Version May 2024
Patients being treated with vitamin K antagonist therapy have underlying disease states that predispose them to thromboembolic events. Potential benefits of reversing vitamin K antagonists should be weighed against the potential risks of thromboembolic events, especially in patients with history of a thromboembolic event. Resumption of anticoagulation should be carefully considered as soon as the risk of thromboembolic events outweighs the risk of acute bleeding.
Both fatal and nonfatal arterial and venous thromboembolic complications have been reported with prothrombin complex concentrate in clinical trials and postmarketing surveillance. Monitor patients receiving prothrombin complex concentrate for signs and symptoms of thromboembolic events.
Prothrombin complex concentrate was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Prothrombin complex concentrate may not be suitable in patients with thromboembolic events in the prior 3 months.
Note: Prothrombin complex concentrate (human) [(factors II, VII, IX, X), protein C, protein S] contains therapeutic levels of factor VII component and should not be confused with factor IX complex (human) [factors II, IX, X] (Bebulin, Profilnine).
Life-threatening hemorrhage associated with direct factor Xa inhibitor or direct thrombin inhibitor (off-label use):
Note: Used for life-threatening bleeding or bleeding into a critical organ that is not controlled with maximal supportive measures (Ref). Dosage is expressed in units of factor IX activity and based on Kcentra studies.
Oral direct factor Xa inhibitor mediated (apixaban, betrixaban, edoxaban, rivaroxaban [if andexanet alfa unavailable]): IV: 2,000 units once or 25 to 50 units/kg once, in addition to other supportive measures as clinically indicated (eg, activated charcoal, antifibrinolytic agent) (Ref).
Direct thrombin inhibitor mediated (argatroban, dabigatran, bivalirudin [if idarucizumab or activated prothrombin complex concentrate unavailable]): IV: 50 units/kg in addition to other supportive measures as clinically indicated (eg, activated charcoal, hemodialysis, antifibrinolytic agent) (Ref).
Perioperative coagulopathy (off label use): Note: Limited data available; also refer to institutional protocols. Dosage is expressed in units of factor IX activity and based on Kcentra studies.
Cardiac surgery (cardiopulmonary bypass-induced coagulopathy): IV: 15 units/kg as a single dose (Ref).
Cardiac transplantation: Dosing based on preoperative INR (Ref):
INR <4: IV: 25 units/kg (maximum dose: 2,500 units).
INR 4 to 6: IV: 35 units/kg (maximum dose: 3,500 units).
INR >6: IV: 50 units/kg (maximum dose: 5,000 units).
Liver transplantation: IV: 25 to 40 units/kg as a single dose; higher dose guided by rotational thromboelastometry and/or laboratory values (Ref).
Coagulopathy following trauma: IV: 25 units/kg as a single dose (in combination with fresh frozen plasma) (Ref).
Reversal of oral direct factor Xa inhibitor in patients who require urgent procedure (if andexanet alfa unavailable) (off-label use):
Note: Reversal agent should be administered only if the procedure cannot safely be performed while the patient is anticoagulated or cannot be delayed (Ref). Dosage is expressed in units of factor IX activity and based on Kcentra studies.
IV: 2,000 units once (Ref).
Reversal of vitamin K antagonist in patients with acute major bleeding or need for an urgent surgery/invasive procedure:
Note: Individualize dosing based on severity of disorder, INR, extent and location of bleeding, and clinical status of patient. Repeat dosing with prothrombin complex concentrate is usually not necessary when given in combination with vitamin K. Dosage is expressed in units of factor IX activity. Balfaxar is only indicated for reversal of vitamin K antagonist in patients with need for an urgent surgery/invasive procedure. Kcentra, Beriplex P/N [Canadian product], and Octaplex [Canadian product] are indicated for reversal of vitamin K antagonist in patients with acute major bleeding or need for an urgent surgery/invasive procedure.
Balfaxar, Kcentra, Beriplex P/N [Canadian product]:
Weight-based dose:
Pretreatment INR: 2 to <4: IV: Administer 25 units/kg; maximum dose: 2,500 units.
