prothrombin complex concentrate, human (Rx)

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

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 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.

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

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