Bebulin VH (Factor IX Complex), Vapor Heated, (Bebulin VH) is a purified, sterile, stable, freeze-dried concentrate of the coagulation Factors IX (Christmas Factor) as well as II (Prothrombin) and X (Stuart Prower Factor) and low amounts of Factor VII. In addition, the product contains small amounts of heparin (≤ 0.15 IU heparin per IU Factor IX).
Bebulin VH is standardized in terms of Factor IX content and each vial is labeled for the Factor IX content indicated in International Units (IU). One International Unit of Factor IX (according to the current International Standard for Human Blood Coagulation Factors II, IX, and X in Concentrates) corresponds to the activity of Factor IX in 1 mL of fresh normal human plasma.
Bebulin VH - Clinical Pharmacology
Bebulin VH is a combination of vitamin K-dependent clotting factors found in normal plasma. The administration of Bebulin VH 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 VH was determined by investigators in Germany, Japan, and the United States 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, respectively 1,2,3.
During the manufacture Bebulin VH is subjected to virus inactivation by two-step vapor heating at 60°C and 80°C4, where Bebulin VH intermediate bulk is heated for a total of 10 hours at >60°C and 1 hour at 80°C. Reduction factor for Parvovirus B19 claimed for the Lyophilization and Vapor Heat Treatment step is based on results derived from experimental infectivity and titration assays. The effectiveness of vapor heating was evaluated in vitro using human immunodeficiency virus (HIV-1) as a relevant blood-borne pathogen as well as hepatitis A virus (HAV) and human parvovirus B19 (B19V) as relevant non-enveloped RNA and DNA viruses, respectively. Furthermore, model viruses have been used to evaluate the virus inactivation capacity of vapor heat treatment: Bovine viral diarrhea virus (BVDV) as a model for lipid enveloped RNA viruses such as hepatitis C virus and pseudorabies virus (PRV) was included as a model for enveloped DNA viruses. MMV was employed as a model for non-enveloped DNA viruses less heat sensitive than B19V5-7. These studies indicate that this specific step during the manufacture of Bebulin VH is capable of eliminating/ inactivating a wide range of relevant target and model viruses exhibiting diverse physicochemical properties. The in vitro viral reduction studies performed on Bebulin VH are summarized in Table 1.
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In Vitro Virus Clearance During Lyophilization and | ||||||
| Process Step Evaluated | Viral Reduction Factor (log10) | |||||
| Lipid-enveloped | Non- Enveloped | |||||
| HIV-1 | BVDV | PRV | HAV | B19V* | MMV | |
| Lyophilization and Vapor Heat Treatment at 60°C and 80°C | 6.7 | > 6.9 | > 7.4 | > 5.0 | 4.6 | < 1.0 |
In the context of two prospective clinical studies 8,9 and a retrospective survey 10, BEBULIN VH was followed up for the risk of transfusion-transmitted viral infections. All patients received blood products for the first time. Using criteria established by the ICTH, 16 patients could be followed up for non-A, non-B hepatitis, 9 for HCV seroconversion, 3 for hepatitis B, and 24 for HIV seroconversion. None tested positive for any of these infections. An additional 3 patients with 2 or more consecutive test samples missing tested negative for non-A, non-B hepatitis for all samples available. Three studies using ICTH criteria for testing 8-10, a retrospective survey 11 and a case report 12 on other vapor heated factors of the prothrombin complex that were subjected to the same inactivation process as Bebulin VH, gave the following results: 27 patients tested negative for non-A, non-B hepatitis, 15 for HCV seroconversion, 25 for hepatitis B, and 75 for HIV seroconversion.
Indications and Usage for Bebulin VH
Bebulin VH is indicated for the prevention and control of hemorrhagic episodes in hemophilia B patients.
Bebulin VH 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.
Contraindications
None known.
Warnings
Bebulin VH is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by effective donor screening, testing for the presence of certain current virus infections, by inactivating and/or removing certain viruses. Despite these measures, such products can still potentially transmit disease. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, and theoretically, the Creutzfeldt-Jacob disease (CJD) agent. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxter Healthcare Corporation at 1-800-423-2862 (in the U.S.). The physician should discuss the risks and benefits of this product with the patient.
Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly non-A, non-B hepatitis. Hepatitis B vaccination is essential for patients with hemophilia and it is recommended that this be done at birth or diagnosis. The risk of thromboembolic complications including DIC and hyperfibrinolysis is present with the administration of Factor IX Complex, particularly in the postoperative period and in patients with risk factors predisposing to thrombosis.