Pretreatment INR: 4 to 6: IV: Administer 35 units/kg; maximum dose: 3,500 units.
Pretreatment INR: >6: IV: Administer 50 units/kg; maximum dose: 5,000 units.
Fixed dose: Note: Dosing based on Kcentra studies.
IV: Initial: 1,000 to 2,000 units once; for intracranial hemorrhage use, 1,500 to 2,000 units is recommended; repeat dosing has not been adequately studied and is not typically recommended unless INR reversal is inadequate (Ref).
Octaplex [Canadian product ]:
Pretreatment INR: 2 to 2.5: IV: 22.5 to 32.5 units/kg; maximum dose: 3,000 units (or 120 mL).
Pretreatment INR: 2.5 to 3: IV: 32.5 to 40 units/kg; maximum dose: 3,000 units (or 120 mL).
Pretreatment INR: 3 to 3.5: IV: 40 to 47.5 units/kg; maximum dose: 3,000 units (or 120 mL).
Pretreatment INR: >3.5: IV: >47.5 units/kg; maximum dose: 3,000 units (or 120 mL).
There are no dosage adjustments provided in the manufacturer’s labeling.
There are no dosage adjustments provided in the manufacturer’s labeling.
The recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.
Class 1, 2, or 3 obesity (BMI ≥30 kg/m2): IV: For patients ≤100 kg, use actual body weight for weight-based dosing (Ref). For patients >100 kg, use a maximum 100 kg for dosing weight. Refer to adult dosing for indication-specific doses.
Rationale for recommendations: There is a lack of studies evaluating the influence of obesity on prothrombin complex concentrate (human) dosing or pharmacokinetics. The pharmacokinetics in healthy subjects without obesity is complicated with different included clotting factors having vastly different half-lives. Observational data support use of actual body weight (with a dose cap strategy) as the preferred weight metric in patients with a BMI ≥30 kg/m2 (Ref). A retrospective, multi-center study evaluated ≤100 kg and >100 kg cohorts in patients receiving warfarin who received prothrombin complex concentrate for elevated INR and life-threatening bleed or required emergent surgery. This study did not show any difference in normalization of INR or thrombosis (Ref). Some retrospective studies have evaluated fixed dosing for vitamin K antagonist reversal; however, there are limited data describing fixed-dosing strategies in patients with obesity, particularly in patients with BMI >40 kg/m2 or high-risk populations such as intracranial hemorrhage. Further studies are required to evaluate weight metrics and clinical outcomes in patients with obesity, especially in patients with BMI >40 kg/m2.
Refer to adult dosing.
Octaplex [Canadian product]: Adolescents ≥17 years: Refer to adult dosing.
There are no dosage adjustments provided in the manufacturer’s labeling.
There are no dosage adjustments provided in the manufacturer’s labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%: Nervous system: Asthenia (12%)
1% to 10%:
Cardiovascular: Arteriovenous fistula site complication (clot: 1%), atrial fibrillation (4%), deep vein thrombosis (1%), heart failure (≤3%), hypotension (7%; including hemorrhagic shock, orthostatic hypotension), tachycardia (5%), thrombosis (microthrombosis of toes: 1%), venous thrombosis (calf: 1%; radial vein: 1%), unstable angina pectoris (1%)
Endocrine & metabolic: Hypervolemia (≤3%), hypokalemia (5%)
Gastrointestinal: Abdominal pain (3%), diarrhea (2%), nausea and vomiting (6%)
Genitourinary: Dysuria (5%)
Hematologic and oncologic: Anemia (6%), bruise (≤4%), subcutaneous hematoma (≤4%)
Nervous system: Cerebrovascular accident (1% to 2%), headache (7%), insomnia (5%)
Respiratory: Dyspnea (≤4%), hypoxia (≤4%), pleural effusion (4%), pulmonary edema (2%), respiratory distress (≤4%)
Miscellaneous: Laceration (≤4%)
Frequency not defined:
Cardiovascular: Peripheral venous insufficiency
Hematologic & oncologic: Hemorrhage (including subdural hemorrhage)
Postmarketing:
Cardiovascular: Bradycardia, circulatory shock, hypertension, thromboembolic complications (including acute myocardial infarction, arterial thrombosis, pulmonary embolism)
Dermatologic: Pruritus, skin rash, urticaria
Hematologic & oncologic: Disseminated intravascular coagulation
Hypersensitivity: Hypersensitivity reaction (including anaphylactic shock, anaphylaxis, angioedema, and nonimmune anaphylaxis)
Nervous system: Chills, paresthesia, tremor
Respiratory: Respiratory failure
Miscellaneous: Fever
Balfaxar: Hypersensitivity (ie, anaphylaxis or severe systemic reaction) to prothrombin complex concentrate (PCC) or any component of the formulation; known allergy to heparin or history of heparin-induced thrombocytopenia (product contains heparin), immunoglobulin A (IgA) deficiency, with known antibodies against IgA.
