Hemophilia therapy Bebulin VH®, also known as human coagulation factor IX, is a purified, freeze-dried, concentrated replacement therapy containing a combination of coagulation factor IX (Christmas factor), factor II (prothrombin), factor X (Stuart Prower factor), small amounts of factor VII, and a small amount of heparin (≤ 0.15 IU heparin per IU Factor IX).1 It was approved for licensure by the Center for Biologic Evaluation and Research (CBER), a division of the US Food and Drug Administration (FDA), on August 21, 1970.2

Bebulin is manufactured from large pools of human plasma collected at FDA-approved blood establishments. These blood samples undergo rigorous screening for potential infections, including hepatitis B, hepatitis C, and human immunodeficiency virus (HIV-1/HIV-2) infection. Additionally, the samples undergo 35nm nanofiltration and vapor heat treatment (10 hours at 60°C and subsequent 1 hour at 80°C under the condition of 7-8% (w/v) residual moisture) to remove or inactivate any viruses.3

Indications

Bebulin is approved by the FDA for the prevention and control of episodes of bleeding in individuals with a diagnosis of hemophilia B, also known as Christmas disease or congenital factor IX deficiency.4 It is not indicated for use in individuals with factor VII deficiency.1

Mechanism of Action

Factor IX is normally produced in the liver and is a vitamin K-dependent clotting factor.4 Hemophilia B is an X-linked recessive clotting disorder characterized by insufficient levels of factor IX protein.4 The administration of Bebulin increases the concentration of factor IX in the plasma, temporarily restoring hemostasis in individuals with hemophilia B.1  

Following an infusion of Bebulin, the newly available factor IX protein is activated by factor XIa in the intrinsic coagulation pathway. The activated factor IX, in combination with factor VII, then activates factor X. Prothrombin is converted to thrombin, which in turn produces a fibrin clot.4 

Read more about prescribing information for Coagulation Factor IX complex (human) at MPR

Efficacy of Bebulin in Trials

A trial was conducted to compare the efficacy of Bebulin with that of an alternative, Profilnine, for the emergent reversal of warfarin-associated major hemorrhaging. Results indicated that the rate of reversal of the international normalized ratio (INR) was significantly higher in patients treated with Bebulin than in those treated with Profilnine (85.5% vs 27.3%; P <.001).5 

Researchers in Germany, Japan, and the United States ascertained the in vivo recovery of Bebulin VH to be 53.3 ± 9.6%, 57.5 ± 21.8%, and 53.24 ± 16.95%, respectively. Similarly, they determined the half-life of Bebulin to be 19.4 ± 3.8 hours, 24.6 ± 3.2 hours, and 19.97 ± 8.24 hours, respectively.1

It was discovered that factor IX concentrate can be purified with monoclonal antibody immunoaffinity techniques. As a result, following intravenous administration, the plasma concentration of factor IX is increased without a rise in the concentrations of factors II, VII, and X. The half-life of the purified form of factor IX is calculated to be 34.6 ± 13.1 hours.6

Warnings, Precautions, and Adverse Reactions

A warning regarding the use of Bebulin is the possible transmission of infectious agents, such as hepatitis virus and HIV, through human plasma products despite donor screening, rigorous testing for viruses, and the treatment of samples with measures to inactivate or remove such viruses.1

Another warning regarding the use of Bebulin is the risk for thromboembolic complications, including disseminated intravascular coagulation (DIC) and hyperfibrinolysis, particularly following surgical procedures, in individuals with a predisposition to thrombosis.1 

The use of Bebulin involves the possibility of severe hypotensive reactions such as anaphylactic shock, which require the immediate administration of epinephrine. Caution is advised when Bebulin is administered to persons with risk factors for thrombosis, including liver disease, coronary heart disease, immobilization following surgery, and a history of DIC, and when it is given to neonates and elderly individuals. Care must be taken during the administration of Bebulin that factor IX levels do not exceed 60% of normal, and individuals at high risk for thrombosis should be monitored for changes in blood pressure and pulse rate as well as respiratory distress, chest pain, and coughing.1 

