Dosing & Uses
Dosage Forms & Strengths
lyophilized concentrate for reconstitution
- 500 units/vial
- 1000 units/vial
Composition/vial
- Exact potency of all coagulation factors and antithrombotic proteins are listed on each carton
- Total protein: 120-280mg
- Factor II: 380-800 units
- Factor VII: 200-500 units
- Factor IX: 400-620 units
- Factor X: 500-1020 units
- Protein C: 420-820 units
- Protein S: 240-680 units
- Heparin: 8-40 units
- Antithrombin III: 4-30 units
- Human albumin: 40-80mg
- NaCl: 60-120mg
- Sodium citrate: 40-80mg
- Buffering agents (HCl, NaOH): Small amounts
Vitamin K Antagonist Reversal
Indicated for urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonists (VKA, eg, warfarin) therapy in adults with acute major bleeding or need for an urgent surgery/invasive procedure
Individualize dosing based on patient’s current pre-dose INR value and body weight
Administer vitamin K concurrently to maintain vitamin K-dependent clotting factor levels once the effects of prothrombin complex concentrate have diminished
Repeat dosing is not supported by clinical data and is not recommended
Dosing guidelines
- Based on pretreatment INR obtained close to time of dosing (coagulation factor levels may be unstable in patients with acute major bleeding who are receiving Vitamin K)
- Dose in units below is based on factor IX content in product
- INR 2 to <4: 25 units/kg; not to exceed 2500 units
- INR 4-6: 35 units/kg; not to exceed 3500 units
- INR >6: 50 units/kg; not to exceed 5000 units
Example dosing calculation
- For 80 kg patient with INR 5.0: 35 units/kg x 80 kg = 2800 units
- For vial with actual potency of 30 units/mL Factor IX, 93 mL would be administered (2800 units ÷ 30 units/mL = 93 mL)
Dosing Considerations
Not indicated for urgent reversal of VKA anticoagulation in patients without acute major bleeding
Unlike plasma, does not require blood group typing or thawing, so it can be administered more quickly than frozen plasma
Administered in a significantly lower volume than plasma at recommended doses, providing an alternative for volume restricted patients
Administration
Reconstituted solution should be at room temperature before infusing
Do not mix with other medicinal products
Administer through a separate infusion line
No blood should enter the syringe, as there is a possibility of fibrin clot formation
Infuse IV at rate of 0.12 mL/kg/min (~3 units/kg/min), up to maximum rate of 8.4 mL/min (~210 units/min)
Record product lot number in patient’s medical record
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
1-10%
Thromboembolic events (8.7%)
Headache (7.8%)
Hypotension (4.9%)
Nausea/vomiting (3.9%)
Arthralgia (3.9%)
Hemorrhage intracranial (2.9%)
Mental status changes (2.9%)
Increased BP/hypertension (2.9%)
Skin laceration/contusion/ hematoma (2.9%)
Respiratory distress/dyspnea/hypoxia (1.9%)
Constipation (1.9%)
Fluid overload (1%)
Breath sounds, abnormal rates (1%)
Chest pain (1%)
Insomnia (1%)
Postmarketing Reports
Hypersensitivity or allergic reactions: Flushing, urticaria, tachycardia, anxiety, angioedema, wheezing, nausea, vomiting, hypotension, tachypnea, dyspnea, pulmonary edema, and bronchospasm
Thromboembolic complications: Arterial thromboembolic events (including acute MI and arterial thrombosis), venous thromboembolic events (including PE and venous thrombosis), and DIC
Warnings
Black Box Warnings
Patients being treated with vitamin K antagonists (VKA) have underlying disease that predispose them to thromboembolic events; potential benefits of reversing VKA should be weighed against the potential risks of thromboembolic events
Both fatal and nonfatal arterial and venous thromboembolic complications reported during clinical trials and postmarketing surveillance; monitor for signs and symptoms
Not studied in individuals who had a thromboembolic event, MI, DIC, CVA, TIA, unstable angina, or severe PVD within the prior 3 months before administration
Contraindications
Anaphylaxis or severe systemic reactions to any component
Disseminated intravascular coagulation (DIC) Known heparin-induced thrombocytopenia (HIT)
Cautions
Fatal and nonfatal arterial and venous thromboembolic complications reported (see Black Box Warnings)
Hypersensitivity reactions reported, including flushing, urticaria, tachycardia, anxiety, angioedema, wheezing, nausea, vomiting, hypotension, tachypnea, dyspnea, pulmonary edema, and bronchospasm