Kcentra, Beriplex P/N [Canadian product]: Hypersensitivity (ie, anaphylaxis or severe systemic reaction) to PCC or any component of the formulation including heparin, factors II, VII, IX, X, protein C and S, antithrombin III and human albumin; disseminated intravascular coagulation (DIC); known heparin-induced thrombocytopenia (product contains heparin).
Octaplex [Canadian product]: Hypersensitivity to PCC or any component of the formulation; heparin-induced thrombocytopenia type II or known allergy to heparin (product contains heparin); non-life-threatening bleeding episodes in individuals with recent myocardial infarction, high risk of thrombosis, or angina pectoris; non-life-threatening bleeding episodes in individuals with untreated disseminated intravascular coagulation (DIC) who can be given fresh frozen plasma (FFP); coagulation disorders due to chronic liver disease or liver transplantation; bleeding associated with hepatic parenchyme disorders, esophageal varices, or major hepatic surgery; immunoglobulin A (IgA) deficiency, with known antibodies against IgA
Concerns related to adverse effects:
• Hypersensitivity reactions: Hypersensitivity reaction (eg, angioedema, bronchospasm, dyspnea, flushing, hypotension, nausea/vomiting, pulmonary edema, urticaria, tachycardia, tachypnea) may occur; if serious reaction occurs, discontinue administration and begin appropriate treatment.
Disease-related concerns:
• Hypercoagulopathy: Administration of prothrombin complex concentrate (PCC) may exacerbate underlying hypercoagulable states in recipients of vitamin K antagonists.
Dosage form specific issues:
• Heparin: Formulations may contain heparin.
• Human plasma: Product of human plasma; may potentially contain infectious agents which could transmit disease. Screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk. Infections thought to be transmitted by this product should be reported to the manufacturer.
Other warnings/precautions:
• Appropriate use: PCC (Human) [(Factors II, VII, IX, X), Protein C, Protein S] contains therapeutic levels of factor VII component and should not be confused with Factor IX complex (Human) [Factors II, IX, X] (Bebulin, Profilnine) which contains low or nontherapeutic levels of factor VII.
• Coagulation factor deficiency: Hepatic synthesis of the prothrombin complex (Factors II, VII, IX and X) coagulation factors is vitamin K dependent. Severe hepatic dysfunction, inadequate absorption of vitamin K (eg, pancreatic disorders, diarrhea) or vitamin K antagonist therapy or overdose may lead to coagulation factor deficiencies. In patients with an acquired deficiency of the vitamin K dependent coagulation factors, administer PCC only if a rapid correction (eg, emergency surgery, major bleeding) is necessary. If not indicated and caused by Vitamin K antagonist therapy, coagulation factor deficiencies may be managed by reducing or discontinuing therapy of the vitamin K antagonist and/or administration of vitamin K.
Note: Potency on the vial label is expressed in terms of the Factor IX nominal strength (500 units or 1,000 units). Consult individual vial labels for exact potency within each vial.
