Posology : מינונים

4.2   Posology and method of administration
Treatment should be under the supervision of a physician experienced in the treatment of haemophilia B.


Treatment monitoring
During the course of treatment, appropriate determination of factor IX levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their responses to factor IX, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor IX activity) is indispensable.

When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining factor IX activity in patients’ blood samples, plasma factor IX activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay. Measurement with a one-stage clotting assay using a kaolin based aPTT reagent or Actin FS aPTT reagent will likely result in an underestimation of activity level. This is of importance particularly when changing the laboratory and/or reagents used in the assay.

Posology
Dose and duration of the substitution therapy depend on the severity of the factor IX deficiency, on the location and extent of the bleeding and on the patient's clinical condition.


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

One International Unit (IU) of factor IX activity is equivalent to that quantity of factor IX in one ml of normal human plasma.

On demand treatment
The calculation of the required dose of factor IX is based on the empirical finding that 1 IU factor IX per kg body weight raises the plasma factor IX activity by an average of 1.3 IU/dl (1.3 % of normal activity) in patients ≥ 12 years of age and by 1.0 IU/dl (1.0 % of normal activity) in patients < 12 years of age. The required dose is determined using the following formulae: 
Required dose (IU) = body weight (kg) x desired factor IX rise (% of normal or IU/dl) x {reciprocal of observed recovery (IU/kg per IU/dl)}

Expected factor IX rise (IU/dl or % of normal) = Dose (IU) x Recovery (IU/dl per IU/kg)/body weight (kg)

The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.

Patients < 12 years of age
For an incremental recovery of 1 IU/dl per 1 IU/kg, the dose is calculated as follows: Required dose (IU) = body weight (kg) x desired factor IX rise (IU/dl) x 1 dl/kg 
Example
1.  A peak level of 50 % of normal is required in a 20 kg patient with severe haemophilia B. The appropriate dose would be 20 kg x 50 IU/dl x 1 dl/kg = 1000 IUs.

2.    A dose of 1000 IUs of IDELVION, administered to a 25 kg patient, should be expected to result in a peak post-injection factor IX increase of 1000 IUs/25 kg x 1.0 (IU/dl per IU/kg) = 40 IU/dl (40 % of normal).

Patients ≥ 12 years of age
For an incremental recovery of 1.3 IU/dl per 1 IU/kg, the dose is calculated as follows: Required dose (IU) = body weight (kg) x desired factor IX rise (IU/dl) x 0.77 dl/kg 
Example
3.  A peak level of 50 % of normal is required in a 80 kg patient with severe haemophilia B. The appropriate dose would be 80 kg x 50 IU/dl x 0.77 dl/kg = 3080 IUs.

4.    A dose of 2000 IUs of IDELVION, administered to a 80 kg patient, should be expected to result in a peak post-injection factor IX increase of 2000 IUs x 1.3 (IU/dl per IU/kg) /80 kg = 32.5 IU/dl (32.5 % of normal).


In the case of the following haemorrhagic events, the factor IX activity should not fall below the given plasma activity level (in % of normal or in IU/dl) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:
Degree of haemorrhage /                Factor IX level              Frequency of doses (hours) Type of surgical procedure             required (%) (IU/dl)         / Duration of therapy (days) Haemorrhage                            30 - 60                      Single dose should be Minor or moderate haemarthrosis,                                    sufficient for majority of muscle bleeding (except iliopsoas)                                  bleeds. Maintenance dose or oral bleeding                                                    after 24 – 72 hours if there is further evidence of bleeding.
Major haemorrhage                      60 - 100                     Repeat every 24 – 72 hours Life threatening haemorrhages,                                      for the first week, and then deep muscle bleeding including                                      maintenance dose weekly iliopsoas                                                           until bleeding stops and healing is achieved.
Minor surgery                          50 – 80 (initial level)      Single dose may be sufficient Including uncomplicated tooth                                       for a majority of minor extraction                                                          surgeries. If needed, maintenance dose can be provided after 24 – 72 hours until bleeding stops and healing is achieved.
Major surgery                          60 - 100                     Repeat every 24 – 72 hours (initial level)              for the first week, and then maintenance dose 1 – 2 times per week until bleeding stops and healing is achieved.

Prophylaxis
For long term prophylaxis against bleeding in patients with severe haemophilia B, the usual doses are 35 to 50 IU/kg once weekly.
Some patients who are well-controlled on a once-weekly regimen might be treated with up to 75 IU/kg on an interval of 10 or 14 days (see section 5.1).

In some cases, especially in younger patients, shorter dose intervals or higher doses may be necessary.

After a bleeding episode during prophylaxis, patients should maintain their prophylaxis regimen as closely as possible, with 2 doses of IDELVION being administered at least 24 hours apart, but longer if deemed suitable for the patient.

Paediatric population
For routine prophylaxis the recommended dose regimen for paediatric subjects is 35 to 50 IU/kg once weekly (see sections 5.1 and 5.2).

Method of administration
Intravenous use.

The reconstituted preparation should be injected slowly intravenously at a rate comfortable for the patient up to a maximum of 5 ml/min.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.