F/Sol

Maximum Dosage
Adults

Individualize dosage based on pre-treatment INR and body weight. In patients with pre-treatment INR 2 to 3.9, do not exceed 2,500 units of factor IX; pre-treatment INR 4 to 6, do not exceed 3,500 units factor IX; pre-treatment INR greater than 6, do not exceed 5,000 units factor IX. For patients weighing more than 100 kg, do not exceed maximum dose.

Geriatric

Individualize dosage based on pre-treatment INR and body weight. In patients with pre-treatment INR 2 to 3.9, do not exceed 2,500 units of factor IX; pre-treatment INR 4 to 6, do not exceed 3,500 units factor IX; pre-treatment INR greater than 6, do not exceed 5,000 units factor IX. For patients weighing more than 100 kg, do not exceed maximum dose.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Mechanism Of Action

The coagulation cascade is a series of procoagulant and antithrombotic reactions involving the activation of zymogens. The vascular endothelium provides a protective barrier separating blood cells and plasma factors from subendothelial vessel wall reactive adhesive proteins and tissue factor; the proteins trigger blood coagulation. During vitamin K antagonist therapy, a dose-dependent acquired deficiency of the vitamin K-dependent coagulation factors occurs. Administration of prothrombin complex concentrate rapidly increases plasma concentrations of vitamin K-dependent coagulation factors II, VII, IX, and X and the antithrombotic proteins C and S.
Factor II: Factor II is converted to thrombin by factor Xa in the presence of calcium, factor V, and phospholipids. Thrombin converts fibrinogen to fibrin for clot formation.
Factor VII: Factor VII is converted to factor VIIa by splitting of an internal peptide link. The factor VIIa-tissue factor complex activates factor IX and initiates the primary coagulation pathway by activating factor X in the presence of phospholipids and calcium ions.
Factor IX: Factor IX may be activated by factor VIIa-tissue factor complex and by factor XIa. In the presence of factor VIIIa, factor IXa activates factor X to factor Xa.
Factor X: Factor X activation involves the cleavage of a peptide bond by the factor VIIIa-factor IXa complex or the tissue factor-factor VIIa complex. Factor Xa forms a complex with factor Va that converts prothrombin to thrombin in the presence of phospholipids and calcium ions.
Protein C: Protein C is activated by thrombin then exerts an antithrombotic effect by inhibiting factor Va and factor VIIIa leading to a decrease in thrombin formation and has indirect profibrinolytic activity by inhibiting plasminogen activator inhibitor-1.
Protein S: Protein S exists in a free form (40%) and in a complex with C4b-binding protein (60%). The free form of protein S functions as a cofactor for activated protein C in the inactivation of factor Va and factor VIIIa, leading to antithrombotic activity.

Pharmacokinetics

Prothrombin complex concentrate (PCC) is administered intravenously. PCC is distributed, metabolized, and excreted in the same manner as the endogenous proteins; however, the following pharmacokinetic parameters of PCC were obtained in healthy subjects and may not be applicable to patients with acute major bleeding and elevated INR due to vitamin K antagonist therapy. Factor II had the longest elimination half-life (60.4 hours) and factor VII had the shortest (5 hours) in healthy subjects. The elimination half-life for factors IX, X, and proteins C and S are as follows: factor IX: 42.4 hours, factor X: 31.8 hours, protein C: 49.6 hours, and protein S: 50.4 hours. In a trial of 98 anticoagulated patients with acute major bleeding, the median INR was 3.9 prior to PCC, and 30 minutes after the start of PCC infusion, the median INR was 1.2. In contrast, patients who received plasma instead of PCC (n=104), the median INR decreased from 3.6 to 2.4 after 30 minutes from start of plasma infusion. In a trial of 105 patients requiring urgent surgery, administration of PCC dropped the median baseline INR from 3.05 (range: 2 to 21.1) to 1.3 (range: 1 to 3.1) at 30 minutes after end of the infusion. After 24 hours, the median INR was 1.25 (range 0.8 to 3.4). The relationship between these INR values and clinical hemostasis in patients has not been established.
 
Affected cytochrome P450 isoenzymes: none

Intravenous Route

In healthy subjects, a single intravenous infusion of prothrombin complex concentrate resulted in a rapid and sustained increase in the plasma concentrations of factors II, VII, IX, and X as well as proteins C and S. Bioavailability is proportional to the dose administered.

Pregnancy And Lactation
Pregnancy

There are no data regarding the use of prothrombin complex concentrate (PCC) during pregnancy. It is not known whether PCC can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Administer PCC to a pregnant woman only if clearly needed.

There are no data regarding the excretion of prothrombin complex concentrate (PCC) in human milk, the effect on the breast-fed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated maternal condition.