Prothrombin concentrates / complexes

CLINICAL PHARMACOLOGY
BEBULIN is a combination of vitamin K-dependent clotting factors (Factor IX, II, X) and found in normal plasma. The administration of BEBULIN provides an increase in plasma levels of Factor IX and can temporarily correct the coagulation defect of patients with Factor IX deficiency. Plasma levels of Factors II and X will also be increased. However, no clinical studies have been conducted to show benefit from this product for treating deficiencies other than Factor IX deficiency.

In vivo recovery of BEBULIN was determined using the former International Standard, WHO 72/32 and was found to be 53.3% ±9.6%, 57.5% ±21.8%, and 53.24% ±16.95%, respectively. In the same studies, using different methodologies, half-lives were determined to be 19.4 hrs ±3.8 hrs, 24.6 hrs ±3.2 hrs, and 19.97 hrs ±8.24 hrs, respectively1.

INDICATIONS AND USAGE: BEBULIN is indicated for the prevention and control of bleeding episodes in adult patients with hemophilia B (congenital Factor IX deficiency or Christmas disease).
BEBULIN is not indicated for use in the treatment of Factor VII deficiency. No clinical studies have been conducted to show benefit from this product for treating deficiencies other than Factor IX deficiency.

HOW SUPPLIED:
BEBULIN is supplied in single dose vials (NDC 64193-445-02) with Sterile Water for Injection, U.S.P., double-ended needle, and filter needle for reconstitution and withdrawal. Factor IX activity in international units is stated on the label of each vial.

STORAGE
Store at refrigerated temperature (2°C-8°C, 35°F-46°F). Do not use BEBULIN past the expiration date printed on the unit carton. Do not freeze.

ABBREVIATED MONOGRAPH - SEE PACKAGE INSERT.

INDICATIONS AND USAGE:
FEIBA NF (Anti-Inhibitor Coagulant Complex) is indicated for the control of spontaneous bleeding episodes or to cover surgical interventions in hemophilia A and hemophilia B patients with inhibitors.

Clinical experience suggests that patients with a Factor VIII inhibitor titer of less than 5 B.U. may be successfully treated with Antihemophilic Factor. Patients with titers ranging between 5 and 10 B.U. may either be treated with Antihemophilic Factor or FEIBA NF. Cases with Factor VIII inhibitor titers greater than 10 B.U. have generally been refractory to treatment with Antihemophilic Factor.

Inadequate response to treatment may result from an abnormal platelet count or impaired platelet function that were present before treatment with FEIBA NF, nanofiltered and vapor-heated.

CONTRAINDICATIONS
The use of FEIBA NF is contraindicated:
in patients who have known anaphylactic or severe hypersensitivity reactions to the product.
in patients who are known to have a normal coagulation mechanism.
for the treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to coagulation factor VIII or coagulation factor IX.
in patients with significant signs of disseminated intravascular coagulation (DIC).
in patients with acute thrombosis or embolism (including myocardial infarction).

DOSAGE AND ADMINISTRATION
Treatment should be initiated and supervised by a physician experienced in the management of hemophilia.

Clinical trials 1, 2 demonstrated that the response to treatment with FEIBA may differ from patient to patient with no correlation to the patient’s inhibitor titer. Response may also vary between different types of hemorrhage (e.g. joint hemorrhage vs. CNS hemorrhage). As a general guideline, a dosage range of 50 to 100 Units of FEIBA NF, per kg of body weight is recommended. However, care should be taken to distinguish between the following four indications:
Dosing Guidelines by Type of Hemorrhage

 Reconstitution

FEIBA NF contains no preservatives. Aseptic technique should be used throughout the entire reconstitution process and the solution should then be used immediately.

Allow the unopened vials of FEIBA NF (concentrate) and Sterile Water for Injection (diluent) to reach room temperature (not above 37°C, 98°F).
Remove caps from the concentrate and diluent vials to expose central portions of the rubber stoppers.

Disinfect the rubber stoppers of both vials using a germicidal solution. Place the vials on an even surface and allow them to dry.
Open the package of BAXJECT device by peeling away the lid without touching the inside .

Do not remove the device from the package. Turn the package over and insert the plastic spike through diluent stopper. .
Grip the package at its edge and pull the package off the device.

Turn the system over, so that the vial is on top. Quickly insert the other plastic spike into the FEIBA NF stopper . The vacuum will draw the diluent into the FEIBA NF vial. Please make sure that the connection of the two vials should be done expeditiously to close the open fluid pathway created by the first insertion of the spike to the diluent vial.

Swirl gently until FEIBA NF is completely dissolved. Make sure that FEIBA NF has been dissolved completely; otherwise, active material will not pass through the device filter.

 Do not refrigerate after reconstitution!

After complete reconstitution of FEIBA NF its injection or infusion should be commenced as promptly as practicable, but must be completed within three hours following reconstitution. The solution must be given by intravenous injection or intravenous drip infusion.

