Posology : מינונים

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

ALPROLIX can be used for all age groups.
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 injections. Individual patients may vary in their response 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. This is of importance particularly when changing the laboratory and/or reagents used in the assay.
Measurements with a one-stage clotting assay utilising a kaolin-based aPTT reagent will likely result in an underestimation of activity level.

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 recombinant factor IX Fc 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 recombinant factor IX Fc is based on the empirical finding that 1 International Unit (IU) factor IX per kg body weight raises the plasma factor IX activity by 1 % of normal activity (IU/dL). The required dose is determined using the following formula: 
Required units = body weight (kg) × desired factor IX rise (%) (IU/dL) × {reciprocal of observed recovery (IU/kg per IU/dL)}


The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case. If a repeat dose is required to control the bleed, the prolonged half-life of ALPROLIX should be taken into account (see section 5.2). The time to peak activity is not expected to be delayed.

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 IU/dL) in the corresponding period. Table 1 can be used to guide dosing in bleeding episodes and surgery:

Table 1: Guide to ALPROLIX dosing for treatment of bleeding episodes and surgery Degree of haemorrhage /            Factor IX level               Frequency of doses (hours)/ Duration of Type of surgical procedure         required (%) (IU/dL)          therapy (days) 
Haemorrhage
Early haemarthrosis, muscle        20-40                         Repeat injection every 48 hours, until the bleeding or oral bleeding                                        bleeding episode as indicated by pain is resolved or healing is achieved.

More extensive                     30-60                         Repeat injection every 24 to 48 hours until haemarthrosis, muscle                                            pain and acute disability are resolved.
bleeding or haematoma
Life threatening                   60-100                        Repeat injection every 8 to 24 hours until haemorrhages                                                     threat is resolved.

Surgery
Minor surgery including            30-60                         Repeat injection after 24 hours, as needed until tooth extraction                                                 healing is achieved1.

Major surgery                      80-100                        Repeat injection every 8 to 24 hours as (pre- and post-operative)     necessary until adequate wound healing, then therapy at least for another 7 days to maintain a factor IX activity of 30% to 60% (IU/dL).


1
In some patients and circumstances the dosing interval can be prolonged up to 48 hours (see section 5.2 for pharmacokinetic data).

Prophylaxis
For long term prophylaxis against bleeding, the recommended starting regimens are either:
•     50 IU/kg once weekly, adjust dose based on individual response or
•     100 IU/kg once every 10 days, adjust interval based on individual response. Some patients who are well-controlled on a once every 10 days regimen might be treated on an interval of 14 days or longer.

The highest recommended dose for prophylaxis is 100 IU/kg

Elderly population
There is limited experience in patients ≥65 years.
Paediatric population
For children below the age of 12 years, higher or more frequent doses may be required, and the recommended starting dose is 50-60 IU/kg every 7 days. For adolescents of 12 years of age and above, the dose recommendations are the same as for adults. See sections 5.1 and 5.2.
The highest recommended dose for prophylaxis is 100 IU/kg



Method of administration
Intravenous use.

In case of self-administration or administration by a caregiver appropriate training is needed.
ALPROLIX should be injected intravenously over several minutes. The rate of administration should be determined by the patient’s comfort level and should not exceed 10 mL/min.

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