Balfaxar:
Total active ingredient composition of 500 unit vial:
Factor II: 340 to 500 units
Factor VII: 240 to 400 units
Factor IX: 400 to 640 units
Factor X: 300 to 540 units
Protein C: 320 to 560 units
Protein S: 240 to 600 units
Heparin: 80 to 384 units
Total active ingredient composition of 1,000 unit vial:
Factor II: 680 to 1,000 units
Factor VII: 480 to 800 units
Factor IX: 800 to 1,280 units
Factor X: 600 to 1,080 units
Protein C: 640 to 1,120 units
Protein S: 480 to 1,200 units
Heparin: 160 to 768 units
Kcentra, Beriplex P/N [Canadian product]:
Total active ingredient composition of 500 unit vial:
Factor II: 380 to 800 units
Factor VII: 200 to 500 units
Factor IX: 400 to 620 units (Kcentra) or 500 units (Beriplex P/N)
Factor X: 500 to 1,020 units
Protein C: 420 to 820 units
Protein S: 240 to 680 units
Heparin: 8 to 40 units (Kcentra) or up to 40 units (Beriplex P/N)
Total active ingredient composition of 1,000 unit vial:
Factor II: 760 to 1,600 units
Factor VII: 400 to 1,000 units
Factor IX: 800 to 1,240 units (Kcentra) or 1,000 units (Beriplex P/N)
Factor X: 1,000 to 2,040 units
Protein C: 840 to 1,640 units
Protein S: 480 to 1,360 units
Heparin: 16 to 80 units (Kcentra) or up to 80 units (Beriplex P/N)
Octaplex [Canadian product]: Note: Potency on the vial label is expressed in terms of the Factor IX nominal strength (500 units or 1,000 units). Consult individual vial labels for exact potency within each vial.
Total active ingredient composition of 500 unit vial:
Factor II: 280 to 760 units
Factor VII: 180 to 480 units
Factor IX: 500 units
Factor X: 360 to 600 units
Protein C: 260 to 620 units
Proteins S: 240 to 640 units
Heparin: 80 to 310 units
Total active ingredient composition of 1,000 unit vial:
Factor II: 560 to 1,520 units
Factor VII: 360 to 960 units
Factor IX: 1,000 units
Factor X: 720 to 1,200 units
Protein C: 520 to 1,240 units
Protein S: 480 to 1,280 units
Heparin: 160 to 620 units
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Kit, Intravenous [preservative free]:
Kcentra: ~500 units, ~1000 units [pyrogen free; contains albumin human, antithrombin iii (human), heparin]
Solution Reconstituted, Intravenous:
Balfaxar: 500 units (1 ea); 1000 units (1 ea)
No
Kit (Kcentra Intravenous)
500 unit (Price provided is per AHF Unit): $3.58
1000 unit (Price provided is per AHF Unit): $3.58
Solution (reconstituted) (Balfaxar Intravenous)
500 unit (Price provided is per AHF Unit): $3.78
1000 unit (Price provided is per AHF Unit): $3.78
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Beriplex P/N: 500 units (1 ea); 1000 units (1 ea) [contains albumin human, heparin]
Octaplex: 500 units (1 ea); 1000 units (1 ea) [contains heparin, polysorbate 80]
Balfaxar, Kcentra, Beriplex P/N [Canadian product]: IV: Administer at room temperature at a rate of 0.12 mL/kg/minute (~3 units/kg/minute); do not exceed 8.4 mL/minute (~210 units/minute). Do not allow blood to enter into syringe (fibrin clot formation may occur).
Octaplex [Canadian product]: IV: Administer at a rate of 1 mL/minute initially, followed by 2 to 3 mL/minute. Reduce infusion rate or interrupt infusion if patient’s pulse rate increases significantly.
IV: Octaplex [Canadian product]: Administer at a rate of 1 mL/minute initially, followed by 2 to 3 mL/minute. Reduce infusion rate or interrupt infusion if patient's pulse rate increases significantly. Do not mix with other drugs; if administering through IV line, ideally a new, clean line should be used; if an existing line must be used, flush with NS or D5W.
