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  • CLASSES

    Blood Coagulation Factors

    DEA CLASS

    Rx

    DESCRIPTION

    Factor IX complex with varying concentrations of factors II, VII, and X made from the pooled plasma of healthy human donors
    FDA-approved for the prevention and control of bleeding episodes in patients with acquired or inherited factor IX deficiency (hemophilia B or Christmas Disease)
    Thrombosis and disseminated intravascular coagulation are potentially fatal adverse reactions particularly in patients predisposed to thromboembolic complications

    COMMON BRAND NAMES

    Bebulin, Profilnine SD

    HOW SUPPLIED

    Bebulin/Profilnine SD Intravenous Inj Pwd F/Sol

    DOSAGE & INDICATIONS

    For the management of hemophilia B (congenital factor IX deficiency or Christmas disease) to prevent and control hemorrhage including surgical bleeding and hemarthrosis.
    NOTE: Guidelines for the treatment of acute bleeding and prevention of bleeding during surgery vary. For all indications, the dose of factor IX should be individualized, taking into consideration the seriousness of the bleed or procedure, the clinical status of the patient, and the baseline factor IX activity concentration.
    Intravenous dosage (General dosage)
    Adults, Adolescents, Children, and Infants

    Adapted from reference . For minor hemorrhage (uncomplicated hemarthroses, superficial muscle or soft tissue), the circulating factor IX activity required is 20—30%. Doses of factor IX should be administered IV every 12—24 hours for 1—2 days. For moderate hemorrhage (intramuscle or soft tissue with dissection, mucous membranes, dental extractions, or hematuria), the circulating factor IX activity required is 25—50%. Doses of factor IX should be administered IV every 12—24 hours for about 2—7 days until bleeding stops and healing begins. For major hemorrhage (pharynx, retropharynx, retroperitoneum, CNS, surgery), the circulating factor IX activity required is 50—100%. Doses of factor IX should be administered IV every 12—24 hours for 7—10 days.

    Intravenous dosage (Bebulin)
    Adults

    Infuse the appropriate dose IV. Generally, 1 International Unit/kg of factor IX activity can be expected to increase the circulating level of factor IX by 0.8% of normal. To maintain factor IX activity levels above 25% for a reasonable time, each dose should be calculated to raise the level to 40—60% of normal. The following formula should be used: Factor IX Dose (International Units) = body weight (kg) x desired factor IX increase (%) x 1.2 International Units/kg.

    Intravenous dosage (Profilnine SD)
    Adults and Adolescents >=16 years

    Infuse the appropriate dose IV. Generally, 1 International Unit/kg of factor IX activity can be expected to increase the circulating level of factor IX by 1% of normal. To maintain factor IX activity levels above 25% for a reasonable time, each dose should be calculated to raise the level to 40—60% of normal. The following formula is a guide to dosage calculations (higher doses may be required in patients with inhibitors): Factor IX Dose (International Units) = body weight (kg) x desired factor IX increase (%) x 1 International Unit/kg.

    Neonates†, Infants†, Children†, and Adolescents < 16 years†

    Data are limited and safety and efficacy have not been demonstrated. However, per the manufacturer, anecdotal evaluation of use in patients < 16 years indicate that there are no safety and efficacy differences between pediatric and adult populations. Infuse the appropriate dose IV. Generally, 1 International Unit/kg of factor IX activity can be expected to increase the circulating level of factor IX by 1% of normal. To maintain factor IX activity levels above 25% for a reasonable time, each dose should be calculated to raise the level to 40—60% of normal. The following formula is a guide to dosage calculations for Profilnine SD (higher doses may be required in patients with inhibitors): Factor IX Dose (International Units) = body weight (kg) x desired factor IX increase (%) x 1 International Unit/kg.

    MAXIMUM DOSAGE

    Adults

    Individualize dosage based on the location and severity of the bleed or type of procedure, the clinical status of the patient, the factor IX activity concentration, and the presence of factor IX inhibitors.

    Geriatric

    Individualize dosage based on the location and severity of the bleed or type of procedure, the clinical status of the patient, the factor IX activity concentration, and the presence of factor IX inhibitors.

    Adolescents

    Adolescents > 16 years: Safety and efficacy of Bebulin have not been established. Individualize the dosage of Profilnine SD based on the location and severity of the bleed or type of procedure, the clinical status of the patient, the factor IX activity concentration, and the presence of factor IX inhibitors.
    Adolescents <= 16 years: Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    The actual potency per vial of Factor IX is stated on each carton.

