Xyntha: Package Insert and Label Information

XYNTHA- antihemophilic factor (recombinant)
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC

1 INDICATIONS AND USAGE

XYNTHA, Antihemophilic Factor (Recombinant), is indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for:

  • On-demand treatment and control of bleeding episodes
  • Perioperative management

XYNTHA does not contain von Willebrand factor, and therefore is not indicated in patients with von Willebrand’s disease.

2 DOSAGE AND ADMINISTRATION

For intravenous use after reconstitution only.

2.1 Dose

  • Dosage and duration of treatment depend on the severity of the factor VIII deficiency, the location and extent of bleeding, and the patient’s clinical condition. Titrate the administered doses to the patient’s clinical response.
  • One International Unit (IU) of factor VIII activity corresponds approximately to the quantity of factor VIII in one milliliter of normal human plasma. The calculation of the required dosage of factor VIII is based upon the empirical finding that, on average, 1 IU of factor VIII per kg body weight raises the plasma factor VIII activity by approximately 2 IU/dL.2

The expected in vivo peak increase in factor VIII level expressed as IU/dL (or % normal) can be estimated using the following formulas:

Dosage (International Units) = body weight (kg) × desired factor VIII rise (IU/dL or % of normal) × 0.5 (IU/kg per IU/dL)

or

IU/dL (or % normal) = Total Dose (IU)/body weight (kg) × 2 [IU/dL]/[IU/kg]

On-demand treatment and Control of Bleeding Episodes

A guide for dosing XYNTHA for on-demand treatment and control of bleeding episodes is provided in Table 1. Maintain the plasma factor VIII activity at or above the levels (in % of normal or in IU/dL) outlined in Table 1 for the indicated period.

Table 1: Dosing for On-demand treatment and Control of Bleeding Episodes
Type of Bleeding Episode Factor VIII Level Required (IU/dL or % of normal) Frequency of Doses (hours) Duration of Therapy
Minor
Early hemarthrosis, minor muscle or oral bleeds. 20–40 12–24 At least 1 day, depending upon the severity of the bleeding episode.
Moderate
Bleeding into muscles.Mild head trauma.Bleeding into the oral cavity. 30–60 12–24 3–4 days or until adequate local hemostasis is achieved.
Major
Gastrointestinal bleeding.Intracranial, intra-abdominal, or intrathoracic bleeding.Fractures. 60–100 8–24 Until bleeding is resolved.

Perioperative Management

A guide for dosing XYNTHA during surgery (perioperative management) is provided in Table 2. Maintain the plasma factor VIII activity level at or above the level (in % of normal or in IU/dL) outlined in Table 2 for the indicated period. Monitor the replacement therapy by means of plasma factor VIII activity.

Table 2: Dosing for Perioperative Management
Type of Surgery Factor VIII Level Required (IU/dL or % of normal) Frequency of Doses (hours) Duration of Therapy(days)
Minor
Minor operations, including tooth extraction. 30–60 12–24 3–4 days or until adequate local hemostasis is achieved. For tooth extraction, a single infusion plus oral antifibrinolytic therapy within 1 hour may be sufficient.
Major
Major operations. 60–100 8–24 Until threat is resolved, or in the case of surgery, until adequate local hemostasis and wound healing are achieved.

2.2 Preparation and Reconstitution

Preparation

  1. Always wash hands before performing the following procedures.
  2. Use aseptic technique during the reconstitution procedures.
  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.

Note:

  • If the patient uses more than one vial of XYNTHA per infusion, reconstitute each vial according to the following instructions. Remove the diluent syringe, leaving the vial adapter in place. Use a separate 10 milliliter or larger luer lock syringe (not included in this kit) to draw back the reconstituted contents of each vial. Do not detach the diluent syringe or the large luer lock syringe until ready to attach the large luer lock syringe to the next vial adapter.
  • If the patient uses one vial of XYNTHA with one XYNTHA SOLOFUSE for the infusion, reconstitute the vial and the syringe according to the instructions for each respective product kit. Use a separate 10 milliliter or larger luer lock syringe (not included in this kit) to draw back the reconstituted contents of the vial and the syringe. [see Dosage and Administration (2.4) ]

