BEBULIN- coagulation factor ix human
Baxalta Incorporated
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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 .
n.d.: Not done | |||||
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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 |
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.
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.
BEBULIN is contraindicated in patients with
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:
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.
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.
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 Baxalta US Inc., at 1-800-423-2090 (in the U.S.).
BEBULIN contains heparin. Take heparin content into account when performing clotting tests sensitive to heparin.
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.
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.
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.
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.
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.
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.
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.
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Type of Bleeding |
Approximate Desired Factor IX Level (% Normal) |
Typical Initial Dose (International Units/kg) |
Average Duration of Treatment (Days) |
Minor
and gingival bleeding, mild hematuria |
20 |
25-35 |
1 |
Moderate
hematemesis, |
40 |
50-65 |
2 or until adequate wound healing |
Major
hematemesis, and |
≥60* |
75-90 |
2-3 or until adequate wound healing |
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.
N/A: Not Applicable. | ||||||
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Type of Surgery |
Day of Operation |
Init. Postop. Period (1st to 2nd Week) |
Late Postop. Period(from 3rd Week Onwards) |
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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.
For Intravenous Administration Only.
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.
To enroll in the confidential, Industry-wide Patient Notification System, call 1 888-873-2838.
BAXALTA® and BEBULIN® are trademarks of Baxalta Incorporated, a wholly-owned, indirect subsidiary of Shire plc.
SHIRE and the Shire Logo are trademarks or registered trademarks of Shire Pharmaceutical Holdings Ireland Limited or its affiliates.
Baxalta US Inc.
Lexington, MA 02421 USA
U.S. License No. 2020
Revised: 06/2018
20 mL size, dried
NDC 64193-445-02
Factor IX Complex
BEBULIN
Nanofiltered and Vapor Heated
Shire
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.
Rx only
20 mL size, dried
NDC 64193-345-01
Factor IX Complex
BEBULIN
Nanofiltered and Vapor Heated
Shire
For Intravenous Use Only
Directions for use: see package insert
Store between 2°and 8°C (35°and 46°F)
Reconstitute with 20 mL of Sterile Water for Injection.
Rx Only
Bebulin is a trademark of Baxalta Incorporated, a wholly-owned,
indirect subsidiary of Shire plc.
SHIRE and the Shire Logo are trademarks or registered trademarks
of Shire Pharmaceutical Holdings Ireland Limited or its affiliates.
20 mL
NDC 52919-006-05
Shire
Sterile Water for Injection, USP
for reconstitution of accompanying product
Do not use unless clear. No antimicrobial agent or other substance has been
added. Do not use for intravascular injection without making approximately
isotonic by addition of suitable solute. Discard unused portion.
Rx only
Single dose container
Nonpyrogenic
BEBULIN
coagulation factor ix human kit |
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Labeler - Baxalta Incorporated (085206634) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
Baxter Aktiengesellschaft | 300434670 | MANUFACTURE(64193-445) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
Siegfried Hameln GmbH | 315869123 | MANUFACTURE(52919-006) , LABEL(52919-006) |