Reversal of vitamin K antagonist in patients with acute major bleeding or need for an urgent surgery/invasive procedure: Urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (eg, warfarin) therapy in adult patients with acute major bleeding (Kcentra, Beriplex P/N [Canadian product], Octaplex [Canadian product]) or with a need for an urgent surgery/invasive procedure (Balfaxar, Kcentra, Beriplex P/N [Canadian product], Octaplex [Canadian product]).
Life-threatening bleeding associated with direct factor Xa inhibitor or direct thrombin inhibitor; Perioperative coagulopathy; Reversal of oral direct factor Xa inhibitor in patients who require urgent procedure (if andexanet alfa unavailable)
The term “Prothrombin Complex Concentrate” or “PCC” has been used to describe both Factor IX Complex (Human) [Factors II, IX, X] and Prothrombin Complex Concentrate (Human) [(Factors II, VII, IX, X), Protein C, Protein S]. Prothrombin Complex Concentrate (Human) [(Factors II, VII, IX, X), Protein C, Protein S] (Balfaxar, Beriplex P/N [Canadian product], Kcentra, Octaplex [Canadian product]) contains therapeutic levels of factor VII component and should not be confused with Factor IX complex (Human) [Factors II, IX, X] (Bebulin, Profilnine) which contains low or nontherapeutic levels of factor VII.
Potency on the vial label is expressed in terms of the factor IX nominal strength (500 units or 1,000 units). Consult individual vial labels for exact potency within each vial. Manufacturer's labeling recommends the exact amount of factor IX units in each vial be used when calculating and preparing the total dose to be administered. However, the Institute for Safe Medication Practices recommends using the nominal strength as described in clinical trials (ISMP 2017).
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Antifibrinolytic Agents: May enhance the adverse/toxic effect of Prothrombin Complex Concentrate (Human) [(Factors II, VII, IX, X), Protein C, and Protein S]. Specifically, the risk for thrombosis may be increased. Risk X: Avoid combination
Animal reproduction studies have not been conducted. This product is derived from purified human plasma.
It is not known if prothrombin complex concentrate is present in breast milk.
The manufacturer recommends that prothrombin complex concentrate be administered only if clearly needed when treating a breastfeeding patient.
INR (baseline and at 30 minutes post dose); clinical response during and after treatment; signs of thromboembolism
Prothrombin complex concentrate provides an increase in the levels of the vitamin K-dependent coagulation factors (II, VII, IX, and X) with the addition of protein C and protein S. Coagulation factors II, IX, and X are part of the intrinsic coagulation pathway, while factor VII is part of the extrinsic coagulation pathway. In the extrinsic pathway, damaged blood vessels release endothelial tissue factor (TF) which complexes with factor VII to form TF-factor VIIa. Within the intrinsic pathway, factor IX is converted to IXa. Factor IXa (as well as TF-factor VIIa) converts factor X to factor Xa in the final common pathway of coagulation. Factor Xa activates prothrombin (factor II) into thrombin (IIa) which converts fibrinogen into fibrin resulting in clot formation. Proteins C and S are vitamin K-dependent inhibiting enzymes involved in regulating the coagulation process. Protein S serves as a cofactor for protein C which is converted to activated protein C (APC). APC is a serine protease which inactivates factors Va and VIIIa, limiting thrombotic formation.
Onset of action: Rapid; significant INR decline within 30 minutes.
Duration: INR reversal usually maintained for up to ≥24 hours.
Distribution: Vdss (Kcentra, Beriplex P/N [Canadian product]): Factor II: 71.4 mL/kg; Factor VII: 45 mL/kg; Factor IX: 114.3 mL/kg; Factor X: 55.5 mL/kg; Protein C: 62.2 mL/kg; Protein S: 78.8 mL/kg. Note: Distribution data for Balfaxar and Octaplex (Canadian product) not reported in the manufacturer's labeling.
Half-life elimination: Factor II: 48 to 60 hours; Factor VII: 1.5 to 6 hours; Factor IX: 20 to 24 hours; Factor X: 24 to 48 hours; Protein C: 1.5 to 6 hours; Protein S: 24 to 48 hours.
Note: Half-lives may be significantly reduced in severe hepatocellular damage, DIC, or extended catabolic metabolism.
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