Posology : מינונים

3. DOSAGE AND ADMINISTRATION

Treatment with Xyntha should be initiated under the supervision of a physician experienced in the treatment of hemophilia A.

Xyntha is appropriate for use in adults and children including newborns.

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. Individual patients may vary in their response to factor VIII, achieving different levels of in vivo recovery and demonstrating different half-lives. Doses administered should be titrated to the patient’s clinical response. In the presence of an inhibitor, higher doses or appropriate alternative treatment may be required. Dosage adjustment for patients with renal or hepatic impairment has not been studied in clinical trials.

The number of units of factor VIII administered is expressed in International Units (IU), which are related to the current World Health Organization (WHO) international standard for factor VIII activity. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in IU (relative to an International Standard for factor VIII in plasma).

One IU of factor VIII activity corresponds approximately to the quantity of factor VIII in one ml 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 2 IU/dl. The required dosage is determined using the following formula: 
Required units = body weight (kg) x desired factor VIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL)

Clinical data support the use of the one-stage clotting assay for monitoring Xyntha therapy.



2
2021-0072524
The labeled potency of Xyntha is based on the European Pharmacopoeia chromogenic substrate assay in which the Pfizer In-House Recombinant Factor VIII Potency Reference Standard has been calibrated using a one-stage clotting assay. This method of potency assignment is intended to harmonize Xyntha with clinical monitoring using a one-stage clotting assay.

Precise monitoring of the replacement therapy by means of plasma factor VIII activity assay should be considered, particularly for surgical intervention.

Dosing for Bleeding and Surgery:
In the case of the following hemorrhagic events, consideration should be given to maintaining the factor VIII activity at or above the plasma levels (in % of normal or in IU/dL) for the indicated period, as outlined in the following table.

Table 2: Maintenance of Factor VIII Activity for Various Hemorrhagic Events Type of Hemorrhage       Factor VIII                Frequency of Doses (h)/ Level Required (% or       Duration of Therapy (d)
IU/dl)
Repeat every 12 to 24 hours as necessary
Minor                    20-40                      until resolved. At least 1 day, depending Early hemarthrosis,                                 upon the severity of the hemorrhage.
superficial muscle or soft tissue and oral bleeds

Repeat infusion every 12 - 24 hours for 3
Moderate                 30-60                      - 4 days or until adequate hemostasis is Hemorrhages into                                    achieved. For tooth extraction a single muscles. Mild head                                  infusion plus oral antifibrinolytic therapy trauma capitus.                                     within 1 hour may be sufficient.
Minor operations including tooth extraction.
Hemorrhages into the oral cavity.
Repeat infusion every 8 - 24 hours until
Major                    60-100                     threat is resolved or in the case of Gastrointestinal                                    surgery, until adequate local hemostasis bleeding.                                           is achieved, then continue therapy for at Intracranial, intra-                                least another 7 days.
abdominal or intrathoracic hemorrhages.
Fractures.
Major operations.

3
2021-0072524

Dosage for Prophylaxis
Xyntha has been administered prophylactically in a pivotal clinical trial in adolescent and adult previously treated patients at a dose of 30 + 5 IU/kg given 3 times weekly.

Inhibitors
Patients using factor VIII replacement therapy should be monitored for the development of factor VIII inhibitors. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor VIII inhibitor is present. In patients with factor VIII inhibitors, factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of patients with hemophilia.

Administration
Patients should follow the specific reconstitution and administration procedures provided by their physicians. For instructions, patients should follow the recommendations in the below Administration and Reconstitution sections. The procedures below are provided as general guidelines for the reconstitution and administration of Xyntha.
Additional instructions are provided after Infusion section that detail the use of a Xyntha vial.
Prenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Whenever solution and container permite.
Xyntha Vial Kit:
Xyntha is administered by IV infusion after reconstitution of the lyophilized powder with the supplied pre-filled diluent (0.9% Sodium Chloride solution) syringe.

Reconstitution
Always wash your hands before performing the following procedures. Use germ-free methods during the preparation procedures.

All components used in the mixing and injection of Xyntha should be used as soon as possible after opening their sterile containers to minimize unnecessary exposure to room air.

