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  • CLASSES

    Blood Coagulation Factors

    BOXED WARNING

    Angina, disseminated intravascular coagulation (DIC), myocardial infarction, peripheral vascular disease, stroke, thromboembolic disease

    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. 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 thromboembolic disease 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]

    DEA CLASS

    Rx

    DESCRIPTION

    Prothrombin complex concentrate comprised of factors II, VII, IX, X and proteins C and S
    For urgent reversal of vitamin K antagonist (VKA) therapy in patients with acute major bleeding or need for urgent surgery or invasive procedure
    Weigh benefits of reversing VKA therapy against risk of fatal and non-fatal arterial and venous thromboembolic complications

    COMMON BRAND NAMES

    Kcentra

    HOW SUPPLIED

    Kcentra Intravenous Inj Pwd F/Sol

    DOSAGE & INDICATIONS

    For coagulation factor replacement in patients with acquired coagulation factor deficiency due to vitamin K antagonist therapy 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.
    Intravenous dosage
    Adults

    Individualize intravenous dosage based on current pre-dose international normalized ratio (INR), body weight (kg), and actual potency of Factor IX as stated on the product carton (range: 20 to 31 Factor IX units/mL). Because coagulation factor concentrations may be unstable in patients with acute major bleeding or urgent need for surgery or other invasive procedure who are receiving vitamin K, INR should be measured prior to treatment, close to the time of dosing. Dosing guidelines are as follows: pre-treatment INR 2 to less than 4: 25 units Factor IX/kg, not to exceed 2,500 units of Factor IX; pre-treatment INR 4 to 6: 35 units Factor IX/kg, not to exceed 3,500 units of Factor IX; pre-treatment INR more than 6: 50 units Factor IX/kg, not to exceed 5,000 units of Factor IX. Administer vitamin K concurrently to maintain vitamin K-dependent clotting factor concentrations once the effects of prothrombin complex concentrate have diminished. In clinical trials, INR decreased to 1.3 or less within 30 minutes in most subjects. Repeat dosing is not recommended.

    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

    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. 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 thromboembolic disease 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
    disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    thrombosis / 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, tPA: (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: (Severe) 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.
    Factor VIIa, Recombinant: (Major) The risk of a potential interaction between factor VIIa, recombinant, and factor IX replacement products has not been adequately evaluated. Simultaneous use of these products should be avoided due to the potential for increased risk of thrombosis.
    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.