Label: BEBULIN- coagulation factor ix human

  • NDC Code(s): 0338-0764-62, 64193-345-01, 64193-445-02
  • Packager: Baxter Healthcare Corporation
  • Category: PLASMA DERIVATIVE
  • DEA Schedule: None
  • Marketing Status: Biologic Licensing Application

Drug Label Information

Updated 07/12

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  • DESCRIPTION

    BEBULIN (Factor IX Complex), Nanofiltered and Vapor Heated is a purified, sterile, freeze-dried concentrate of the Coagulation Factor IX (Christmas Factor) as well as Factor II (Prothrombin) and Factor 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 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 is manufactured from large plasma pools of human plasma. Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma collection and plasma preparation. Each individual plasma donation used in the manufacture of BEBULIN is collected only at FDA approved blood establishments and is tested by FDA licensed serological tests for Hepatitis B Surface Antigen (HBsAg), for antibodies to Human Immunodeficiency Virus (HIV-1/HIV-2) and Hepatitis C Virus (HCV) in accordance with U.S. regulatory requirements. As an additional safety measure, mini-pools of the plasma are tested for the presence of HIV-1 and HCV by FDA licensed Nucleic Acid Testing (NAT) and found negative. Validated virus removal/inactivation steps have been integrated into the manufacturing process, namely 35 nm nanofiltration1 and a vapor heat treatment process2 [10 hours at 60°C and subsequent 1 hour at 80°C under the condition of 7-8% (w/v) residual moisture]. In addition DEAE-Sephadex adsorption contributes to the virus safety profile of BEBULIN. Despite these measures, this product can still potentially transmit disease3 [see Warnings].

    In vitro spiking studies have been used to validate the capability of the manufacturing process to remove and inactivate viruses. To establish virus clearance capacity of the manufacturing process, these virus clearance studies were performed in accordance with good laboratory practices under extreme conditions (e.g. at minimum incubation times and temperatures below specifications for vapor-heat treatment). The in vitro viral reduction studies performed on nanofiltered BEBULIN are summarized in Table 1 .

    Table 1 Mean log10 Reduction Factors (RFs) For Each Virus and Manufacturing Step*  
    *
    Reduction factors < 1 log are not used for calculation of the overall reduction factor.
    Studies on B19V, which are considered experimental in nature, have demonstrated a virus reduction factor of not more than 3.6 log 10 and 4.6 log 10 by DEAE-Sephadex adsorption and vapor -heat treatment, respectively.
    HIV-1, Human Immunodeficiency Virus Type 1
    BVDV, Bovine Viral Diarrhea Virus (model for Hepatitis C Virus and other lipid enveloped RNA viruses)
    PRV, Pseudorabies Virus (model for lipid enveloped DNA viruses including Hepatitis B Virus)
    HAV, Hepatitis A Virus
    MMV, Mice Minute Virus (model for non-lipid enveloped DNA viruses, including human parvovirus B19 [B19V])
    §
    n.d.: Not done
    Studies on West Nile Virus (WNV), have demonstrated a virus reduction factor of 3.1 log 10 by the 35 nm nanofiltration step.
    Virus Type Enveloped RNA Enveloped DNA Non-enveloped RNA Non-enveloped DNA
    Virus Family Retroviridae Flaviviridae Herpesviridae Picornaviridae Parvoviridae
    Virus HIV-1 BVDV PRV HAV MMV
    DEAE Sephadex Adsorption n.d§ n.d n.d 1.4 1.3
    35 nm Nanofiltration > 6.4 2.0 > 6.0 1.7 ≤1.0
    Vapor-Heat Treatment > 6.8 > 7.1 > 7.4 > 4.5 ≤1.0
    Overall log reduction factor (ORF) > 13.2 > 9.1 > 13.4 > 7.6 1.3
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  • 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.

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  • 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.

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  • CONTRAINDICATIONS

    BEBULIN is contraindicated in patients with

    • Known history of hypersensitivity reactions to the product
    • Known allergy to heparin
    • Known history of heparin-induced thrombocytopenia
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  • WARNINGS

    Thrombosis

    Thromboembolic events (deep vein thrombosis, pulmonary embolism, thrombotic stroke) as well as disseminated intravascular coagulation (DIC) have been reported with BEBULIN. The risk of thromboembolic complications including DIC and hyperfibrinolysis is higher in patients with congenital or acquired coagulation disorders, with repeated dosing or high doses of BEBULIN. Because of the risk of thromboembolic complications, closely monitor patients when administering BEBULIN:

    • Monitor patients closely for signs and symptoms of intravascular coagulation or thrombosis.
    • Monitor Factor IX level in patients predisposed to thromboembolic complications including patients with a history of coronary artery disease, patients with liver disease, pre- or postoperative patients, and neonates.
    • Stop the infusion immediately and initiate appropriate diagnostic and therapeutic measures at the first signs or symptoms of thrombosis or embolism.

