Posology : מינונים

4.2    Posology and method of administration
Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia and with resuscitation support immediately available in case of anaphylaxis.

Posology
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and on the patient’s clinical condition.


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

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

On demand treatment

The calculation of the required dose of factor VIII is based on the empirical finding that 1 IU factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dose is determined using the following formula:

Required units (IU) = body weight (kg) x desired factor VIII rise (%) x 0.5 

In case of the following haemorrhagic events, the factor VIII activity should not fall below the given plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table 1 can be used to guide dosing in bleeding episodes and surgery:


Table 1 Guide for dosing in bleeding episodes and surgery
Degree of haemorrhage/type of        Factor VIII level            Frequency of doses surgical procedure                   required (% or IU/dl)        (hours)/duration of therapy (days)
Haemorrhage

Early haemarthrosis, muscle bleeding         20 – 40                    Repeat injections every 12 to 24 or oral bleeding.                                                       hours (8 to 24 hours for patients under the age of 6) for at least 1
                                                                       day, until the bleeding episode,
as indicated by pain, is resolved or healing is achieved.

More extensive haemarthrosis, muscle      30 – 60                      Repeat injections every 12 to 24 bleeding or haematoma.                                                 hours (8 to 24 hours for patients under the age of 6) for 3 – 4 days or more until pain and acute disability are resolved.

Life threatening haemorrhages.            60 – 100                     Repeat injections every 8 to 24 hours (6 to 12 hours for patients under the age of 6) until threat is resolved.
Surgery

Minor                                     30 – 60                      Every 24 hours (12 to 24 hours Including tooth extraction.                                            for patients under the age of 6), at least 1 day, until healing is achieved.

Major                                     80 – 100                     Repeat injections every 8 to 24 (pre- and postoperative)     hours (6 to 24 hours for patients under the age of 6) until adequate wound healing, then continue therapy for at least another 7 days to maintain a factor VIII activity of 30% to
60% (IU/dl).


The dose and frequency of administration should be adapted to the clinical response in the individual case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those calculated using the formula may be necessary.

During the course of treatment, appropriate determination of plasma factor VIII levels is advised to guide the dose to be administered and the frequency of repeated injections. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of plasma factor VIII activity assay is indispensable. Individual patients may vary in their response to factor VIII, achieving different levels of in vivo recovery and demonstrating different half-lives.

Prophylaxis
For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days.

Paediatric population
For on demand treatment dosing in paediatric patients (0 to 18 years of age) does not differ from adult patients. In patients under the age of 6, doses of 20 to 50 IU of factor VIII per kg body weight 3 to 4 times weekly are recommended for prophylactic therapy.

Method of administration
ADVATE should be administered via the intravenous route. In case of administration by a non health care professional appropriate training is needed.

The rate of administration should be determined to ensure the comfort of the patient up to a maximum of 10 ml/min.
After reconstitution, the solution is clear, colourless, free from foreign particles and has a pH of 6.7 to 7.3.

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