Rate of Administration:

The maximum injection or infusion rate must not exceed 2 units per kg of body weight per minute. For a patient with a body weight of 75 kg, this corresponds to an infusion rate of 2.5 - 7.5 mL per minute depending on the number of units per vial (see label on vial).
Intravenous Injection or Infusion:

• Inspect for particulate matter and discoloration after reconstituting the concentrate as described under Reconstitution prior to administration. The appearance of the solution should be colorless to slightly yellowish and essentially free of visible particles. Do not use solutions that are cloudy or have deposits.
• Mixing of FEIBA NF with other products or substances must be avoided. It is advisable to flush venous access lines with isotonic saline prior to and after infusion of FEIBA NF.
• If devices other than those supplied with FEIBA NF are used, ensure use of an adequate filter.
• Plastic Luer lock syringes are recommended for use with this product since protein such as FEIBA NF tends to stick to the surface of all-glass syringes.

1. Turn the BAXJECT device handle down towards the FEIBA NF concentrate vial and remove the cap attached to the syringe connection of the BAXJECT device.
2. Draw air into the syringe, connect the syringe to the BAXJECT device, inject air into the concentrate vial.
3. While keeping the syringe plunger in place, turn the system upside down (concentrate vial now on top). Draw the concentrate into the syringe by pulling the plunger back slowly.
4. Turn the BAXJECT handle to its original position (facing side way).
5. Disconnect the syringe, attach a suitable needle and inject or infuse intravenously as instructed under Rate of Administration.

HOW SUPPLIED:
FEIBA NF is available in single-dose vials in the following nominal dosage strengths:

Blue - 500 Units per vial (NDC 64193-223-02)
Green - 1000 Units per vial (NDC 64193-224-02)
Purple - 2500 Units per vial (NDC 64193-225-02)

The number of Units of Factor VIII inhibitor bypassing activity is stated on the label of each vial.
FEIBA NF is packaged with a suitable volume (20 mL or 50 mL) of Sterile Water for Injection, U.S.P., one BAXJECT Needleless Transfer Device, and one Package Insert.
The 50 mL SWFI stoppers are not latex-free and may contain Dry Natural Rubber Latex.

Storage
Store at room temperature, not to exceed 25°C (77°F).
Avoid freezing, which may damage the diluent vial.
Store in the original package in order to protect from light.

Drug UPDATE:  KCENTRA (Prothrombin Complex Concentrate (Human))
For Intravenous Use, Lyophilized Powder for Reconstitution
[Drug information   
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

ABBREVIATED MONOGRAPH - SEE PACKAGE INSERT.

Initial U.S. Approval:  2013

BOXED WARNING:
WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS Patients being treated with Vitamin K antagonists (VKA) therapy have underlying disease states that predispose them to thromboembolic events. Potential benefits of reversing VKA should be weighed against the potential risks of thromboembolic events, especially in patients with the 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 non-fatal arterial and venous thromboembolic complications have been reported with Kcentra in clinical trials and post marketing surveillance. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events.
• Kcentra 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. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months. (5.2)

INDICATIONS AND USAGE
Kcentra, Prothrombin Complex Concentrate (Human), is a blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with:

• acute major bleeding or
• need for an urgent surgery/invasive procedure.

DOSAGE AND ADMINISTRATION
For intravenous use only.

• Kcentra dosing should be individualized based on the patient's baseline International Normalized Ratio (INR) value, and body weight.
• Administer Vitamin K concurrently to patients receiving Kcentra to maintain factor levels once the effects of Kcentra have diminished.
• The safety and effectiveness of repeat dosing have not been established and it is not recommended.
• Administer reconstituted Kcentra at a rate of 0.12 mL/kg/min (~3 units/kg/min) up to a maximum rate of 8.4 mL/min (~210 units/min).

*Dosing is based on body weight. Dose based on actual potency as stated on the carton, which will vary from 20--31 Factor IX units/mL after reconstitution. Nominal potency is 500 or 1000 units per vial, approximately 25 units per mL after reconstitution.

†Units refer to International Units.

‡Dose is based on body weight up to but not exceeding 100 kg. For patients weighing more than 100 kg, maximum dose should not be exceeded.

CONTRAINDICATIONS
Kcentra is contraindicated in patients with:

Known anaphylactic or severe systemic reactions to Kcentra or any components in Kcentra including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and human albumin.
Disseminated intravascular coagulation.
Known heparin-induced thrombocytopenia. Kcentra contains heparin.