    Anaphylaxis and Hypersensitivity Reactions

    Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions have been reported with BEBULIN. Manifestations of hypersensitivity or allergic reactions include anaphylactic shock, hypotension, hypertension, chest tightness, dizziness, paresthesia, lethargy, restlessness, vomiting, urticaria, erythema, pyrexia, chills, and rash. In the event of an anaphylactic/anaphylactoid reaction, stop the infusion immediately and administer appropriate emergency treatment. Evaluate patients experiencing allergic reactions for the presence of an inhibitor.

    Development of Inhibitor

    Formation of circulating antibodies inhibiting Factor IX has been reported with the administration of BEBULIN. If such an inhibitor occurs, the condition will manifest itself as a poor clinical response. Nephrotic syndrome has been reported following attempted immune tolerance induction in hemophilia B with Factor IX inhibitor receiving factor IX products including BEBULIN.4 The safety and efficacy of using factor IX products including BEBULIN for immune tolerance induction have not been established.

    Transmission of Infectious Agents

    Because BEBULIN is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the classic Creutzfeldt-Jakob disease agent. This also applies to unknown or emerging viruses and other pathogens. No cases of transmission of viral diseases or vCJD have been associated with BEBULIN.

    ALL infections thought by a physician to possibly 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.).

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  • PRECAUTIONS

    Interference with Heparin Sensitivity Laboratory Testing

    BEBULIN contains heparin. Take heparin content into account when performing clotting tests sensitive to heparin.

    Information for Patients

    Inform patients of all signs and symptoms of immediate hypersensitivity reactions such as fever, urticaria/hives, rashes, nausea, retching, angioedema/swelling of face or other body areas, laryngeal edema, stridor, dysphonia, bronchospasm/wheezing, hypotension, dizziness, lightheadedness, or loss of consciousness. Advise patients to discontinue use of the product and contact their physician if these symptoms occur and seek emergency care immediately for serious symptoms.

    Inform patients of all signs and symptoms of parvovirus B19 infection, which is especially serious in 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.

    Drug Interactions

    No drug interaction studies were performed. The effect of vitamin K antagonists (e.g. warfarin) can be temporarily overcome by the administration of human prothrombin complex products, including BEBULIN, which provides increased plasma levels of functional vitamin-K dependent coagulation Factors (II, IX and X)6.

    Pregnancy

    Pregnancy Category C - Animal reproduction studies have not been conducted with BEBULIN. It is also not known whether BEBULIN can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

    Pediatric Use

    The safety and efficacy of the use of BEBULIN in pediatric patients have not been established.

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  • ADVERSE REACTIONS

    Clinical Trial Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

    The following adverse reactions were reported in clinical studies with a previous formulation of BEBULIN:

    Hypotension, Dizziness, Urticaria, Erythema, Pyrexia, and Chills.

    The formation of inhibitor antibodies to Factor IX has been observed with the administration of BEBULIN.

    Postmarketing Experience

    Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

    Table 2 lists the adverse reactions reported during postmarketing use of BEBULIN.

    Table 2 Postmarketing Adverse Reactions
    Blood and Lymphatic System Disorders

    Disseminated intravascular coagulation

    Immune System Disorders

    Anaphylactic/Anaphylactoid reactions,

    Hypersensitivity
    Nervous System Disorders Headache
    Cardiac Disorders Tachycardia
    Vascular Disorders

    Thromboembolic events (including Deep vein

    thrombosis, Pulmonary embolism, Thrombotic stroke), Flushing
    Respiratory, Thoracic, and Mediastinal Disorders

    Dyspnea, Bronchospasm, Wheezing, Cough

    Gastrointestinal Disorders

    Abdominal pain, Nausea

    Skin and Subcutaneous Tissue Disorders

    Angioedema, Facial edema, Rash, Pruritus

    Renal and Urinary Disorders

    Nephrotic syndrome (following attempted

    immune tolerance induction)
    General Disorders and Administration Site Conditions Infusion site reactions, including Infusion site pain

    In addition to reactions listed above, myocardial infarction has been identified in the published literature with other Factor IX products.

