Posology : מינונים

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

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 response to factor IX, demonstrating different half-lives and recoveries. Dose based on body weight 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.


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 International Unit (IU) of factor IX per kg body weight raises the plasma factor IX activity by 1.16% of normal activity. The required dose is determined using the following formula: 
Required units = body weight (kg) x desired factor IX rise (%) or (IU/dl) x 0.85 
The amount to be administered and the frequency of administration should always be orientated to the clinical effectiveness in the individual case.

In the case of the following haemorrhagic events, the factor IX activity should not fall below the given plasma activity level (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            Frequency of doses (hours)/ Type of surgical procedure      level required         Duration of therapy (days) (%) or
(IU/dl)
Haemorrhage

Repeat every 24 hours. At least 1
Early haemarthrosis, muscle           20-40        day, until the bleeding episode as bleed or oral bleeding                             indicated by pain is resolved or healing is achieved.
More extensive                         30-60         Repeat infusion every 24 hours for 3 haemarthrosis, muscle bleed                          to 4 days or more until pain and or haematoma.                                        acute disability are resolved.
Life threatening                      60-100         Repeat infusion every 8 to 24 hours haemorrhages.                                        until threat is resolved.

Surgery

Minor surgery          including       30-60         Every 24 hours, at least 1 day, until tooth extraction                                     healing is achieved.
Major surgery                         80-100         Repeat infusion every 8 to 24 hours until adequate wound healing, then
(pre- and post-   therapy for at least another 7 days to operative)      maintain a Factor IX activity of 30% to 60% (IU/dl).

Prophylaxis
For long term prophylaxis against bleeding in patients with severe haemophilia B, the usual doses are 20 to 40 IU of factor IX per kilogram of body weight at intervals of 3 to 4 days.

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

Continuous infusion
Prior to surgery, a pharmacokinetic analysis should be performed to obtain an estimate of clearance.

The initial infusion rate can be calculated as follows:
Clearance x desired steady state level = infusion rate (IU/kg/hr)

After the initial 24 hours of continuous infusion, the clearance should be calculated again every day using the steady state equation with the measured level and the known rate of infusion (see section 5.2).

Paediatric population

Children under 12 years of age
There are limited data on the use of Replenine-VF in children under 12 years of age (see section 5.1).
The recommended dose and dosing frequency in adolescents (aged 12-17 years) are as recommended for adults.

Method of administration

Intravenous use
Replenine-VF should be administered via the intravenous route at a rate not exceeding 3 ml per minute.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.