Bebulin is categorized as a Category C pregnancy medication. In the absence of studies proving that Bebulin causes fetal harm, it is advised that Bebulin be given to pregnant women only if necessary.1

Adverse reactions to Bebulin include anaphylactic shock, pyrexia, chills, dizziness, hypotension, nausea, dyspnea, retching, erythema, urticarial rashes, nephrotic syndrome, infusion-site pain/reactions, pruritus, tachycardia, headache, and vascular problems (eg, deep vein thrombosis, pulmonary embolism, thrombotic stroke, DIC, and myocardial infarction). Severe adverse reactions to Bebulin require the immediate cessation of replacement therapy. For milder adverse reactions, such as rash, management with antihistamines is effective.1,3 Inhibitor antibodies to factor IX may form following Bebulin use.3 

Contraindications to the use of Bebulin include a known allergy to heparin, a history of hypersensitivity to Bebulin, and a pre-existing history of heparin-induced thrombocytopenia.3

Dosage and Administration

The activity of 1 IU of factor IX is equivalent to the factor IX activity of 1 mL of human plasma and will raise the plasma concentration of factor IX by 0.8%.1 The exact dose of Bebulin to be administered is based on the location and severity of bleeding, the desired level of factor IX in the plasma, and the body weight of the patient. The following formula is applied:

Number of international units of factor IX required=Body weight (kg)xDesired factor IX increase (percentage of normal)x1.2

For minor bleeds, an increase of 20% of the normal level of factor IX is recommended (25-35 IU/kg). For moderate bleeds, an increase of 40% of the normal level of factor IX is recommended (40-55 IU/kg). For major bleeds, an increase of 60% or more of the normal level of factor IX is recommended (60-70 IU/kg). For individuals predisposed to thrombosis, the dose should not exceed 60% of normal factor IX levels.1

Following surgical procedures, factor IX replacement therapy must be administered every 12 hours for the first 2 weeks and then every 24 hours from the third postoperative week onward. This treatment should continue for several weeks until sufficient wound healing has been achieved.1

Administration is via intravenous injection. Reconstitution of the concentrate and examination for particulate matter and discoloration are required before administration. Bebulin is stable when stored before its expiration date at a temperature of 2° to 8°C or 35° to 46°F. Bebulin should not be frozen; freezing can damage the vial.1

Discontinuation of Bebulin

In July 2018, Shire, the company that manufactured Bebulin, informed the public that the company would discontinue the production and distribution of Bebulin because of a reduced demand for the product.7 

References

  1. Bebulin – FDA prescribing information, side effects and uses. Drugs.com. Accessed December 11, 2021.
  2. List of licensed biological products with (1) reference product exclusivity and (2) biosimilarity or interchangeability evaluations to date. Center for Biologic Evaluation and Research. Accessed December 11, 2021.
  3. Bebulin VH (factor ix complex intravenous administration). RxList. Updated November 13, 2017. Accessed December 11, 2021.
  4. Clinical policy: factor IX complex (human- Bebulin, Profilnine). PA Health & Wellness. Accessed December 11, 2021.
  5. Jones GM, Cave B, Cook R. A retrospective comparison of 3-factor prothrombin complex concentrate products for warfarin reversal. Neurohospitalist. 2020;10(3):201-207. doi:10.1177/1941874420905755
  6. Kim HC, McMillan CW, White GC, Bergman GE, Saidi P. Clinical experience of a new monoclonal antibody purified factor IX: half-life, recovery, and safety in patients with hemophilia B. Semin Hematol. 1990;27(2 Suppl 2):30-35. 
  7. Shire discontinuing manufacture and distribution of Bebulin®. News release. National Hemophilia Foundation. July 30, 2018.

Reviewed by Debjyoti Talukdar, MD, on 12/13/2021.

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