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  • DOSAGE AND ADMINISTRATION

    For intravenous administration only

    One International Unit (IU) 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 IX IU required = bodyweight (kg) x desired Factor IX increase (% of normal) x 1.2.

    The response to treatment will vary from patient to patient. Exact dosage determination should be based on localization and extent of hemorrhage, and the level of Factor IX to be achieved. Close laboratory monitoring of the Factor IX level is required to determine proper dosage, particularly with severe hemorrhage and major surgery. Larger doses than those derived from the above formula may be required; particularly if treatment is delayed.

    Management of Bleeding 7-11

    Approximate desired Factor IX levels, typical initial doses, and the average duration of treatment are suggested in Table 3. 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 several doses at approximately 24-hours intervals. For maintenance therapy, usually two thirds of the initial dose is infused.

    Table 3 Management of Specific Types of Bleeding
    *
    For patients predisposing to thrombosis see Precautions section.
    Type of Bleeding

    ApproximateDesired Factor IX Level

    (% Normal)

    Typical InitialDose

    (International Units/kg)

    Average Durationof 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 50-65

    2 or until adequate

    wound healing

    Major
    Severe hematoma major trauma, Severe hemoptysis,

    hematemesis, and
    melena
    ≥60* 75-90

    2-3 or until adequate

    wound healing

    Management of Surgical Procedures 7-11

    Dosage guidelines for surgical procedures are suggested in Table 4. Administer preoperative loading dose one hour prior to surgery. Depending on the type of surgery, continue replacement therapy 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 adequate.

    Table 4 Management of Surgical Procedures
    *
    N/A– Not Applicable.
    For patients predisposing to thrombosis see Precautions section.

    Type ofSurgery

    Day of Operation

    Init. Postop. Period

    (1st to 2nd Week)

    Late Postop. Period(from 3rd Week Onwards)

    Approx. Level Factor IX

    (% Normal)

    Dose

    (IU/kg)

    Approx. Level Factor IX

    (% Normal)

    Dose

    (IU/kg)

    Approx. Level Factor IX

    (% Normal)

    Dose

    (IU/kg)
    Minor 40-60 50-75

    20-40

    25-65

    N/A* N/A*
    Major

    ≥60

    75-90 20-60 25-75 20 25-35

    For tooth extraction, the same initial dose as for minor surgery is recommended and one infusion should 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 surgery8-11.


    Reconstitution

    • Do not mix BEBULIN with other medicinal products or solvents, other than the enclosed sterilized water for injection.
    • Administer BEBULIN within 3 hours after reconstitution as the solution does not contain a preservative. Do not refrigerate after reconstitution.
    1. Warm unopened vials of both diluent and concentrate to room temperature (not to exceed 37°C, 98°F).
    2. Remove caps from both vials to expose central portions of the rubber stoppers.
    3. Cleanse exposed surface of the rubber stoppers with germicidal solution and allow to dry.
    4. Using aseptic technique, remove protective covering from one end of the double-ended needle and insert the exposed end through the diluent vial stopper.
    5. Remove protective covering from the other end of the double-ended needle. Do not 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.
    6. Disconnect the two vials by removing needle from the concentrate vial stopper.
      Gently agitate or rotate the concentrate vial until all material is dissolved.

    Administration

    For Intravenous Administration Only.

    • Parenteral drug products should be inspected for particulate matter and discoloration prior to administration.
    • The reconstituted product should be colorless to slightly yellowish and clear to slightly turbid solution. Do not administer if particulate matter or discoloration is found and notify Baxter immediately.
    • Record the name of the patient and batch number of the product in order to maintain a link between the patient and the batch of the product.
    1. 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.
    2. Inject air and withdraw solution into the syringe.
    3. Remove and discard filter needle. Attach a suitable intravenous needle or infusion set with winged adapter.
    4. Administer the solution intravenously at a rate comfortable to the patient. The infusion rate should not exceed 2 mL per minute.
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  • 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.

