BeneFIX: Package Insert and Label Information

BENEFIX- coagulation factor ix (recombinant)
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC

1 INDICATIONS AND USAGE

BeneFIX® , Coagulation Factor IX (Recombinant), is a human blood coagulation factor indicated in adult and pediatric patients with hemophilia B (congenital factor IX deficiency or Christmas disease) for:

  • control and prevention of bleeding episodes
  • peri-operative management

Limitations of Use

BeneFIX is NOT indicated for:

  • treatment of other factor deficiencies (e.g., factors II, VII, VIII, and X),
  • treatment of hemophilia A patients with inhibitors to factor VIII,
  • reversal of coumarin-induced anticoagulation,
  • treatment of bleeding due to low levels of liver-dependent coagulation factors.

2 DOSAGE AND ADMINISTRATION

For intravenous use after reconstitution only

  • Each vial of BeneFIX has the recombinant Factor IX (rFIX) potency in the International Units (IU) stated on the vial.
  • Initiate treatment under the supervision of a physician experienced in the treatment of hemophilia B.
  • Dosage and duration of treatment with BeneFIX depend on the severity of the factor IX deficiency, the location and extent of bleeding, and the patient’s clinical condition, age and recovery of factor IX.
  • Dosing of BeneFIX may differ from that of plasma-derived factor IX products [see Clinical Pharmacology (12)]. Subjects at the low end of the observed factor IX recovery may require upward dosage adjustment of BeneFIX to as much as two times (2X) the initial empirically calculated dose in order to achieve the intended rise in circulating factor IX activity.
  • Monitor patients using a factor IX activity assay to ensure that the desired factor IX activity level has been achieved. Titrate the dose using the factor IX activity, pharmacokinetic parameters, such as half-life and recovery, as well as taking the clinical situation into consideration in order to adjust the dose as appropriate.
  • The safety and efficacy of BeneFIX administration by continuous infusion have not been established [see Warnings and Precautions (5.2)].

2.1 Dose

Calculating Initial Dose

Use the following formula to calculate the initial dose of BeneFIX:

number of factor IX IU required (IU) = body weight (kg) × desired factor IX increase (% or IU/dL) × reciprocal of observed recovery (IU/kg per IU/dL)

Average Recovery

Adult Patients (≥15 years)

In adults, on average, one International Unit (IU) of BeneFIX per kilogram of body weight increased the circulating activity of factor IX by 0.8 ± 0.2 IU/dL (range 0.4 to 1.2 IU/dL). Use the following formula to estimate the dose with 0.8 IU/dL average increase of factor IX per IU/kg body weight administered:

number of factor IX IU required (IU) = body weight (kg) × desired factor IX increase (% or IU/dL) × 1.3 (IU/kg per IU/dL)

Pediatric Patients (<15 years)

In pediatric patients, on average, one international unit of BeneFIX per kilogram of body weight increased the circulating activity of factor IX by 0.7 ± 0.3 IU/dL (range 0.2 to 2.1 IU/dL; median of 0.6 IU/dL per IU/kg). Use the following formula to estimate the dose with 0.7 IU/dL average increase of factor IX per IU/kg body weight administered:

number of factor IX IU required (IU) = body weight (kg) × desired factor IX increase (% or IU/dL) × 1.4 (IU/kg per IU/dL)

Doses administered should be titrated to the patient’s clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to BeneFIX. Although the dose can be estimated by the calculations above, it is highly recommended that, whenever possible, appropriate laboratory tests, including serial factor IX activity assays, be performed.

Dosing Guide for Control and Prevention of Bleeding Episodes and Peri-operative Management

Table 1
Type of Hemorrhage Circulating Factor IX Activity Required [% or (IU/dL)] Dosing Interval [hours] Duration of Therapy [days]
Adapted from: Roberts and Eberst1
Minor
Uncomplicated hemarthroses, superficial muscle, or soft tissue 20–30 12–24 1–2
Moderate
Intramuscle or soft tissue with dissection, mucous membranes, dental extractions, or hematuria 25–50 12–24 Treat until bleeding stops and healing begins, about 2 to 7 days
Major
Pharynx, retropharynx, retroperitoneum, CNS, surgery 50–100 12–24 7–10

2.2 Preparation and Reconstitution

The procedures below are provided as general guidelines for the preparation and reconstitution of BeneFIX.

Preparation

  1. Always wash hands before performing the following procedures.
  2. Use aseptic technique (meaning clean and germ-free) during the reconstitution procedure.
  3. Use all components in the reconstitution and administration of this product as soon as possible after opening their sterile containers to minimize unnecessary exposure to the atmosphere.
  4. Pooling: If needing more than one vial of BeneFIX per infusion, reconstitute each vial according to the following instructions. Remove the diluent syringe leaving the vial adapter in place, and use a separate large luer lock syringe to draw back the reconstituted contents of each vial. Do not detach the diluent syringes or the large luer lock syringe until you are ready to attach the large luer lock syringe to the next vial adapter.