Precautions
In patients with risk factors predisposing to thrombosis the Factor IX level should not be raised to more than approximately 60% of normal 13. In addition, it is recommended that such patients as well as patients who require high doses of Factor IX because of major surgical interventions be monitored for the possible development of DIC and/or thrombosis. In case changes occur in blood pressure or pulse rate or symptoms such as respiratory distress, chest pain or cough, treatment should be stopped immediately.
Information for Patients
Some viruses, such as parvovirus B19, are particularly difficult to remove or inactivate at this time. Parvovirus B19 most seriously affects pregnant women or immune-compromised individuals. Symptoms of parvovirus B19 infection include fever, drowsiness, chills, and runny nose followed about two weeks later by a rash, and joint pain.
Patients should be informed of the early signs of hypersensitivity reactions such as fever, urticaria, rashes, nausea or retching and should be advised to discontinue use of the product and contact their physician if these symptoms occur.
Pregnancy Category C
Animal reproduction studies have not been conducted with Bebulin VH It is also not known whether Bebulin VH can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. BEBULIN should be given to a pregnant woman only if clearly needed.
Adverse Reactions
As with any other infused plasma derivatives, anaphylactoid or anaphylactic reactions may occur in rare cases. The occurrence of these reactions (e.g. fever, urticarial rashes, nausea, retching, dyspnea, anaphylactic shock) necessitates the interruption of replacement therapy. Mild reactions can be managed with antihistamines; severe hypotensive reactions require immediate intervention using current principles of shock therapy.
Bebulin VH Dosage and Administration
General
Bebulin VH is intended for intravenous administration only.
As a general rule, 1 International Unit of Factor IX activity/kg will increase the plasma level of Factor IX by 0.8%.
Accordingly, the following formula is provided for dosage calculations
| Number of Factor | bodyweight | desired Factor IX increase | x | 1.2 | ||
| IX IU required | = | (kg) | x | (% of normal) |
It must, however, be emphasized that the response to treatment will vary from patient to patient and that occasionally larger doses than those derived from the above formula will be required, particularly if treatment is delayed. Exact dosage determination should be based on localization and extent of hemorrhage, and the level of Factor IX to be achieved. It must be emphasized that particularly with severe hemorrhage and major surgery, close laboratory monitoring of the Factor IX level is required to determine proper dosage.
Management of Specific Types of Bleeding 14-18
Approximate Factor IX levels, typical initial doses, and the average duration of treatment are suggested in the table below. For minor bleeding a single dose will usually be sufficient, otherwise a second dose may be given after 24 hours. More severe hemorrhage will require the administration of several doses at approximately 24 hours intervals. For maintenance therapy, usually two thirds of the initial dose is infused.
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| Type of Bleeding | Approximate Factor IX Level (% Normal) | Typical Initial Dose (IU/kg) | Average Duration of Treatment (Days) |
Minor early hemarthrosis, and gingival bleeding, mild hematuria | 20 | 25-35 | 1 |
Moderate severe joint bleeding, major open bleeding, minor trauma, minor hemoptysis hematemesis, and melena, major hematuria | 40 | 40-55 | 2 or until adequate wound healing |
Major Severe hemoptysis, Hematemesis, and melena | ≥60* | 60-70 | 2-3 or until adequate wound healing |
Management of Surgical Procedures 14-18.
Dosage guidelines for surgical procedures are suggested below. The preoperative loading dose should be administered one hour prior to surgery. Depending on the type of surgery, replacement therapy has to be continued over one to several weeks until adequate wound healing is achieved. The average treatment interval will initially be 12 hours, while in the later postoperative period 24 hours is generally adequate.
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Type of Surgery | Day of Operation | Init. Postop. Period (1st to 2nd Week) | Late Postop. Period (from 3rd Week Onwards) | |||
Approx. Level F IX (% Normal) | Dose (I.U./kg) | Approx. Level F IX (% Normal) | Dose (I.U./kg) | Approx. Level F IX (% Normal) | Dose (I.U./kg) | |
| Major | ≥60* | 70-95 | 60-20 | 70-35 | 20 | 35-25 |
| Minor | 40-60 | 50-60 | 40-20 | 55-25 | N/A | N/A |
For tooth extraction the same initial dose as for minor surgery is recommended.
Generally, one infusion will be sufficient. In case of extraction of several teeth, replacement therapy for up to one week may be necessary using the same doses as for minor surgery 13-15
Long-Term Prophylactic Treatment
Prophylactic doses of 20-30 IU/kg administered once, or preferably up to twice a week have been shown to significantly reduce the frequency of spontaneous hemorrhage 13,16. It is, however, recommended that prophylactic dosage regimens be tailored to individual needs.
