Bebulin

Baxter Healthcare Corporation

BEBULIN VH(Factor IX Complex),Vapor Heated

FULL PRESCRIBING INFORMATION: CONTENTS*

• BEBULIN DESCRIPTION
• CLINICAL PHARMACOLOGY
• BEBULIN INDICATIONS AND USAGE
• BEBULIN CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
  • Information for Patients
  • Pregnancy Category C
• BEBULIN ADVERSE REACTIONS
• BEBULIN DOSAGE AND ADMINISTRATION
  • General
  • Management of Specific Types of Bleeding
  • Management of Surgical Procedures .
  • Long-Term Prophylactic Treatment
  • Reconstitution
  • Administration
  • Intravenous Injection
• HOW SUPPLIED
• STORAGE
• REFERENCES
• Principle Display Panel

FULL PRESCRIBING INFORMATION

BEBULIN DESCRIPTION

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.

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 B19V^5-7. 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.

Table 1

In Vitro Virus Clearance During Lyophilization and Two-Step Vapor Heat Treatment of BEBULIN VH
Process Step Evaluated	Viral Reduction Factor (log10)
	Lipid-enveloped			Non- Enveloped
	HIV-1	BVDV	PRV	HAV	B19VReduction factor for Parvovirus B19 claimed for the Lyophilization and Vapor Heat Treatment is based on results derived from experimental infectivity and titration assays.	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.

BEBULIN INDICATIONS AND USAGE

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.

BEBULIN 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.

BEBULIN 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 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

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

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.

Type of Bleeding	Approximate Factor IX Level (% Normal)	Typical Initial Dose (IU/kg)	Average Duration of Treatment (Days)
Minor early hemarthrosis, minor epistaxis, and gingival bleeding, mild hematuria	20	25-35	1
Moderate severe joint bleeding, early hematoma, major open bleeding, minor trauma, minor hemoptysis hematemesis, and melena, major hematuria	40	40-55	2 or until adequate wound healing
Major severe hematoma major trauma, Severe hemoptysis, Hematemesis, and melena	≥60For patients predisposing to thrombosis see “PRECAUTIONS” section.	60-70	2-3 or until adequate wound healing

Management of Surgical Procedures .

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.

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 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.

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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

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