Reconstitution

  1. Allow the XYNTHA vial and the prefilled diluent syringe to reach room temperature.
  2. Remove the plastic flip-top cap from the XYNTHA vial to expose the central portions of the rubber stopper.Image
  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 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 XYNTHA vial on a flat surface. While holding the adapter package, place the vial adapter over the XYNTHA vial and press down firmly on the package until the adapter spike penetrates the vial stopper.Image
  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.Image
  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 XYNTHA 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.Image
  8. Lift the package away from the adapter and discard the package.Image
  9. Place the XYNTHA vial, with the adapter attached, 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.Image
  10. Slowly depress the plunger rod to inject all the diluent into the XYNTHA vial.Image
  11. Without removing the syringe, gently swirl the contents of the XYNTHA vial until the powder is dissolved.
    Note: The final solution should be inspected visually for particulate matter before administration. The solution should be clear to slightly opalescent and colorless. If it is not, discard the solution and use a new kit.
  12. Invert the XYNTHA vial and slowly draw the solution into the syringe.Image
  13. Detach the syringe from the vial adapter by gently pulling and turning the syringe counterclockwise. Discard the empty XYNTHA vial with the adapter attached.

Note:

  • If the solution is not used immediately, carefully replace the syringe cap. Do not touch the syringe tip or the inside of the cap.
  • Store the reconstituted solution at room temperature prior to administration, but use within 3 hours after reconstitution.
  • XYNTHA, 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 XYNTHA, including storage time elapsed in a PVC container following reconstitution. The tubing of the infusion set included with this kit does not contain DEHP.
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2.3 Administration

For intravenous infusion after reconstitution only.

Inspect the final XYNTHA solution visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be clear to slightly opalescent and colorless. If it is not, discard the solution and use a new kit.

Use the tubing and the prefilled diluent syringe provided in this kit or a single sterile disposable plastic syringe. Do not administer XYNTHA in the same tubing or container with other medicinal products.

  1. Attach the syringe to the luer end of the infusion set tubing provided.
  2. Apply a tourniquet and prepare the injection site by wiping the skin well with an alcohol swab provided in the kit.Image
  3. Remove the protective needle cover and perform venipuncture. Insert the needle on the infusion set tubing into the vein, and remove the tourniquet. Verify proper needle placement.
  4. Inject the reconstituted XYNTHA product intravenously over several minutes. The rate of administration should be determined by the patient’s comfort level. Image
  5. After infusing XYNTHA, remove and discard the infusion set. The amount of drug product left in the infusion set will not affect treatment.
    Note: Dispose of all unused solution, the empty vial(s), and other used medical supplies in an appropriate container.
ImageImage

2.4 Use of a XYNTHA Vial Kit with a XYNTHA SOLOFUSE Kit

These instructions are for the use of only one XYNTHA Vial Kit with one XYNTHA SOLOFUSE Kit. For further information, please contact the Medical Information Department at Wyeth Pharmaceuticals, 1-800-438-1985.

  1. Reconstitute the XYNTHA vial using the instructions described in Preparation and Reconstitution [see Dosage and Administration (2.2) ].
  2. Detach the empty diluent syringe from the vial adapter by gently turning and pulling the syringe counterclockwise, leaving the contents in the XYNTHA vial with the vial adapter in place.Image
  3. Reconstitute the XYNTHA SOLOFUSE using the instructions included with the product kit, remembering to remove most, but not all, of the air from the drug product chamber.Image
  4. After removing the protective blue vented cap, connect the XYNTHA SOLOFUSE to the vial adapter by inserting the tip into the adapter opening while firmly pushing and turning the syringe clockwise until secured.Image
  5. Slowly depress the plunger rod of the XYNTHA SOLOFUSE until the contents empty into the XYNTHA vial. The plunger rod may move back slightly after release.Image
  6. Detach and discard the empty XYNTHA SOLOFUSE from the vial adapter.Note: If the syringe turns without detaching from the vial adapter, grasp the white collar and turn.Image
  7. Connect a sterile 10 milliliter or larger luer lock syringe to the vial adapter. Inject some air into the vial to make withdrawing the vial contents easier.Image
  8. Invert the vial and slowly draw the solution into the large luer lock syringe.Image
  9. Detach the syringe from the vial adapter by gently turning and pulling the syringe counterclockwise. Discard the vial with the adapter attached.
  10. Attach the infusion set to the large luer lock syringe as directed [see Dosage and Administration (2.3) ].
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3 DOSAGE FORMS AND STRENGTHS