Reconstitution
Bebulin VH should be reconstituted immediately before application. The solution does not contain a preservative and must be used within 3 hours after reconstitution.
For reconstitution proceed as follows:
- Warm both diluent and concentrate in unopened vials to room temperature (not above 37 °C, 98 °F).
- Remove caps from both vials to expose central portions of the rubber stoppers.
- Cleanse exposed surface of the rubber stoppers with germicidal solution and allow to dry.
- Using aseptic technique, remove protective covering from one end of the double-ended needle and insert the exposed end through the diluent vial stopper.
- Remove protective covering from the other end of the double-ended needle, taking care not to touch the exposed end. Invert diluent vial over the concentrate vial, then insert free end of the needle through the concentrate vial stopper. Diluent will be drawn into the concentrate vial by vacuum.
- Disconnect the two vials by removing needle from the concentrate vial stopper.
Gently agitate or rotate the concentrate vial until all material is dissolved.
Do not refrigerate after reconstitution!
Administration
Parenteral drug products should be inspected for particulate matter and discoloration prior to administration, whenever solution and container permit.
Intravenous Injection
- After reconstituting the concentrate as described above, attach the enclosed filter needle to a sterile disposable syringe using aseptic technique. Insert filter needle through the concentrate vial stopper.
- Inject air and withdraw solution into the syringe.
- Remove and discard filter needle. Attach a suitable intravenous needle or infusion set with winged adapter.
- Administer the solution intravenously at a rate comfortable to the patient (maximum rate 2 mL per minute).
How is Bebulin VH Supplied
Bebulin VH is supplied in single dose vials with Sterile Water for Injection, U.S.P., double-ended needle, and filter needle for reconstitution and withdrawal.
Some components of the packaging material contain Dry Natural Rubber Latex.
Factor IX activity in International Units is stated on the label of each vial.
Rx only
STORAGE
When stored at refrigerated temperature (2°C-8°C, 35°F-46°F), Bebulin VH is stable for the period indicated by the expiration date on its label. Avoid freezing, which may damage the diluent vial.
REFERENCES
- H. H. Brackmann: A Study to Investigate the In Vivo Recovery and Half-Life Time of Factor IX Concentrate S-TIM 4. Unpublished Report, 1985.
- T. Abe et al.: Clinical Study with BENOBIL TIM 4, Steam-Treated Factor IX Complex, Single Administration. Jap. Pharm. & Ther., 14, 1986, 1, pp. 19-31.
- C. Kasper, A. Andes, L. M. Aledort: Clinical Study of Recovery and Half-Life of Factor IX Complex (Human) IMMUNO, Vapor Heated, Bebulin VH. Unpublished Report, 1990.
- Vapor Heating is described in: World Health Organization (WHO) Technical Report, Series No. 924, 2004, Annex 4, Guidelines on viral inactivation and removal, procedures intended to assure the viral safety, of human blood plasma products.
- J Blumel, I.Schmidt, H. Willkommen and J. LÐwer. Inactivation of parvovirus B19 during pasteurization of human serum albumin. Transfusion, 42, 2002, pp.1011-1018.
- M. Yunoki, M. Tsujikawa, T. Urayama Y. Sasaki, M. Morita, H. Tanaka, S. Hattori, K. Takechi and K. Ikuta: Heat Sensitivity of human parvovirus B19, Vox Snaguinis, 84, 2003, pp164-169.
- M. Yunoki, T. Urayama, M, Tsujikawa, Y. Sasaki, S Abe, K. Takechi and K. Ikuta: Inactivation of parvovirus B19 by liquid heatingg incorporated in the manufacturing process of human intravenous immunoglobin preparations. British Journal of Haematology, 184, 2004, pp 401-414.
- Kl. Schimpf: Klinische Studien zur Infektiosität von konventionellen und virusinaktivierten Gerinnungsfaktorenkonzentraten. In: G. Landbeck, Kl. Schimpf (Eds.): 3. Rundtischgespräch über aktuelle Probleme der Substitutionstherapie Hämophiler. Berlin: Springer Verlag, 1986, pp. 69 - 79.
- A Study to Determine the Safety of Virus Inactivated Factor Concentrates in Hemophiliacs Naive to Blood Product Administration. Data on file.
- Kl. Schimpf: Substitutionstherapie bei angeborenen Gerinnungsstörungen. In: O.H. Just, C. Krier (Eds.): Haemostasis in Anaesthesia and Intensive Medicine. Berlin: Springer Verlag, 1988, pp. 17-31.
- D.U. Preiss, B. Eberspächer, D. Abdullah, I. Rosner: Safety of Vapour Heated Prothrombin Complex Concentrate (PCC) Prothromplex S-TIM4. Thrombosis Research, 63, 1991, pp. 651-659.