    Intravenous Administration

    Reconstitution:
    Bebulin:
    Allow vials of concentrate and diluent (provided) to reach room temperature, and use aseptic technique to reconstitute.
    Remove the protective covering from one end of the double-ended needle and insert through the diluent vial stopper.
    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 and insert the free end of the needle into the concentrate vial. Diluent will be drawn into the concentrate vial by vacuum.
    Disconnect the vials by removing needle from the concentrate vial stopper. 
    Gently agitate or rotate the concentrate vial until all material is dissolved.
    Attach the enclosed filter needle to a sterile disposable syringe. Insert filter needle through the concentrate vial stopper.
    Inject air and withdraw the solution into the syringe.
    Remove and discard filter needle. Attach a suitable intravenous needle or infusion set with winged adapter.
    Storage following reconstitution: After reconstitution, administer within 3 hours. Do not refrigerate.
    Profilnine SD:
    Allow vials of concentrate and diluent (provided) to reach room temperature, and use aseptic technique to reconstitute.
    Place diluent vial on a flat surface and hold tightly. Grip the Mix2Vial transfer set together with the clear package and push the plastic spike at the blue end of the Mix2Vial transfer set firmly through the center of the stopper of the diluent vial.
    Carefully remove the clear package from the Mix2Vial transfer set.
    Invert diluent vial with Mix2Vial transfer set attached and push the plastic spike of the transparent adapter firmly through the center of the stopper of the concentrate vial. The diluent will automatically transfer into the vial.
    Gently swirl (do not shake) the vial until fully dissolved then unscrew the transfer set into 2 pieces.
    Draw air into an empty, sterile syringe. While the concentrate vial is upright, screw the syringe to the Mix2Vial transfer set and inject air into the vial. Keep plunger pressed, and invert the system upside down; draw the concentrate into the syringe by pulling back slowly on the plunger.
    Unscrew the syringe from the Mix2Vial transfer set.
    To administer, attach the syringe to a suitable intravenous administration set.
    If patient is to receive more than one vial, the contents of multiple vials may be pooled together; however, use a separate unused Mix2Vial transfer set for each product vial.
    Storage following reconstitution: After reconstitution, administer within 3 hours. Do not refrigerate.
     
    Intermittent intravenous infusion:
    Bebulin:
    Infuse at maximum rate of 2 mL/minute.
    Profilnine SD:
    Infuse at maximum rate of 10 mL/minute.

    STORAGE

    Bebulin:
    - Product is stable until the expiration date on the label if refrigerated (36 to 46 degrees F)
    - Protect from freezing
    - Reconstituted product should be used within 3 hours
    Bebulin VH:
    - Product is stable until the expiration date on the label if refrigerated (36 to 46 degrees F)
    - Protect from freezing
    Profilnine SD:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Store below 77 degrees F
    Proplex T:
    - Protect from freezing
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Factor IX complex, specifically Bebulin, is contraindicated in patients with known history of hypersensitivity reactions to the product.

    Heparin hypersensitivity

    Bebulin contains small amount of heparin and is therefore contraindicated in patients with heparin hypersensitivity.

    Coronary artery disease, hepatic disease, neonates, surgery

    Serious and potentially fatal thromboembolic complications including thromboembolic events (deep vein thrombosis, pulmonary embolism, thrombotic stroke) as well as disseminated intravascular coagulation (DIC) have been associated with use of factor IX complex. This risk is increased in patients predisposed to thromboembolic complications including patients with congenital or acquired coagulation disorders, with repeated dosing or high doses of factor IX complex, a history of coronary artery disease, patients with hepatic disease, pre- or post-surgery patients, and neonates. Monitor Factor IX concentrations as needed, and monitor for signs and symptoms of thromboembolic disease during and after administration of factor IX complex. Stop the infusion immediately and initiate appropriate diagnostic and therapeutic measures at the first signs or symptoms of thrombosis or embolism.

    Heparin-induced thrombocytopenia (HIT)

    The factor IX complex product Bebulin contains heparin and is therefore contraindicated in patients with known history of heparin-induced thrombocytopenia (HIT).

    Pregnancy

    Factor IX complex is a FDA pregnancy category C agent. It is not known whether factor IX complex can cause fetal harm when administered to a pregnant woman. According to the manufacturer, administer factor IX complex to a pregnant woman only if clearly needed.

    Breast-feeding

    The manufacturers do not provide a recommendation regarding use of factor IX complex in a breast-feeding woman. However, according to the World Health Organization (WHO), factor IX complex is compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Factor IX inhibitors

    Factor IX inhibitors have been detected in patients receiving factor IX products. Patients with factor IX inhibitors may be at increased risk of hypersensitivity type reactions including anaphylaxis. Patients experiencing allergic reactions should be evaluated for the presence of inhibitors. The presence of major deletion mutations in a patient's factor IX gene may increase the risk for formation of factor IX inhibitors and allergic reactions. Patients with known major deletion mutations of the factor IX gene should be observed closely for signs and symptoms of hypersensitivity, especially during early exposure to factor IX concentrates. For all patients, the initial 10—20 administrations of factor IX should be performed under medical supervision where proper medical care for allergic reactions can be provided. In addition, in patients undergoing immune tolerance induction, nephrotic syndrome has been reported in patients with factor IX inhibitors and a history of allergic reactions to factor IX. The efficacy of factor IX therapy for immune tolerance induction in hemophilia B patients with inhibitors to factor IX is low. Based on minimal efficacy and the risk of adverse events in patients with hemophilia B, consensus recommendations from an international workshop for immune tolerance induction could not be made.

