Prothrombin Complex Concentrate (Human) [(Factors II, VII, IX, X), Protein C, and Protein S]

Dosage Forms

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]

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 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

Onset of Action

Rapid; significant INR decline within 10 minutes

Duration of Action

~6 to 8 hours

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.

Use: Labeled Indications

Bleeding, treatment and prophylaxis: Urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (VKA) (eg, warfarin) therapy in patients with acute major bleeding or a need for an urgent surgery/invasive procedure

Use: Off Label

Life-threatening bleeding associated with non-vitamin K antagonist anticoagulantsyes

Based on the Updated European Heart Rhythm Association Practical Guide on the Use of Non-vitamin K Antagonist Anticoagulants in Patients with Non-valvular Atrial Fibrillation, the American Heart Association/American Stroke Association (AHA/ASA) Guidelines for the Management of Spontaneous Intracerebral Hemorrhage, and the American College of Cardiology 2017 Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants, the use of prothrombin complex concentrate (human) (ie, 4-factor PCC) may be considered for the treatment of life-threatening bleeding associated with dabigatran (if idarucizumab is not available) or oral direct factor Xa inhibitors (eg, apixaban, edoxaban, or rivaroxaban) if it is readily available in the hospital.

Additionally, the Neurocritical Care Society and Society of Critical Care Medicine guidelines for the reversal of antithrombotics in intracranial hemorrhage suggests the use of either 4-factor PCC or anti-inhibitor coagulant complex (human) (ie, activated PCC) for patients with intracranial hemorrhage associated with dabigatran (if idarucizumab is unavailable) or oral direct factor Xa inhibitors (eg, apixaban, edoxaban, or rivaroxaban) if intracranial hemorrhage occurred within 3 to 5 terminal half-lives of drug exposure or if liver failure exists.

Contraindications

Kcentra, Beriplex P/N [Canadian product]: Hypersensitivity (ie, anaphylaxis or severe systemic reaction) to prothrombin complex concentrate (PCC) or any component of the formulation including 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 prothrombin complex concentrate (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

Dosage and Administration

Dosing: Adult

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) which contains low or nontherapeutic levels of factor VII.

Kcentra, Beriplex P/N [Canadian product]: Vitamin K antagonist (VKA) reversal in patients with acute major bleeding or need for an urgent surgery/invasive procedure: IV: Individualize dosing based on current pre-dose INR. Dosage is expressed in units of factor IX activity. Administer with vitamin K concurrently. Repeat dosing is not recommended (has not been studied).

Pretreatment INR: 2 to <4: Administer 25 units/kg; maximum dose: 2,500 units

Pretreatment INR: 4 to 6: Administer 35 units/kg; maximum dose: 3,500 units

Pretreatment INR: >6: Administer 50 units/kg; maximum dose: 5,000 units

Octaplex [Canadian product]: Bleeding/perioperative prophylaxis of bleeding during vitamin K antagonist therapy: Individualize dosing based on severity of disorder, extent and location of bleeding, and clinical status of patient. IV: Approximate doses required for normalization of INR (≤1.2 within 1 hour); dosage is expressed in units of factor IX activity:

Pretreatment INR: 2 to 2.5: Administer 22.5 to 32.5 units/kg; maximum dose: 3,000 units (or 120 mL)

Pretreatment INR: 2.5 to 3: Administer 32.5 to 40 units/kg; maximum dose: 3,000 units (or 120 mL)

Pretreatment INR: 3 to 3.5: Administer 40 to 47.5 units/kg; maximum dose: 3,000 units (or 120 mL)

Pretreatment INR: >3.5: Administer >47.5 units/kg; maximum dose: 3,000 units (or 120 mL)

With the correction of vitamin K antagonist-induced impairment of hemostasis in patients who have been treated concomitantly with an appropriate vitamin K dose, repeat dosing with PCC is usually not necessary.

Life-threatening hemorrhage associated with non-vitamin K antagonist anticoagulation (off-label use): IV: Optimal dosing has not been established. According to the European Heart Rhythm Association, the use of 50 units/kg (with additional 25 units/kg if clinically necessary) is recommended based on very limited evidence in healthy volunteers (EHRA [Heidbuchel 2015]).

Intracranial hemorrhage (ICH) due to various antithrombotic agents according to the Neurocritical Care Society/Society of Critical Care Medicine (NCS/SCCM [Frontera 2016]):

Oral direct factor Xa inhibitor-mediated (apixaban, edoxaban, rivaroxaban): 50 units/kg if ICH occurred within 3 to 5 terminal half-lives of drug exposure or when liver failure co-exists.

Direct thrombin inhibitor-mediated (argatroban, dabigatran [if idarucizumab unavailable], bivalirudin, desirudin): 50 units/kg if direct thrombin inhibitor was administered within a period of 3 to 5 half-lives prior and there is no evidence of renal failure or there is renal impairment leading to drug exposure beyond 3 to 5 half-lives.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Octaplex [Canadian product]: Adolescents ≥17 years: Refer to adult dosing.