XYNTHA is available as a white to off-white lyophilized powder in the following nominal dosages:

  • 250 International Units
  • 500 International Units
  • 1000 International Units
  • 2000 International Units

Each XYNTHA vial has the actual recombinant factor VIII (rFVIII) potency in International Units stated on the label.

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Allergic-type hypersensitivity reactions, including anaphylaxis, are possible with XYNTHA. Inform patients of the early signs or symptoms of hypersensitivity reactions (including hives [rash with itching], generalized urticaria, chest tightness, wheezing, and hypotension) and anaphylaxis. Discontinue XYNTHA if hypersensitivity symptoms occur and administer appropriate emergency treatment.

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

5.2 Neutralizing Antibodies

Inhibitors have been reported following administration of XYNTHA. Monitor patients for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures factor VIII inhibitor concentration to determine if a factor VIII inhibitor is present [see Warnings and Precautions (5.3) ].4,5,6,7,8,9,10,11,12

5.3 Monitoring Laboratory Tests

  • Use individual factor VIII values for recovery and, if clinically indicated, other pharmacokinetic characteristics to guide dosing and administration.
  • Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm that adequate factor VIII levels have been achieved and are maintained, when clinically indicated [see Dosage and Administration (2) ].
  • Monitor for development of factor VIII inhibitors. Perform assay to determine if factor VIII inhibitor is present when expected factor VIII activity plasma levels are not attained, or when bleeding is not controlled with the expected dose of XYNTHA. Use Bethesda Units (BU) to titer inhibitors.

6 ADVERSE REACTIONS

The most common adverse reactions (≥10%) with XYNTHA in adult and pediatric previously treated patients (PTPs) were headache, arthralgia, pyrexia, and cough.

6.1 Clinical Trials 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.

XYNTHA was evaluated in five completed clinical studies (N=178), comprising four studies with adult and pediatric PTPs.

The safety and efficacy of XYNTHA was evaluated in two completed pivotal studies. In the first study (n=94), safety and efficacy were examined in PTPs with severe to moderately severe hemophilia A (factor VIII activity in plasma [FVIII:C] ≤2%) who received XYNTHA for routine prophylaxis and on-demand treatment. Ninety-four subjects received at least one dose of XYNTHA, resulting in a total of 6,775 infusions [see Clinical Studies (14) ]. The second study (n=30) examined the use of XYNTHA for surgical prophylaxis in PTPs with severe to moderately severe hemophilia A (FVIII:C ≤2%) who required elective major surgery and were expected to receive XYNTHA replacement therapy for at least 6 days post-surgery. All subjects received at least one dose of XYNTHA, resulting in 1,161 infusions. One subject received XYNTHA for a pre-surgery pharmacokinetic assessment only and did not undergo surgery [see Clinical Studies (14) ].

Across all studies, safety was evaluated in 72 pediatric PTPs <17 years of age (46 subjects <6 years of age (4 subjects were 0 to <2 years of age), 4 subjects 6 to <12 years of age, and 22 adolescents, 12 to <17 years of age). A total of 13,109 infusions of XYNTHA were administered with a median dose per infusion of 28 IU/kg (min-max: 6–108 IU/kg).

Across all studies, the most common adverse reactions (≥10%) with XYNTHA in adult and pediatric PTPs were headache (24%), arthralgia (23%), pyrexia (23%), and cough (12%). Other adverse reactions reported in ≥5% of subjects were: diarrhea (8%), vomiting (8%), and asthenia (6%).

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