Posology : מינונים

2    DOSAGE AND ADMINISTRATION

Each vial of Koate-DVI is labeled with the actual Factor VIII potency in international units (IU).
The reconstituted product must be administered intravenously by either direct syringe injection or drip infusion. The product must be administered within 3 hours after reconstitution.

General Approach to Treatment and Assessment of Treatment Efficacy

The dosages described below are presented as general guidance. It should be emphasized that the dosage of Koate-DVI required for hemostasis must be individualized according to the needs of the patient, the severity of the deficiency, the severity of the hemorrhage, the presence of inhibitors, and the factor VIII level desired. It is often critical to follow the course of therapy with factor VIII level assays.

The clinical effect of Koate-DVI is the most important element in evaluating the effectiveness of treatment. It may be necessary to administer more Koate-DVI than would be estimated in order to attain satisfactory clinical results. If the calculated dose fails to attain the expected factor VIII levels, or if bleeding is not controlled after administration of the calculated dosage, the presence of a circulating inhibitor in the patient should be suspected. Its presence should be substantiated and the inhibitor level quantitated by appropriate laboratory tests.

When an inhibitor is present, the dosage requirement for Antihemophilic Factor (Human) is extremely variable and the dosage can be determined only by the clinical response. Some patients with low titer inhibitors, (10 Bethesda units) can be successfully treated with factor VIII without a resultant anamnestic rise in inhibitor titer.1 Factor VIII levels and clinical response to treatment must be assessed to insure adequate response. Use of alternative treatment products, such as Factor IX Complex concentrates, Antihemophilic Factor (Porcine) or Anti-Inhibitor Coagulant Complex, may be necessary for patients with high titer inhibitors. Immune tolerance therapy using repeated doses of Factor VIII concentrate administered frequently on a predetermined schedule may result in eradication of the Factor VIII inhibitor.2,3 Most successful regimens have employed high doses of Factor VIII administered at least once daily, but no single dosage regimen has been universally 
accepted as the most effective. Consultation with a hemophilia expert experienced with the management of immune tolerance regimens is also advisable.

Calculation of Dosage

The in vivo percent elevation in factor VIII level (percent of normal) can be estimated by multiplying the dose of Antihemophilic Factor (Human) per kilogram of body weight (IU/kg) by 2%. This method of calculation is based on clinical findings by Abildgaard et al,4 and is illustrated in the following examples:

Expected % factor VIII increase (% of normal) = # units administered × 2%/IU/kg body weight (kg)

Example for a 70 kg adult:         1400 IU × 2%/IU/kg = 40%
70 kg or

Dosage required (IU) = body weight (kg)×desired % factor VIII increase (% of normal) 2%/IU/kg

Example for a 15 kg child:       15 kg × 100% = 750 IU required
2%/IU/kg

The dosage necessary to achieve hemostasis depends upon the type and severity of the bleeding episode, according to the following general guidelines:

Mild Hemorrhage

Mild superficial or early hemorrhages may respond to a single dose of 10 IU per kg,5 leading to an in vivo rise of approximately 20% in the factor VIII level. Therapy need not be repeated unless there is evidence of further bleeding.

Moderate Hemorrhage

For more serious bleeding episodes (e.g., definite hemarthroses, known trauma), the factor VIII level should be raised to 30%-50% by administering approximately 15-25 IU per kg. If further therapy is required, repeated doses of 10-15 IU per kg every 8-12 hours may be given.6 
Severe Hemorrhage

In patients with life-threatening bleeding or possible hemorrhage involving vital structures (e.g., central nervous system, retropharyngeal and retroperitoneal spaces, iliopsoas sheath), the factor VIII level should be raised to 80%-100% of normal in order to achieve hemostasis. This may be achieved in most patients with an initial Antihemophilic Factor (Human), dose of 40-50 IU per kg and a maintenance dose of 20-25 IU per kg every 8-12 hours.7,8 For major surgical procedures, Factor VIII levels should be checked throughout the perioperative course to ensure adequate replacement therapy.


Surgery
For major surgical procedures, the factor VIII level should be raised to approximately 100% by giving a preoperative dose of 50 IU/kg. The factor VIII level should be checked to assure that the expected level is achieved before the patient goes to surgery. In order to maintain hemostatic levels, repeat infusions may be necessary every 6 to 12 hours initially, and for a total of 10 to 14 days until healing is complete. The intensity of factor VIII replacement therapy required depends on the type of surgery and postoperative regimen employed. For minor surgical procedures, less intensive treatment schedules may provide adequate hemostasis.8,9

Prophylaxis

Factor VIII concentrates may also be administered on a regular schedule for prophylaxis of bleeding, as reported by Nilsson et al.9

2.1       Preparation and Reconstitution

1. Use aseptic technique (clean and sanitized) and a flat work surface during the reconstitution procedure.
2. Bring the vials of Koate-DVI and the diluent (Sterile Water for Injection) to room temperature before use.
3. Remove shrink band from the Koate-DVI vial. Do not use Koate-DVI if the shrink band is absent or shows signs of tampering.
4. Remove the plastic cap from the Koate-DVI vial (Fig. A) and clean the top of the stopper with an alcohol swab. Allow the stopper to dry.
5. Repeat this step with the vial of sterile water.
6. Carefully remove the plastic sheath from the short end of the transfer needle and insert the exposed needle into the diluent vial to the hub. (Fig. B)
7. Place the Koate-DVI vial upright on a flat surface. Remove the sheath from the other end of the transfer needle.
8. While holding the Koate-DVI vial securely on a flat surface, insert the needle into the vial at a     45˚ angle to minimize foaming (Fig. C). The vacuum will draw the diluent into the concentrate vial. If vacuum is lost, use a sterile syringe and needle to remove the sterile water from the diluent vial and inject it into the Koate-DVI vial, directing the stream of fluid against the wall of the vial.
9. Remove the diluent vial and transfer needle (Fig. D).
10. Agitate vigorously for 10-15 seconds, (Fig. E1) then swirl continuously until completely dissolved (Fig. E2). Avoid excessive foaming. The reconstituted solution should be clear to opalescent. Do not use if particulate matter and discoloration are observed.
11. Clean the top of the vial of reconstituted Koate-DVI with alcohol swab and let surface dry.
12. Attach the filter needle (from the package) to a sterile syringe. Withdraw the Koate-DVI solution into the syringe through the filter needle (Fig. F).
13. Remove the filter needle from the syringe and discard the filter needle into a puncture proof container. Use Koate-DVI within 3 hours after reconstitution. Do not refrigerate after reconstitution.


2.2      Administration
For intravenous administration only
•     If the dose requires more than one vial of Koate-DVI: • Reconstitute each vial using a new transfer needle.
• Draw up all the solution into a single syringe.
•     Visually inspect the final solution for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if particulate matter or discoloration is observed.
•     Attach the syringe to the connector end of an infusion set.
•     Administer intravenously. The rate of administration should be determined by the patient’s comfort level, and no faster than 10 mL per minute.