WARNINGS AND PRECAUTIONS
Hypersensitivity reactions may occur. If necessary, discontinue administration and institute appropriate treatment. (5.1)
Arterial and venous thromboembolic complications have been reported in patients receiving Kcentra. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thrombotic or thromboembolic (TE) event within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months. (5.2)
Kcentra is made from human blood and may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. (5.3)

ADVERSE REACTIONS
The most common adverse reactions (ARs) (frequency >/= 2.8%) observed in subjects receiving Kcentra were headache, nausea/vomiting, hypotension, and anemia. (6)
The most serious ARs were thromboembolic events including stroke, pulmonary embolism, and deep vein thrombosis. (6)

Mechanism of Action:
Kcentra contains the Vitamin K-dependent coagulation Factors II (FII), VII (FVII), IX (FIX), and X (FX), together known as the Prothrombin Complex, and the antithrombotic Protein C and Protein S.

A dose-dependent acquired deficiency of the Vitamin K-dependent coagulation factors occurs during Vitamin K antagonist treatment. Vitamin K antagonists exert anticoagulant effects by blocking carboxylation of glutamic acid residues of the Vitamin K-dependent coagulation factors during hepatic synthesis, lowering both factor synthesis and function. The administration of Kcentra rapidly increases plasma levels of the Vitamin K-dependent coagulation Factors II, VII, IX, and X as well as the antithrombotic Proteins C and S.

Coagulation Factor II
Factor II (prothrombin) is converted to thrombin by activated FX (FXa) in the presence of Ca2+, FV, and phospholipids.

Coagulation Factor VII
Factor VII (proconvertin) is converted to the activated form (FVIIa) by splitting of an internal peptide link. The FVIIa-TF complex activates Factor IX and initiates the primary coagulation pathway by activating FX in the presence of phospholipids and calcium ions.

Coagulation Factor IX
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.

Coagulation Factor X
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
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
Protein S exists in a free form (40%) and in a complex with C4b-binding protein (60%). Protein S (free form) functions as a cofactor for activated Protein C in the inactivation of FVa and FVIIIa, leading to antithrombotic activity.

HOW SUPPLIED:

• Kcentra is available as a single use vial containing coagulation Factors II, VII, IX and X, antithrombotic Proteins C and S as a lyophilized concentrate.
• Kcentra potency (units) is defined by Factor IX content. The range of Factor IX units per vial is 400–620 units for the 500 U kit and 800-1240 units for the 1000 U kit. When reconstituted, the final concentration of drug product in Factor IX units will be in a range from 20–31 units/mL.
• The actual content of Factor IX as measured in units of potency is stated on the vial.
• The actual units of potency for each coagulation factor (Factors II, VII, IX and X), and Proteins C and S are stated on the carton.

ABBREVIATED MONOGRAPH - SEE PACKAGE INSERT.

BOXED WARNING: WARNING: THROMBOSIS
Serious arterial and venous thrombotic events following administration of NovoSeven RT have been reported. [See Warnings and Precautions (5.1)]
Discuss the risks and explain the signs and symptoms of thrombotic and thromboembolic events to patients who will receive NovoSeven RT. [See Warnings and Precautions (5.1)]
Monitor patients for signs or symptoms of activation of the coagulation system and for thrombosis. [See Warnings and Precautions(5.1)]
Initial U.S. Approval:  1999

Mechanism of Action: NovoSeven RT is recombinant Factor VIIa and, when complexed with tissue factor can activate coagulation Factor X to Factor Xa, as well as coagulation Factor IX to Factor IXa. Factor Xa, in complex with other factors, then converts prothrombin to thrombin, which leads to the formation of a hemostatic plug by converting fibrinogen to fibrin and thereby inducing local hemostasis. This process may also occur on the surface of activated platelets.

INDICATIONS AND USAGE:
NovoSeven RT, Coagulation Factor VIIa (Recombinant) is indicated for:

• Treatment of bleeding episodes and perioperative management in adults and children with hemophilia A or B with inhibitors, congenital Factor VII (FVII) deficiency, and Glanzmann’s thrombasthenia with refractoriness to platelet transfusions, with or without antibodies to platelets.
• Treatment of bleeding episodes and perioperative management in adults with acquired hemophilia.

DOSAGE AND ADMINISTRATION
For intravenous bolus injection only
ABBREVIATED MONOGRAPH - SEE PACKAGE INSERT.

Bleeding Episodes (2.1)

Peri-operative Management (2.1)

HOW SUPPLIED:
NovoSeven RT is available as a white lyophilized powder in single-use vials containing 1 mg (1000 micrograms), 2 mg (2000 micrograms), 5 mg (5000 micrograms), or 8 mg (8000 micrograms) recombinant coagulation Factor VIIa (rFVIIa) per vial.

The diluent for reconstitution of NovoSeven RT is a 10 mmol solution of L-histidine in water for injection. It is a clear colorless solution provided in a vial or a pre-filled diluent syringe and is referred to as the histidine diluent.

After reconstitution with the histidine diluent, the final solution contains approximately 1 mg per mL NovoSeven RT (1000 micrograms per mL).