    Hepatitis, infection

    As with other products derived from or purified with human blood components, the possibility of contamination with hepatitis and other viral or bacterial infections exists in patients receiving human plasma derived factor IX products. Screening plasma donors for prior exposure to certain viruses, testing for the presence of viruses, and inactivating and/or reducing viruses has reduced the risk of transmission of infectious agents. The manufacturing processes are designed to reduce the risk of transmitting viral infection; however, none of the processes are completely effective. There is also the possibility that unknown infectious agents may be present in this product. It is recommended that all patients with hemophilia receive vaccination against hepatitis A and B at birth or at diagnosis of hemophilia.

    ADVERSE REACTIONS

    Severe

    anaphylactic shock / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known

    Moderate

    dysphonia / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    dyspnea / Early / Incidence not known
    hypertension / Early / Incidence not known
    wheezing / Rapid / Incidence not known
    antibody formation / Delayed / Incidence not known
    sinus tachycardia / Rapid / Incidence not known

    Mild

    chills / Rapid / Incidence not known
    vomiting / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    paresthesias / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known
    fever / Early / Incidence not known
    nausea / Early / Incidence not known
    dizziness / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    infection / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known
    drowsiness / Early / Incidence not known
    lethargy / Early / Incidence not known
    headache / Early / Incidence not known
    flushing / Rapid / Incidence not known
    cough / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known

    DRUG INTERACTIONS

    Aminocaproic Acid: (Major) In general, aminocaproic acid should not be administered simultaneously with factor IX complex, factor IX concentrates, factor IX Fc fusion protein, recombinant, and factor IX albumin fusion protein, recombinant due to the increased risk of thrombosis. Some hematologists recommend separating administration of aminocaproic acid from these clotting factor complexes by 8 hours. Aminocaproic acid has been used concurrently with human factor IX complexes or anti-inhibitor coagulant complex perioperatively in hemophiliac patients. The risk of developing thrombosis, however, is increased. In rare instances, thrombosis leading to acute myocardial infarction or gangrene has been reported in patients with hemophilia receiving combination therapy with factor IX concentrate and aminocaproic acid. Concomitant administration of aminocaproic acid with purer formulations of factor IX may also result in an increased risk of thrombosis.
    Factor VIIa, Recombinant: (Major) The risk of a potential interaction between factor VIIa, recombinant, and factor IX replacement products has not been adequately evaluated. Simultaneous use of these products should be avoided due to the potential for increased risk of thrombosis.
    Tranexamic Acid: (Major) Tranexamic acid should not be administered concomitantly with factor IX complex, Factor IX Fc fusion protein, recombinant, or Factor IX concentrates, due to the increased risk of thrombosis.

    PREGNANCY AND LACTATION

    Pregnancy

    Factor IX complex is a FDA pregnancy category C agent. It is not known whether factor IX complex can cause fetal harm when administered to a pregnant woman. According to the manufacturer, administer factor IX complex to a pregnant woman only if clearly needed.

    The manufacturers do not provide a recommendation regarding use of factor IX complex in a breast-feeding woman. However, according to the World Health Organization (WHO), factor IX complex is compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    The coagulation cascade is a series of procoagulant and antithrombotic reactions involving the activation of zymogens. The vascular endothelium provides a protective barrier separating blood cells and plasma factors from subendothelial vessel wall reactive adhesive proteins and tissue factor; the proteins trigger blood coagulation. Factor IX complex increases plasma concentrations of Factor IX and temporarily corrects the coagulation defect of patients with Factor IX deficiency. Plasma concentrations of the other vitamin K-dependent clotting factors will also be increased; however, no clinical studies have been conducted to show benefit for treating deficiencies other than Factor IX deficiency.

    PHARMACOKINETICS

    Factor IX complex is administered intravenously.
    Bebulin: The elimination half-lives of Factor IX, II and X were determined as follows: Factor IX: 19.4 hours +/-3.8 hours, Factor II: 24.6 hours +/- 3.2 hours, and Factor X: 19.97 hours +/- 8.24 hours.
    Profilnine SD: In a clinical study of 12 subjects with hemophilia B, the in vivo half-life of Factor IX was 24.68 +/- 8.29 hours following administration of Profilnine SD.