Xyntha Vial Kit:
Use only the materials provided in the Xyntha kit for dissolving the Xyntha powder with the sodium chloride diluent.

Xyntha is administered by intravenous injection after dissolving with the supplied diluent (0.9% sodium chloride) in the pre-filled syringe.

Note: If you use more than one vial of Xyntha per injection, each vial should be dissolved according to the following instructions. The empty syringe should be removed leaving the vial adapter in place, and a separate large luer lock syringe may be used to draw back the dissolved 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.


Xyntha Vial Kit:
2021-0072524

1. Allow the vial of freeze-dried Xyntha powder and the pre-filled 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.



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. Press down firmly on the package until the adapter snaps into place on top of the vial, with the adapter spike penetrating the vial stopper.



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 by pushing and turning firmly.



2021-0072524

7. Break off the tamper-resistant, plastic-tip cap from the diluent syringe by snapping the perforation of the cap. This is done by bending the cap up and down until the perforation is broken. Do not touch the inside of the cap or the syringe tip. The diluent syringe may need to be recapped (if the dissolved Xyntha is not used immediately), so place the cap on its top on a clean surface in a spot where it would be least likely to become contaminated.



8. Lift the package away from the adapter and discard the package.



9. Place the vial on a flat surface. Connect the diluent syringe to the vial adapter by inserting the tip of the syringe into the adapter opening while firmly pushing and turning the syringe clockwise until the connection is secured.



2021-0072524

10. Slowly depress the plunger rod to inject all the diluent into the Xyntha vial.


11. With the syringe still connected to the adapter, gently swirl the contents of the 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 pearly and colorless. If it is not, the solution should be discarded and a new kit should be used.

12. Ensuring that the syringe plunger rod is still fully depressed, invert the vial. Slowly draw the solution into the syringe.

Note: If you prepared more than one vial of Xyntha, remove the diluent syringe from the vial adapter, leaving the vial adapter attached to the vial. Quickly attach a separate large luer lock syringe and draw back the dissolved contents as instructed above. Repeat this procedure with each vial in turn. 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.



13. Detach the syringe from the vial adapter by gently pulling and turning the syringe counterclockwise. Discard the vial with the adapter attached.

Note: If the solution is not to be used immediately, the syringe cap should be carefully 

2021-0072524
        replaced. Do not touch the syringe tip or the inside of the cap.


Xyntha should be infused within 3 hours after dissolving. The dissolved solution may be stored at room temperature prior to infusion.

Infusion (Intravenous Injection)
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. It is important that the recommendations in DOSAGE AND ADMINISTRATION section be followed closely.

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

Xyntha Vial kit:
You should inject Xyntha as instructed by your hemophilia doctor or nurse. Once you learn how to self-infuse, you can follow the instructions in this insert.

Always wash your hands before doing the following procedures. Germ-free methods should be used during injection.

Xyntha should be administered using the pre-filled diluent syringe provided or a single sterile disposable plastic luer-lock syringe. In addition, the solution should be withdrawn from the vial using the vial adapter.

1. Attach the syringe to the luer end of the provided infusion set tubing and perform venipuncture as instructed by your hemophilia doctor or nurse.

2. Apply a tourniquet and prepare the injection site by wiping the skin well with an alcohol swab provided in the kit.



3. Insert the needle on the infusion set tubing into the vein, and remove the tourniquet. Infuse the reconstituted Xyntha product over several minutes. Your comfort level should determine the rate of infusion.



2021-0072524

3. After injecting Xyntha, remove the infusion set and discard. The amount of drug product left in the infusion set will not affect your treatment. Dispose of all unused solution, the empty vial(s), and the used needles and syringes in an appropriate sharps container used for throwing away waste that might hurt others if not handled properly.


You should record the lot number of the product every time you use Xyntha. The lot number can be found on the vial label. The peel-off label on the vial may be used to record the lot number.

In the absence of incompatibility studies, reconstituted Xyntha should not be administered in the same tubing or container with other medicinal products. Infusion kit components supplied in this carton are compatible with Xyntha for administration.

The reconstituted Xyntha solution does not contain a preservative and should be used within 3 hours of reconstitution.