CLASSES
Blood Coagulation Factors
BOXED WARNING
Angina, disseminated intravascular coagulation (DIC), 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. Carefully consider resuming anticoagulation after administration of PCC once the risk of thromboembolic events outweighs the risk of acute bleeding.[54467]
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
COMMON BRAND NAMES
Kcentra
HOW SUPPLIED
Kcentra Intravenous Inj Pwd F/Sol
DOSAGE & 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 or need for urgent surgery or invasive procedure.
Intravenous dosage (weight-based dose)
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 or 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.
Intravenous dosage (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 or 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 vitamin K antagonist reversal in persons with an INR of 2 or more and acute intracranial major bleeding or need for urgent surgery or invasive procedure.
Intravenous dosage (weight-based dose)
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 or 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.
Intravenous dosage (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 or 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 vitamin K antagonist reversal in persons with an INR 1.4 to 1.9 and acute intracranial major bleeding†.
Intravenous dosage (weight-based dose)
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 or 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
MAXIMUM DOSAGE
Adults
Individualize dosage based on pre-treatment INR and body weight. In patients with pre-treatment INR 2—< 4, do not exceed 2500 units of factor IX; pre-treatment INR 4—6, do not exceed 3500 units factor IX; INR > 6, do not exceed 5000 units factor IX. For patients weighing > 100 kg, maximum dose should not be exceeded.
Geriatric
Individualize dosage based on pre-treatment INR and body weight. In patients with pre-treatment INR 2—< 4, do not exceed 2500 units of factor IX; pre-treatment INR 4—6, do not exceed 3500 units factor IX; INR > 6, do not exceed 5000 units factor IX. For patients weighing > 100 kg, maximum dose should not be exceeded.
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.
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.
ADMINISTRATION
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
The actual potency units per vial of Factors II, VII, IX, X and proteins C and S are stated on the carton.
Intravenous Administration
Reconstitution:
Ensure vials of prothrombin complex concentrate (PCC) and diluent (provided) are at room temperature, and use aseptic technique to reconstitute.
Place diluent vial on a flat surface and hold tightly. Grip the Mix2Vial transfer set together with the clear package and push the plastic spike at the blue end of the Mix2Vial transfer set firmly through the center of the stopper of the diluent vial.
Carefully remove the clear package from the Mix2Vial transfer set.
Invert diluent vial with Mix2Vial transfer set attached and push the plastic spike of the transparent adapter firmly through the center of the stopper of the PCC vial. 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.
Draw air into an empty, sterile syringe. While the PCC vial is upright, screw the syringe to the Mix2Vial transfer set and inject air into the vial. Keep plunger pressed, and invert the system upside down; draw the concentrate into the syringe by pulling back slowly on the plunger.
Unscrew the syringe from the Mix2Vial transfer set.
To administer, attach the syringe to a suitable intravenous administration set.
If patient is to receive more than one vial, the contents of multiple vials may be pooled together; however, use a separate unused Mix2Vial transfer set for each product vial.
Storage following reconstitution: After reconstitution, administration should begin promptly or within 4 hours. Reconstituted product can be stored at 2—25 degrees C (36—77 degrees F). If cooled, warm to 20—25 degrees C (68—77 degrees F) prior to administration. Do not freeze. Each vial contains no preservatives and is for single use only. Discard partially used vials.
Intermittent intravenous infusion:
Do not mix with other medicinal products; administer through a separate infusion line.
Administer at room temperature using aseptic technique.
Administer by intravenous infusion at a rate of 0.12 ml/kg/min (approximately 3 units/kg/min), up to a maximum rate of 8.4 ml/min (approximately 210 units/min).
Do not allow blood to enter the syringe as there is a possibility of fibrin clot formation.
STORAGE
Kcentra:
- Discard unused portion. Do not store for later use.
- Do not freeze
- Protect from light
- Reconstituted product must be used within 4 hours
- Store between 36 to 77 degrees F
- Store in original container
CONTRAINDICATIONS / PRECAUTIONS
Albumin hypersensitivity, heparin hypersensitivity, plasma protein hypersensitivity
Prothrombin complex concentrate is contraindicated in patients with known anaphylactic or severe systemic reactions to prothrombin complex concentrate, heparin hypersensitivity, plasma protein hypersensitivity (i.e., proteins C and S, antithrombin III), hypersensitivity to coagulation factors II, VII, IX, and X, and human albumin hypersensitivity.
Angina, disseminated intravascular coagulation (DIC), 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. Carefully consider resuming anticoagulation after administration of PCC once the risk of thromboembolic events outweighs the risk of acute bleeding.[54467]
Heparin-induced thrombocytopenia (HIT)
Prothrombin complex concentrate contains heparin and is therefore contraindicated in patients with known heparin-induced thrombocytopenia (HIT).
Labor, obstetric delivery, pregnancy
Prothrombin complex concentrate (PCC) is a FDA pregnancy category C agent. It is not known whether PCC can cause fetal harm when administered to a pregnant woman. According to the manufacturer, administer PCC to a pregnant woman only if clearly needed. PCC has not been studied for use during labor and delivery. Safety and efficacy in labor and obstetric delivery have not been established.
Breast-feeding
According to the manufacturer, prothrombin complex concentrate (PCC) should only be used if clearly needed in a breast-feeding woman. It is not known whether PCC is excreted in human milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Hepatitis, infection
As with other products derived from or purified with human blood components, the possibility of contamination with hepatitis and other viruses or infectious agents exists in patients receiving human plasma derived factor products like prothrombin complex concentrate. The manufacturing processes are designed to reduce the risk of transmitting viral infection; however, disease may still be potentially transmitted. There is also the possibility that unknown infectious agents may be present.
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
myocardial infarction / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
thrombosis / Delayed / Incidence not known
disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
thromboembolism / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
Moderate
hypotension / Rapid / 7.3-7.3
anemia / Delayed / 5.8-5.8
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
wheezing / Rapid / Incidence not known
tachypnea / Early / Incidence not known
Mild
headache / Early / 7.3-7.3
vomiting / Early / 6.3-6.3
nausea / Early / 6.3-6.3
insomnia / Early / 4.7-4.7
urticaria / Rapid / Incidence not known
anxiety / Delayed / Incidence not known
flushing / Rapid / Incidence not known
infection / Delayed / Incidence not known
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.
PREGNANCY AND LACTATION
Pregnancy
According to the manufacturer, prothrombin complex concentrate (PCC) should only be used if clearly needed in a breast-feeding woman. It is not known whether PCC is excreted in human milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
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. The 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.
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.