Dosing: Obesity

Kcentra, Beriplex [Canadian product]: In patients weighing >100 kg; do not exceed maximum dose recommended according to pretreatment INR.

Octaplex [Canadian product]: There are no dosage adjustments provided in the manufacturer’s labeling.

Reconstitution

Reconstitute with 20 mL (500 unit vial) or 40 mL (1,000 unit vial) of provided diluent (SWFI). Prior to reconstitution, allow diluent (SWFI) and prothrombin complex concentrate (PCC) vials to warm to room temperature. Aseptically push the plastic spike at the blue end of the Mix2Vial transfer set through the center of the stopper of the diluent vial. After carefully removing only the clear blister package from the Mix2Vial transfer set, invert the diluent vial with the transfer set still attached and push the plastic spike through the center of the stopper of PCC vial; diluent will automatically transfer. While still attached, gently swirl PCC vial to ensure product is dissolved; do not shake. Disconnect the 2 vials; contents of PCC vial are now available for removal by screwing a syringe onto the transfer set. Inject appropriate amount of air into vial, invert vial, and withdraw amount needed. Remove syringe from transfer set and attach an administration set to the syringe. Refer to manufacturer's labeling for detailed preparation instructions.

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. 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).

Administration

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.

Storage

Kcentra, Beriplex P/N [Canadian product]: Store at 2°C to 25°C (36°F to 77°F); do not freeze. Protect from light. Reconstituted product may be stored at 2°C to 25°C (36°F to 77°F) and used within 4 hours (Kcentra) or 3 hours (Beriplex P/N) following reconstitution. If cooled, warm to 20°C to 25°C (68°F to 77°F) prior to administration.

Octaplex [Canadian product]: Store at 2°C to 25°C (36°F to 77°F); do not freeze. Protect from light. Reconstituted solution should be administered immediately, but may be stored for up to 8 hours at 2°C to 25°C (36°F to 77°F) if sterility is maintained.

Drug Interactions

There are no known significant interactions.

Test Interactions

aPTT (formulation contains heparin)

Adverse Reactions

1% to 10%:

Cardiovascular: Hypotension (5% to 7%), tachycardia (3% to 5%), atrial fibrillation (4%), hypertension (1% to 3%), pulmonary embolism (≤2%), pulmonary edema (2%), cerebrovascular accident (1% to 2%), arteriovenous fistula site complication (clot, ≤1%), chest pain (1%), deep vein thrombosis (1%), venous thrombosis (calf, 1%; radial vein: ≤1%), thrombosis (microthrombosis of toes, ≤1%)

Central nervous system: Headache (1% to 8%), insomnia (1% to 5%), intracranial hemorrhage (3%), mental status changes (3%)

Endocrine & metabolic: Hypervolemia (1% to 6%), hypokalemia (2% to 5%)

Gastrointestinal: Nausea and vomiting (4% to 6%), constipation (2%), diarrhea (2%)

Hematologic and oncologic: Anemia (3% to 6%), prolonged bleeding time (skin laceration, contusion, subcutaneous hematoma, 4%)

Hepatic: Increased serum transaminases (1%)

Immunologic: Antibody development (parvovirus B19 seropositive, 3%)

Local: Burning sensation at injection site (1%)

Neuromuscular & skeletal: Arthralgia (4%)

Respiratory: Pleural effusion (4%), respiratory distress (2% to 4%), rales (1%)

Postmarketing and/or case reports: Angioedema, anxiety, arterial thrombosis, bronchospasm, disseminated intravascular coagulation, flushing, hypersensitivity reaction, myocardial infarction, peripheral ischemia, tachypnea, thromboembolic complications, thrombosis, transient ischemic attacks, urticaria, venous insufficiency, wheezing

Warnings/Precautions

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.
• Thromboembolic events: [US Boxed Warning]: Because patients being treated with vitamin K antagonist (VKA) therapy have an underlying risk of or a diagnosed thromboembolic disease state, administration of prothrombin complex concentrate (PCC) may predispose the patient to a thromboembolic complication. Benefits of reversing VKA therapy should be weighed against the potential risk of a thromboembolic event. Resumption of anticoagulation should occur once the risk of thromboembolism outweighs the risk of acute bleeding. Fatal and nonfatal arterial and venous thromboembolic complications and DIC have been reported; closely monitor for thromboembolic events during and after administration. Use has not been evaluated in patients who have experienced a thromboembolic event, MI, DIC, CVA, TIA, unstable angina, or severe peripheral vascular disease within the prior 3 months.

Disease-related concerns:

• Hypercoagulopathy: Administration of 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: 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) 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.

Monitoring Parameters

INR (baseline and at 30 minutes post dose); clinical response during and after treatment; signs of thromboembolism

Pregnancy

Pregnancy Considerations

This product is derived from purified human plasma.

Patient Education

What is this drug used for?

• It is used to undo the effects of certain blood thinners like warfarin.

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Severe cerebrovascular disease like change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes.
• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood.
• Flushing
• Fast heartbeat
• Anxiety
• Severe nausea
• Vomiting
• Severe dizziness
• Passing out
• Fast breathing
• Severe headache
• Severe loss of strength and energy
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.