Reconstitution

  1. If refrigerated, allow the vial of lyophilized BeneFIX and the pre-filled diluent syringe to reach room temperature.
  2. Remove the plastic flip-top cap from the BeneFIX vial to expose the central portions of the rubber stopper.
    Figure
  3. Wipe the top of the vial with the alcohol swab provided, or use another antiseptic solution, and allow to dry. After cleaning, do not touch the rubber stopper with your hand or allow it to touch any surface.
  4. Peel back the cover from the clear plastic vial adapter package. Do not remove the adapter from the package.
  5. Place the vial on a flat surface. While holding the adapter in the package, place the vial adapter over the vial and press down firmly on the package until the adapter spike penetrates the vial stopper.
    Figure
  6. Grasp the plunger rod as shown in the diagram. Avoid contact with the shaft of the plunger rod. Attach the threaded end of the plunger rod to the diluent syringe plunger by pushing and turning firmly.
    Figure
  7. Break off the tamper-resistant plastic-tip cap from the diluent syringe by snapping the perforation of the cap. Do not touch the inside of the cap or the syringe tip. The diluent syringe may need to be recapped (if not administering reconstituted BeneFIX immediately), so place the cap on its top on a clean surface in a spot where it would be least likely to become environmentally contaminated.
    Figure
  8. Lift the package away from the adapter and discard the package.
    Figure
  9. Place the vial on a flat surface. Connect the diluent syringe to the vial adapter by inserting the tip into the adapter opening while firmly pushing and turning the syringe clockwise until secured.
    Figure
  10. Slowly depress the plunger rod to inject all the diluent into the BeneFIX vial.
    Figure
  11. Without removing the syringe, gently swirl the contents of the vial until the powder is dissolved.
  12. Invert the vial and slowly draw the solution into the syringe.
    Figure
  13. Detach the syringe from the vial adapter by gently pulling and turning the syringe counter-clockwise. Discard the vial with the adapter attached.
  14. The reconstituted solution should be clear and colorless. If it is not, discard and use a new kit. If the solution is not to be used immediately, recap the syringe. Do not touch the syringe tip or the inside of the cap.
  15. Store the reconstituted solution at room temperature and use it within 3 hours.

Note: BeneFIX, when reconstituted, contains polysorbate-80, which is known to increase the rate of di-(2-ethylhexyl) phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of BeneFIX, including storage time elapsed in a PVC container following reconstitution. It is important that the recommendations for dosage and administration be followed closely [see Dosage and Administration (2.1, 2.3)].

Note: The tubing of the infusion set included with this kit does not contain DEHP.

2.3 Administration

For intravenous use after reconstitution only.

The safety and efficacy of administration by continuous infusion have not been established [see Warnings and Precautions (5.2)].

  • Inspect BeneFIX solution for particulate matter and discoloration prior to administration, whenever solution and container permit.
  • Administer BeneFIX using the tubing provided in this kit, and the pre-filled diluent syringe provided, or a single sterile disposable plastic syringe.
  • Do not mix or administer BeneFIX in the same tubing or container with other medicinal products.

Administration

  1. Attach the syringe to the luer end of the infusion set tubing provided.
  2. Apply a tourniquet and prepare the injections site by wiping the skin well with an alcohol swab provided in the kit.
    Figure
  3. Perform venipuncture. Insert the needle on the infusion set tubing into the vein, and remove the tourniquet. Inject the reconstituted BeneFIX intravenously over several minutes. Adjust the rate of administration based on the patient’s comfort level.
    FigureNote: Agglutination of red blood cells in the tubing/syringe has been reported with the administration of BeneFIX. No adverse events have been reported in association with this observation. To minimize the possibility of agglutination, it is important to limit the amount of blood entering the tubing. Blood should not enter the syringe. If red blood cell agglutination is observed in the tubing or syringe, discard all material (tubing, syringe and BeneFIX solution) and resume administration with a new package.
  4. Following completion of BeneFIX treatment, remove and discard the infusion set. Dispose of all unused solution, empty vial(s), and used needles and syringes in an appropriate container.

3 DOSAGE FORMS AND STRENGTHS

BeneFIX is supplied as a white lyophilized powder in the following dosages:

  • 250 IU
  • 500 IU
  • 1000 IU
  • 2000 IU
  • 3000 IU

4 CONTRAINDICATIONS

BeneFIX is contraindicated in patients who have manifested life-threatening, immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster protein.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, have been reported with BeneFIX and have manifested as pruritus, rash, urticaria, hives, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, discomfort (generalized) and fatigue. Frequently, these events have occurred in close temporal association with the development of factor IX inhibitors.

Closely monitor patients for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to product. Because of the potential for allergic reactions with factor IX concentrates, perform the initial (approximately 10 – 20) administrations of factor IX under medical supervision where proper medical care for allergic reactions could be provided. Advise patients to discontinue use of the product and contact their physician and/or seek immediate emergency care. Immediately discontinue the administration and initiate appropriate treatment if symptoms occur.

BeneFIX contains trace amounts of hamster (CHO) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

5.2 Thromboembolic Complications

There have been post-marketing reports of thrombotic events in patients receiving continuous-infusion BeneFIX through a central venous catheter, including life-threatening superior vena cava (SVC) syndrome in critically ill neonates [see Adverse Reactions (6.2)]. The safety and efficacy of BeneFIX administration by continuous infusion have not been established [see Dosage and Administration (2.1, 2.3)].

5.3 Nephrotic Syndrome

Nephrotic syndrome has been reported following immune tolerance induction with factor IX products in hemophilia B patients with factor IX inhibitors and a history of allergic reactions to factor IX. The safety and efficacy of using BeneFIX for immune tolerance induction have not been established.

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