Made from human blood; risk of transmitting infectious agents (eg, viruses including hepatitis and HIV, Creutzfeldt-Jakob variant or disease)
Pregnancy & Lactation
Pregnancy Category: C
Lactation: Unknown whether distributed in human breast milk; breast feeding not advised
Pregnancy Categories
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Pharmacology
Mechanism of Action
Contains vitamin-K-dependent coagulation Factors II, VII, IX, and X, together known as prothrombin complex and the antithrombotic protein C and protein S
A dose-dependent acquired deficiency of vitamin K-dependent coagulation factors occurs during vitamin K antagonist treatment; vitamin K antagonists exert anticoagulant effects by blocking carboxylation of glutamic acid of vitamin K-dependent coagulation factors during hepatic synthesis, lowering both factor synthesis and function
Administration of prothrombin complex rapidly increases plasma levels of coagulation factors and the anti-thrombotic proteins
Median INR before treatment (3.0) dropped to median value of 1.2 at 30 minutes after starting infusion (in contrast to plasma which dropped to 2.4 after 30 minutes)
Coagulation factors MOA
- Factor II (prothrombin) is converted to thrombin by activated FX (FXa) in the presence of Ca2+, FV, and phospholipids
- Factor VII (proconvertin) is converted to the activated form (FVIIa) by splitting of an internal peptide link; FVIIa-TF complex activates factor IX and initiates the primary coagulation pathway by activating FX in the presence of phospholipids and calcium ions
- Factor IX (antihemophilic globulin B, or Christmas factor) is activated by the FVIIa-TF complex and by FXIa; factor IXa in the presence of FVIIIa activates FX to FXa
- Factor X (Stuart-Prower factor) activation involves the cleavage of a peptide bond by the FVIIIa-factor IXa complex or the TF-FVIIa complex; factor Xa forms a complex with activated FV (FVa) that converts prothrombin to thrombin in the presence of phospholipids and calcium ions
- Protein C, when activated by thrombin, exerts an antithrombotic effect by inhibiting FVa and FVIIIa leading to a decrease in thrombin formation, and has indirect profibrinolytic activity by inhibiting plasminogen activator inhibitor-1
- Protein S exists in a free form (40%) and in a complex with C4b-binding protein (60%); the free form functions as a cofactor for activated protein C in the inactivation of FVa and FVIIIa, leading to antithrombotic activity
Pharmacokinetics
AUC (IU/dL x hr)
- Factor IX: 1490
- Factor II: 6577
- Factor VII: 424
- Factor X: 6707
- Protein C: 5276
- Protein S: 3667
Vd (mL/kg)
- Factor IX: 92.4
- Factor II: 71.0
- Factor VII: 41.8
- Factor X: 56.1
- Protein C: 62.9
- Protein S: 76.6
Half-life, terminal (hr)
- Factor IX: 16.7
- Factor II: 59.7
- Factor VII: 4.2
- Factor X: 30.7
- Protein C: 47.2
- Protein S: 49.1
Administration
IV Preparation
Reconstitute vial with 20 mL of diluent provided in kit using Mix2Vial transfer set provided (see package instructions)
Visually inspect reconstituted vial for particulate matter and discoloration; it should be colorless, clear to slightly opalescent, and free from visible particles
Do not use solutions that are cloudy or have deposits
For single use only, contains no preservatives
Discard partially used vials
When reconstituted, final concentration of drug product in Factor IX units will range between 20-31 units/mL (depending on actual potency listed on the carton)
IV Administration
Reconstituted solution should be at room temperature before infusing Do not mix with other medicinal products
Administer through a separate infusion line
No blood should enter the syringe, as there is a possibility of fibrin clot formation
Infuse IV at rate of 0.12 mL/kg/min (~3 units/kg/min), up to maximum rate of 8.4 mL/min (~210 units/min)
Record product lot number in patient’s medical record
Storage
Unopened vials
- Stable until date indicated on package (36 months from manufacture date)
- Store between 2-25°C [36-77°F]) in original carton and protect from light
- Do not freeze
Reconstituted vials
- Use within 4 hr following reconstitution
- Store between 2-25°C (36-36-77°F)
- If cooled, the solution should be warmed to 20-25°C before administration
- Do not freeze
- Discard partially used vials
Images
Patient Handout
Formulary
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