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  • REFERENCES

    1. 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.
    2. 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.
    3. 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.
    4. I. Warrier: Management of haemophilia B patients with inhibitors and anaphylaxis. Haemophilia, 4 (4), pp.574-576.
    5. A. Shapiro, T. Abe, L. M. Aledort, K. Anderle, M. W. Hilgartner, M. Kunschak,
      F. E. Preston, G. E. Rivard, K. Schimpf and International Factor Safety Study Group: Transfusion, 35, 1995, pp 204-208.
    6. Ansell J, Hirsch J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008, 133:160S-198S.
    7. 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.
    8. 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.
    9. T. Abe, M. Kazama: An International Survey on the Appropriate Dosage of Hemophilias and Related Congenital Coagulopathies. In: Proceedings of the 3rd International Symposium on Haemostasis and Thrombosis, 1982, pp. 273-304.
    10. I. M. Nilsson, Å. Ahlberg, G. Björlin: Clinical Experience with a Swedish Factor IX Concentrate. Acta Med. Scand., 190, 1971, pp. 257-266.
    11. J. N. George, R. T. Breckenridge: The Use of Factor VIII and Factor IX Concentrates During Surgery. JAMA, 214, 1970, 9, pp. 1673-1676.

    To enroll in the confidential, Industry-wide Patient Notification System, call 1 888-873-2838.

    Baxter and Bebulin are trademarks of Baxter International Inc., its subsidiaries or affiliates.

    Baxter Healthcare Corporation

    Westlake Village, CA-91362

    USA

    U.S. License No. 140                                            Revised: Jul 2012

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  • Principle Display Panel

     BEBULIN unit carton for 200-1200 potency ranges

    BEBULIN unit carton for 200-1200 potency ranges

    20 mL size, dried

    NDC 64193-445-02

    Factor IX Complex

    BEBULIN

    Nanofiltered and Vapor Heated

    BAXTER

    For Intravenous Use Only

    WARNING: Human plasma product. 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.

    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 Vial Label

    BEBULIN vial label for 200-1200 potency ranges

    20 mL size, dried

    NDC 64193-345-01

    Factor IX Complex

    BEBULIN

    Nanofiltered and Vapor Heated

    BAXTER

    For Intravenous Use Only

    Rx Only

    Directions for use: see package insert

    Store between 2º and 8ºC (35º and 46ºF).

    Reconstitute with 20 mL of Sterile Water for Injection

    Baxter and Bebulin are trademarks of Baxter International Inc, Its subsidiaries or affiliates

    Baxter Healthcare Corporation

    Westlake Village, CA 91362 USA

    U.S. License No. 140

    20 mL Sterile Water for Injection vial label

    20 mL Sterile Water for Injection vial label

    NDC 0338-0764-62

    Nonpyrogenic

    Single-Dose Container

    20 mL

    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.

    BAXTER

    Manufactured by

    Baxter Healthcare Corporation

    Deerfield, IL 60015 USA

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  • INGREDIENTS AND APPEARANCE
    BEBULIN 
    coagulation factor ix human kit
    Product Information
    Product Type PLASMA DERIVATIVE Item Code (Source) NDC:64193-445
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:64193-445-02 1 in 1 CARTON
    Quantity of Parts
    Part # Package Quantity Total Product Quantity
    Part 1 1 VIAL, GLASS 20 mL
    Part 2 1 VIAL, GLASS 20 mL
    Part 1 of 2
    BEBULIN 
    coagulation factor ix human injection, powder, lyophilized, for solution
    Product Information
    Item Code (Source) NDC:64193-345
    Route of Administration INTRAVENOUS DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    COAGULATION FACTOR IX HUMAN (COAGULATION FACTOR IX HUMAN) COAGULATION FACTOR IX HUMAN 300 [iU]  in 1 mL
    Inactive Ingredients
    Ingredient Name Strength
    SODIUM CITRATE  
    SODIUM CHLORIDE  
    HEPARIN  
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:64193-345-01 20 mL in 1 VIAL, GLASS
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    BLA BLA103112 08/19/1992
    Part 2 of 2
    STERILE WATER 
    water liquid
    Product Information
    Item Code (Source) NDC:0338-0764
    Route of Administration INTRAVENOUS DEA Schedule     
    Inactive Ingredients
    Ingredient Name Strength
    WATER 20 mL  in 20 mL
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0338-0764-62 20 mL in 1 VIAL, GLASS
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    BLA BLA103112 08/19/1992
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    BLA BLA103112 08/19/1992
    Labeler - Baxter Healthcare Corporation (085206634)
    Establishment
    Name Address ID/FEI Business Operations
    Baxter Healthcare Corporation 001728059 MANUFACTURE
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