- M. Köhler, P. Hellstern, G. Pindur, E. Wenzel, G. v. Blohn: Factor VII Half-Life after Transfusion of a Steam-Treated Prothrombin Complex Concentrate in a Patient with Homozygous Factor VII Deficiency. Vox Sang., 56, 1989, pp. 200-201.
- P. H. Levine: Clinical Manifestations and Therapy of Hemophilias A and B. In: R. W. Colman, J. Hirsh, V. J. Marder, E.W. Salzman (Eds.): Hemostasis and Thrombosis. Philadelphia: J. B. Lippincott Company, 1987, pp. 97-111
- C. R. Rizza, P. Jones: Management of patients with inherited blood coagulation defects. In: A.L. Bloom, D.P. Thomas (Eds.): Hemostasis and Thrombosis. Edinburgh: Churchill Livingstone, 1987, pp. 465-493.
- T. Abe, M. Kazama: An International Survey on the Appropriate Dosage of Hemophilias and Related Congenital Coagulopathies. In: Proceedings of the 3rd International Symposion on Haemostasis and Thrombosis, 1982, pp. 273-304.
- I. M. Nilsson, Å. Ahlberg, G. Björlin: Clinical Experience with a Swedish Factor IX Concentrate. Acta Med. Scand., 190, 1971, pp. 257-266.
- J. N. George, R. T. Breckenridge: The Use of Factor VIII and Factor IX Concentrates During Surgery. JAMA, 214, 1970, 9, pp. 1673-1676.
- E. Ludwig, K. Lechner: Prophylaktische Behandlung bei schwerer Hämophilie B mit einem Faktor-IX-Konzentrat. Dtsch. Med. Wschr., 99, 1974, 25, pp. 1355-1361.
To enroll in the confidential, Industry-wide Patient Notification System, call 1-888-UPDATE U(1 888-873-2838).
BEBULIN is a trademark of Baxter AG, Vienna Austria; Baxter is a trademark of Baxter International Inc., registered in the U.S. Patent and Trademark office.
Baxter Healthcare Corporation
Westlake Village, CA-91362
USA
U.S. License No. 140 Revised: 09/2006
U.S. Pat. No 4,640,834 and 4,388,232
Principle Display Panel
Bebulin VH 200-1200 unit carton
20 mL size, dried
NDC 64193-244-02
Bebulin VH
(Factor IX Complex),
Vapor Heated
BAXTER (Logo)
WARNING: This product is prepared from large pools of human plasma. Human blood and its components may transmit infectious agents. The physician and patient should discuss the risks and benefits of this product.
Some components of the packaging material contain Dry Natural Rubber Latex.
The process has been subjected to in-process virus inactivation. For details, see package insert.
Rx Only
BEBULIN is a trademark of Baxter AG, Vienna, Austria: Baxter is a trademark of Baxter International Inc., registered in the U.S. Patent and Trademark Office.
Bebulin VH 200-1200 vial label
20 mL size, dried
NDC 64193-244-03
Bebulin VH (Factor IX Complex), Vapor Heated
BAXTER (logo)
Contains no preservative. Reconstituted with 20 mL of Sterile Water of Injection, U.S.P. and keep at room temperature. Use within 3 hours after reconstitution. Administer by the intravenous route only. For complete information and dosage see accompanying directions for use. WARNING: This product is prepared from large pools of human plasma. Human blood and its components may transmit infectious agents. The physician and patient should discuss the risks and benefits of this product. Rx only. Store between 2º and 8ºC (35º and 46ºF).
BEBULIN is a trademark of Baxter AG, Vienna, Austria: Baxter is a trademark of Baxter International Inc., registered in the U.S. Patent and Trademark Office.
Baxter Healthcare Corporation
Westlake Village, CA 91362 USA
U.S. License No. 140
U.S. Pat. Nos. 4,640,834
20 mL Sterile Water for Injection
NDC 0338-0764-62
20 mL
Single-Dose Container
Nonpyrogenic
Sterile Water for Injection, USP for reconstitution of accompanying product
Do not use unless clear. No antimicrobial agent or other substances has been added. Do not use for intravascular injection without making approximately isotonic by addition of suitable solute. Discard unused portion. Rx Only. This Product Contains Dry Natural Rubber.
BAXTER
Manufactured by
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| BLA | BLA103112 | 03/16/2011 | |
| Labeler - Baxter Healthcare Corporation (085206634) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| Baxter Healthcare Corporation | 001728059 | MANUFACTURE, LABEL | |
